Journal: Eur Heart J Cardiovasc Pharmacother

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Abstract

Efficacy and Safety of Edoxaban Compared to Warfarin According to the Burden of Diseases in Patients with Atrial Fibrillation: Insights from the ENGAGE AF-TIMI 48.

Nicolau AM, Corbalan R, Nicolau JC, Ruff CT, ... Antman EM, Giugliano RP
Introduction
Non-vitamin K antagonist oral anticoagulants represent a new option for prevention of embolic events in patients with atrial fibrillation (AF). However, little is known about the impact of non-cardiac comorbidities on the efficacy and safety profile of these drugs.
Methods
In a post-hoc analysis of the ENGAGE AF-TIMI 48 trial, we analyzed 21,105 patients with AF followed for an average of 2.8 years and randomized to either a higher-dose edoxaban regimen (HDER), a lower-dose edoxaban regimen (LDER), or warfarin. We used the Updated Charlson Comorbidity Index (CCI) to stratify the patients according to the burden of concomitant disease (CCI=0, 1, 2, 3 and ≥4). The treatment groups were then compared for safety, efficacy, and net clinical outcomes across CCI categories.
Results
There were 32.0%, 7.3%, 42.1%, 12.7%, and 6.0% of patients with CCI scores of 0, 1, 2, 3, and ≥4, respectively. A CCI score ≥4 was associated with significantly higher rates of thromboembolic events, bleeding, and death compared to CCI=0 (P < 0.05 for each). The annualized rates of the primary net clinical outcome (stroke/systemic embolism, major bleeding, or death) for CCI=0, 1, 2, 3 or ≥ 4 were 5.9%, 8.7%, 6.6%, 10.3% and 13.6% (Ptrend <0.001). There were no significant interactions between treatment with HDER vs warfarin and efficacy, safety, and net outcomes across the CCI groups (P-interaction >0.10 for each).
Conclusions
Although increasing CCI scores are associated with worse outcomes, the efficacy, safety, and net clinical outcomes of edoxaban vs warfarin were independent of the degree of comorbidity present.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 04 Nov 2019; epub ahead of print
Nicolau AM, Corbalan R, Nicolau JC, Ruff CT, ... Antman EM, Giugliano RP
Eur Heart J Cardiovasc Pharmacother: 04 Nov 2019; epub ahead of print | PMID: 31687762
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Abstract

Rationale, Experimental Data, and Emerging Clinical Evidence on Early and Preventive Use of Levosimendan in Patients with Ventricular Dysfunction.

Cosentino N, Niccoli G, Fracassi F, Rebuzzi A, Agostoni P, Marenzi G

Acute ventricular dysfunction is a complex condition with substantial morbidity and mortality, still featuring unique therapeutic challenges. Levosimendan is a calcium sensitizer and ATP-dependent potassium channel opener that was developed as an inodilating drug for the treatment of acute heart failure and cardiogenic shock. Differently from other more widely used inotropic agents, levosimendan has some exclusive characteristics, in terms of mechanisms of action, pharmacodynamic profile, and hemodynamic effects. This may have important clinical implications. In particular, in patients with acute ventricular dysfunction or in patients with pre-existing severe ventricular impairment undergoing planned myocardial stress, the administration of levosimendan before the onset of overt symptoms or before cardiovascular therapeutic procedures may have the potential to bridge the patient through the critical phase. In this review, we will focus on the rationale, the existing experimental data, and the emerging clinical experience supporting an early, even preventive use of levosimendan in severe ventricular dysfunction, beyond its recognized indications.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 04 Nov 2019; epub ahead of print
Cosentino N, Niccoli G, Fracassi F, Rebuzzi A, Agostoni P, Marenzi G
Eur Heart J Cardiovasc Pharmacother: 04 Nov 2019; epub ahead of print | PMID: 31688906
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Abstract

High burden of drug therapy in adult congenital heart disease: polypharmacy as marker of morbidity and mortality.

Woudstra OI, Kuijpers JM, Meijboom FJ, Post MC, ... Mulder BJM, Bouma BJ
Aims
To assess medication use in adult congenital heart disease (ACHD) patients compared to the age- and sex-matched general population, identify patterns of pharmacotherapy, and analyse associations between pharmacotherapy and adverse outcomes in ACHD.
Methods and results
Data of 14 138 ACHD patients from the CONCOR registry [35 (24-48) years, 49% male] and age- and sex-matched referents (1:10 ratio) were extracted from the Dutch Dispensed Drug Register for the years 2006-14. Adult congenital heart disease patients had more cardiovascular and non-cardiovascular drugs than referents (median 3 vs. 1, P < 0.001). Polypharmacy, defined as ≥5 dispensed drug types yearly, was present in 30% of ACHD and 15% of referents {odds ratio [OR] = 2.47 [95% confidence interval (CI) 2.39-2.54]}. Polypharmacy was independently associated with female sex [OR = 1.92 (95% CI 1.88-1.96)], older age [for men: OR = 2.3/10 years (95% CI 2.2-2.4) and for women: OR = 1.6/10 years (95% CI 1.5-1.6); Pinteraction < 0.001], and ACHD severity [mild: OR = 2.51 (95% CI 2.40-2.61), moderate: OR = 3.22 (95% CI 3.06-3.40), severe: OR = 4.87 (95% CI 4.41-5.38)]. Cluster analysis identified three subgroups with distinct medication patterns; a low medication use group (8-year cumulative survival: 98%), and a cardiovascular and comorbidity group with lower survival (92% and 95%, respectively). Cox regression revealed a strong association between polypharmacy and mortality [hazard ratio (HR) = 3.94 (95% CI 3.22-4.81)], corrected for age, sex, and defect severity. Polypharmacy also increased the risk of hospitalization for adverse drug events [HR = 4.58 (95% CI 2.04-10.29)].
Conclusion
Both cardiovascular and non-cardiovascular medication use is high in ACHD with twice as much polypharmacy compared with the matched general population. Patients with polypharmacy had a four-fold increased risk of mortality and adverse drug events. Recognition of distinct medication patterns can help identify patients at highest risk. Drug regimens need repeating evaluation to assess the appropriateness of all prescriptions. More high-quality studies are needed to improve ACHD care with more evidence-based pharmacotherapy.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 30 Sep 2019; 5:216-225
Woudstra OI, Kuijpers JM, Meijboom FJ, Post MC, ... Mulder BJM, Bouma BJ
Eur Heart J Cardiovasc Pharmacother: 30 Sep 2019; 5:216-225 | PMID: 30903133
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Abstract

Vitamin K Antagonists versus Direct Oral Anticoagulants After Transcatheter Aortic Valve Implantation in Atrial Fibrillation.

Butt JH, Backer O, Olesen JB, Gerds TA, ... Køber L, Fosbøl EL
Aim
To examine the risk of arterial thromboembolism, bleeding, and all-cause mortality in AF patients treated with direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) undergoing transcatheter aortic valve implantation (TAVI).
Methods and results
In this nationwide observational cohort study, 735 patients undergoing TAVI from January 1, 2012 to June 30, 2017 with a history of AF and who were treated with oral anticoagulants were identified using data from Danish nationwide registries. Of these, 219 (29.8%) and 516 (70.2%) patients were treated with DOACs and VKAs, respectively. The DOAC group was characterized by a higher prevalence of previous arterial thromboembolism and a lower prevalence of chronic kidney disease compared with the VKA group. The distribution of age, sex, CHA2DS2-VASc and HAS-BLED-score, and concomitant antiplatelet therapy was similar between groups. Compared with VKA, treatment with DOACs was not associated with a significantly different 3-year absolute risk of arterial thromboembolism (9.6% [95% confidence interval [CI], 4.7%-16.5%] versus 7.4% [95%CI, 4.9%-10.5%] in the DOAC and VKA group, respectively), bleeding (14.3% [95%CI, 7.6%-22.9%] versus 13.3% [95%CI, 9.9%-17.1%]), or all-cause mortality 32.7% [95%CI, 21.8%-44.0%] versus 32.0% [95%CI, 26.8%-37.3%]). In adjusted analyses, treatment with DOACs, as compared with VKAs, was not associated with a significantly different rate of arterial thromboembolism (hazard ratio [HR], 1.23 [95%CI, 0.58-2.59]), bleeding (HR, 1.14 [95%CI, 0.63-2.06]), or all-cause mortality (HR, 0.93 [95%CI, 0.61-1.40]).
Conclusions
In patients with AF undergoing TAVI, treatment with DOACs was not associated with a significantly different risk of arterial thromboembolism, bleeding, or all-cause mortality compared with VKA.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 25 Oct 2019; epub ahead of print
Butt JH, Backer O, Olesen JB, Gerds TA, ... Køber L, Fosbøl EL
Eur Heart J Cardiovasc Pharmacother: 25 Oct 2019; epub ahead of print | PMID: 31665260
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Abstract

Differential Epigenetic Factors in the Prediction of Cardiovascular Risk in Diabetic Patients.

Napoli C, Benincasa G, Schiano C, Salvatore M

Hyperglycemia can strongly alter the epigenetic signatures in many types of human vascular cells providing persistent perturbations of protein-protein interactions both in micro- and macro domains. The establishment of these epigenetic changes may precede cardiovascular (CV) complications and help us to predict vascular lesions in diabetic patients. Importantly, these epigenetic marks may be transmitted across several generations (transgenerational effect) and increase the individual risk of disease. Aberrant DNA methylation and imbalance of histone modifications, mainly acetylation and methylation of H3, represent key determinants of vascular lesions and, thus, putative useful biomarkers for prevention and diagnosis of CV risk in diabetics. Moreover, a differential expression of some micro-RNAs (miRNAs), mainly miR-126, may be a useful prognostic biomarker for atherosclerosis development in asymptomatic subjects. Recently, also environmental-induced chemical perturbations in mRNA (epitranscriptome), mainly the N6-methyladenosine, have been associated with obesity and diabetes. Importantly, reversal of epigenetic changes by modulation of lifestyle and use of metformin, statins, fenofibrate and apabetalone may offer useful therapeutic options to prevent or delay CV events in diabetics increasing the opportunity for personalized therapy. Network medicine is a promising molecular-bioinformatic approach to identify the signaling pathways underlying the pathogenesis of CV lesions in diabetic patients. Moreover, machine learning tools combined with tomography are advancing the individualized assessment of CV risk in these patients. We remark the need of combining epigenetics and advanced bioinformatic platforms to improve the prediction of vascular lesions in diabetics increasing the opportunity for CV precision medicine.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 25 Oct 2019; epub ahead of print
Napoli C, Benincasa G, Schiano C, Salvatore M
Eur Heart J Cardiovasc Pharmacother: 25 Oct 2019; epub ahead of print | PMID: 31665258
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Abstract

Association of Preceding Antithrombotic Therapy in Atrial Fibrillation Patients With Ischemic Stroke, Intracranial Hemorrhage, or Gastrointestinal Bleed and Mortality.

Komen JJ, Forslund T, Mantel-Teeuwisse AK, Klungel OH, ... Wallén H, Hjemdahl P
Aims
To analyze 90-day mortality in AF patients after a stroke or a severe bleed and assess associations with the type of antithrombotic treatment at the event.
Methods and results
From the Stockholm Healthcare database, we selected 6 017 patients with a known history of AF who were diagnosed with ischemic stroke, 3 006 with intracranial hemorrhage, and 4 291 with a severe gastrointestinal bleed (GIB). The 90-day mortality rates were 25.1% after ischemic stroke, 31.6% after intracranial hemorrhage, and 16.2% after severe GIB. We used Cox regression and propensity score matched analyses to test the association between antithrombotic treatment at the event and 90-day mortality. After intracranial hemorrhage, there was a significantly higher mortality rate in warfarin compared to NOAC treated patients (adjusted hazard ratio (aHR): 1.36 CI: 1.04 - 1.78). After an ischemic stroke and a severe GIB, patients receiving antiplatelets or no antithrombotic treatment had significantly higher mortality rates compared to patients on NOACs, but there was no difference comparing warfarin to NOACs (aHR 0.84 CI: 0.63 - 1.12 after ischemic stroke, aHR 0.91 CI: 0.66 - 1.25 after severe GIB). Propensity score matched analysis yielded similar results.
Conclusion
Mortality rates were high in AF patients suffering from an ischemic stroke, an intracranial hemorrhage, or a severe GIB. NOAC treatment was associated with a lower 90 day mortality after intracranial hemorrhage than warfarin.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 25 Oct 2019; epub ahead of print
Komen JJ, Forslund T, Mantel-Teeuwisse AK, Klungel OH, ... Wallén H, Hjemdahl P
Eur Heart J Cardiovasc Pharmacother: 25 Oct 2019; epub ahead of print | PMID: 31665368
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Abstract

Switching from Vitamin K Antagonist to Dabigatran in Atrial Fibrillation: Differences According to Dose.

Vinding NE, Staerk L, Gislason GH, Torp-Pedersen C, ... Køber L, Fosbøl EL

In atrial fibrillation (AF) patients 150mg b.i.d. dabigatran is the standard dose, yet guidelines recommend 110mg b.i.d. when bleeding risk is high. It is unknown to which extend these recommendations are followed in patients switching from vitamin K antagonist (VKA) to dabigatran. The aim of this study was to investigate if AF patients are switched from vitamin K antagonist to the appropriate dose of dabigatran.
Methods
Using nationwide registries (Aug 22, 2011-Dec 31, 2012) we identified VKA-experienced AF patients with available creatinine values who switched to dabigatran. European guidelines criteria 2012 on dabigatran dosing were examined: age≥80 years, HAS-BLED≥3, estimated glomerular filtration rate (eGFR)<50mL/min/1.73 m2, or use of interacting drugs.
Results
We identified 1,626 VKA-experienced AF patients who switched to dabigatran 110mg (820 patients) or 150mg (806 patients). Patients who switched to 110mg compared with 150mg were older (median age 82 years [Q1-Q3:77-86] vs. 68 years [Q1-Q3:64-74]), more often female (54% vs. 35%), had a higher comorbidity burden, higher proportion with CHA2DS2-VASc score≥2 (98% vs. 80%), and more with a HAS-BLED score ≥ 3 (46% vs. 28%). Patients switched to 110mg had a higher absolute risk of mortality compared to patients switched to 150mg. Overall, 26% were inappropriately dosed and 14% were switched to 110mg although the higher dose was indicated. Further, 39% of patients switched to 150mg fulfilled one or more criteria for 110mg, this mostly driven by high HAS-BLED scores (28.2% of patients on 150mg). Female sex, age>80 years, eGFR<50 mL/min/1.73 m2, drugs interacting with dabigatran, and prior bleeding were associated with switch to 110mg. Patients inappropriately dosed had similar risk of mortality as patients appropriately dosed.
Conclusion
Among VKA-experienced AF patients one in four were switched to a dabigatran dose contrary to guideline recommendations.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 14 Nov 2019; epub ahead of print
Vinding NE, Staerk L, Gislason GH, Torp-Pedersen C, ... Køber L, Fosbøl EL
Eur Heart J Cardiovasc Pharmacother: 14 Nov 2019; epub ahead of print | PMID: 31730151
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Abstract

Low-quality of some generic medicinal products represents a matter for growing concern.

Tamargo J, Rosano G
Aims
Generic medicinal products (GMPs) are low-priced copies of off-patent medicines that reduce healthcare costs and broaden access to healthcare. Thus, healthcare authorities, professionals and providers, recommend their use. In recent years, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved hundreds of GMPs based on specific bioequivalent trials. The question is whether the brand-name drugs and GMPs or the different GMPs similar in purity, efficacy and safety.
Methods and results
We have reviewed the progressive increasing recalls and warning letters of cardiovascular GMPs issued recently by the FDA/EMA. Both Agencies found numerous irregularities in the purity, safety, effectiveness and current good manufacturing practices in some GMPs widely used in cardiovascular therapy. This evidence and the recent identification of nitrosamine impurities classified as probable human carcinogens in several angiotensin receptor blockers confirm that the presence of low-quality/substandard GMPs represents a serious public health problem with significant impact on national clinical and economic burden.
Conclusion
A global strategy that unifies the efforts of all the stakeholders, including drug manufacturers, healthcare providers, Governments, health professionals, patients and judicial systems are needed to protect the drug chain supply and ensure that only high-quality GMPs are available for use.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 09 Sep 2019; epub ahead of print
Tamargo J, Rosano G
Eur Heart J Cardiovasc Pharmacother: 09 Sep 2019; epub ahead of print | PMID: 31501855
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Abstract

Mortality and adverse events with brand and generic clopidogrel in the US Food and Drug Administration Adverse Event Reporting System.

Serebruany VL, Hall TS, Atar D, Agewall S, ... Lomakin N, Marciniak TA
Aims
Clopidogrel is commonly used even after expiring patents. The brand clopidogrel (BC) was dealt by single company, while numerous manufacturers produce generic clopidogrel (GC). There are no convincing data to compare the safety of different formulations. Therefore, the data yielded from international, uniform, government-mandated registries may be useful.
Methods and results
We assessed primary causative adverse events (PCAE) after BC and GC in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The outcomes were divided into death, cardiac, thrombotic/embolic, haemorrhagic, and rash/dermal complications. These primary endpoints were then examined by proportional reporting ratios (PRR) and chi-square (χ2). Among total FAERS (n = 9 466 679) reports, overall BC (n = 88 863) cases were more common than after GC (n = 36 559). When triaged by PCAE role, BC (n = 18 328) was also more abundant than GC (n = 3987). The reported death rates were more than doubled after BC [18.4% vs. 7.0%; PRR = 0.38; 95% confidence interval (95% CI) 0.32-0.43; χ2=369.7; P<0.0001] for total FAERS, and consistent for late 2010-2017 (17.6% vs. 7.0% PRR = 0.40; 95% CI 0.37-0.45; χ2=286.2; P<0.004) PCAE cases. In contrast, GC trended to co-report more cardiac (14.6% vs. 13.3%; PRR = 1.12; 95% CI 1.0-1.25; χ2=3.5; P<0.06). The haemorrhagic (40.9% vs. 32.3%; PRR = 1.45; 95% CI 1.33-1.57; χ2=75.8; P<0.0001), and rash/dermal (5.4% vs. 4.6%; PRR = 1.20; 95% CI 1.0-1.44; χ2=3.75; P<0.05) events were also more common for GC. Thrombotic/embolic events were reported equally (at 7.0%) after each formulation.
Conclusion
The PCAE profiles differ with BC and GC in FAERS. While deaths reports were higher, the rates of cardiac, haemorrhagic, and skin complications were less common for BC. Despite expected reporting bias, this may indicate that the manufacturers of GC are reluctant to report deaths to the FDA. However, the overall adverse event profile suggests potentially better safety of BC over GC formulations.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 30 Sep 2019; 5:210-215
Serebruany VL, Hall TS, Atar D, Agewall S, ... Lomakin N, Marciniak TA
Eur Heart J Cardiovasc Pharmacother: 30 Sep 2019; 5:210-215 | PMID: 30192939
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Abstract

Personalized antiplatelet therapy guided by a novel detection of platelet aggregation function in stable coronary artery disease patients undergoing PCI: a randomized controlled clinical trial.

Zheng YY, Wu TT, Yang Y, Hou XG, ... Ma YT, Xie X
Aim
A number of studies have attempted to demonstrate the benefits associated with personalized antiplatelet therapy guided by platelet function testing (PFT), which has led to disappointing findings. In this study, we used a new platelet function test to guide antiplatelet therapy in stable CAD patients after PCI.
Methods and results
In the present randomized controlled trial, a total of 2237 patients with stable coronary artery disease (CAD) undergoing PCI were randomly chosen to be administered personalized antiplatelet therapy (personalized group; n = 1123) or standard antiplatelet treatment (standard group; n = 1114). The patients in the standard therapy group, without detecting the platelet aggregation rate, were administered a 75 mg/day clopidogrel maintenance dosage plus 100 mg/day of aspirin for at least 6 months after the procedure. For the patients in the personalized therapy group, the antiplatelet strategy was performed according to the maximum aggregation rate (MAR), determined using a novel platelet analyser, PL-12. If MAR>55%, 90 mg ticagrelor was administered twice daily plus 100 mg/day of aspirin after PCI. If MAR ≤55%, 75 mg/day clopidogrel plus 100 mg/day of aspirin was administered after PCI. The primary endpoint was net clinical adverse events, which were a composite of cardiac death, myocardial infarction (MI), stroke, stent thrombosis, urgent revascularization, and bleeding (Bleeding Academic Research Consortium (BARC) definitions, type 2, 3, or 5), in the 180-day period after randomization. The primary endpoint was reached in 58 patients in the personalized group, compared with 85 patients in the standard group (5.1% vs. 7.5%, HR: 0.678, 95% CI: 0.486-0.947, P = 0.023), on intention-to-treat (ITT) analysis. We also found that the net clinical adverse events (including ischaemic and bleeding events) were significantly reduced in the personalized group at 30 days after PCI compared to the standard group (1.5% vs. 3.0%, HR: 0.510, 95% CI: 0.284-0.915, P = 0.020). We did not find a significant difference in major bleeding events at either the 30-day (0.5% vs. 0.3%, P = 0.322) or the 180-day follow-up (2.1% vs. 1.6%, P = 0.364) between the two groups.
Conclusion
The present study suggests that personalized antiplatelet therapy according to MAR can significantly improve the net clinical benefit 180 days after PCI.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 10 Oct 2019; epub ahead of print
Zheng YY, Wu TT, Yang Y, Hou XG, ... Ma YT, Xie X
Eur Heart J Cardiovasc Pharmacother: 10 Oct 2019; epub ahead of print | PMID: 31603191
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Abstract

Bleeding and ischaemic outcomes in patients treated with dual or triple antithrombotic therapy: systematic review and meta-analysis.

Haller PM, Sulzgruber P, Kaufmann C, Geelhoed B, ... Niessner A, Gremmel T
Aims
The combination of oral anticoagulation with a P2Y12 inhibitor and aspirin in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) is associated with a high bleeding risk. Dual antithrombotic therapy (DAT) with omission of aspirin is a promising option to reduce bleedings, but carries a yet unknown risk of ischaemic events. We therefore sought to systematically review and analyse randomized controlled trials investigating DAT vs. triple antithrombotic therapy (TAT) in patients with AF following PCI and/or acute coronary syndrome (ACS).
Methods and results
We included four trials with overall 9317 patients (5039 DAT, 4278 TAT) in our analysis. Dual antithrombotic therapy was associated with a significant reduction in thrombolysis in myocardial infarction major bleeding [hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.42-0.65; P = 0.0001], while the composite trial-defined ischaemic endpoint did not differ significantly between DAT and TAT (HR 0.98, 95% CI 0.79-1.22; P = 0.88). There was also no difference regarding the occurrence of myocardial infarction (MI; HR 1.16, 95% CI 0.92-1.46; P = 0.21) or stent thrombosis (HR 1.25, 95% CI 0.69-2.26; P = 0.46). Absolute numbers for MI were 131/4278 (3.1%) with TAT and 182/5039 (3.6%) with DAT, and for stent thrombosis 32/4278 (0.75%) and 52/5039 (1%), respectively. A post hoc power calculation based on the size and event rate of this meta-analysis revealed 80% power to detect a 37% and 100% increase in MI and stent thrombosis, respectively.
Conclusion
Dual antithrombotic therapy significantly reduces bleedings compared with TAT and seems to have a similar effect in preventing ischaemic endpoints in AF patients post-PCI or ACS. Future investigations are needed to determine its applicability specifically in patients at high risk of ischaemic outcomes.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 30 Sep 2019; 5:226-236
Haller PM, Sulzgruber P, Kaufmann C, Geelhoed B, ... Niessner A, Gremmel T
Eur Heart J Cardiovasc Pharmacother: 30 Sep 2019; 5:226-236 | PMID: 31198930
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Impact:
Abstract

Risk of gastrointestinal bleeding associated with oral anticoagulation and non-steroidal anti-inflammatory drugs in patients with atrial fibrillation: a nationwide study.

Schjerning Olsen AM, McGettigan P, Gerds TA, Fosbøl EL, ... Gislason GH, Lamberts M
Aims
Non-vitamin K antagonist oral anticoagulants (NOACs) are displacing Vitamin K antagonists (VKAs) for stroke prophylaxis in patients with atrial fibrillation (AF). Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) could increase gastrointestinal bleeding (GIB) risks among these patients. The aim of this study was to examine the risk of GIB among Danish AF patients taking oral anticoagulants (OACs) and NSAID.
Methods and results
Using nationwide administrative registries, we determined concomitant NSAID use among anticoagulant-naïve patients with AF initiating OACs between August 2011 and June 2017. We calculated short-term absolute risks differences and hazard ratios (HRs) for GIB based on multiple adjusted cause-specific Cox regressions with time-dependent NSAID treatment.Among 41,183 patients (median age 70 years (IQR 64-78); 55% men), 21% of patients on NOACs and 18% on VKA were co-prescribed NSAIDs. The differences in absolute risk (95% Confidence Interval (CI)) of GIB within 14 days of commencing concomitant NSAID therapy (versus no concomitant NSAID therapy) were 0.10% (0.04%-0.18%) for NOACs and 0.13% (0.03%-0.24%) for VKA. NOACs overall were associated with less GIB than VKA (HR 0.77 [95% CI 0.69-0.85]). Compared with OACs alone, concomitant NSAIDs doubled the GIB risk associated with NOACs overall (HR 2.01 [95% CI 1.40-2.61] and with VKA (HR 1.95 [95% CI 1.21-2.69]).
Conclusion
Among this nationwide AF population taking OACs, concomitant NSAID therapy increased the short-term absolute risk of GIB. NOACs alone were associated with lower GIB risks than VKA but concomitant NSAIDs abolished this advantage. The findings align with post-hoc analyses from randomized studies. Physicians should exercise appropriate caution when prescribing NSAIDs for patients with AF taking NOACs or VKA.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 18 Nov 2019; epub ahead of print
Schjerning Olsen AM, McGettigan P, Gerds TA, Fosbøl EL, ... Gislason GH, Lamberts M
Eur Heart J Cardiovasc Pharmacother: 18 Nov 2019; epub ahead of print | PMID: 31742339
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Abstract

PCSK9 and inflammation: a review of experimental and clinical evidence.

Momtazi-Borojeni AA, Sabouri-Rad S, Gotto AM, Pirro M, ... Barreto GE, Sahebkar A

Proprotein convertase subtilisin/kexin Type 9 (PCSK9) is now identified as an important and major player in hypercholesterolaemia and atherosclerosis pathophysiology. PCSK9, through promoting lysosomal degradation of hepatic low-density lipoprotein (LDL) receptor, can decrease the clearance of plasma LDLs, leading to hypercholesterolaemia and consequent atherosclerotic plaque formation. Hypercholesterolaemia has been found to promote systemic and vascular inflammation, which can cause atherosclerotic lesion formation and progression and subsequent incidence of cardiovascular disease. Recent studies have shown the involvement of PCSK9 in the inflammatory pathway of atherosclerosis. Although trials with PCSK9 inhibitors have not shown any alteration in plasma C-reactive protein levels, there is accumulating evidence showing lessened inflammatory response in the arterial wall that could attenuate atherosclerotic plaque development beyond the established LDL-lowering effect of PCSK9 inhibition. In this review, we represent mounting evidence indicating that PCSK9 can locally increase vascular inflammation and contribute to atherosclerotic plaque progression in patients with hypercholesterolaemia.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 30 Sep 2019; 5:237-245
Momtazi-Borojeni AA, Sabouri-Rad S, Gotto AM, Pirro M, ... Barreto GE, Sahebkar A
Eur Heart J Cardiovasc Pharmacother: 30 Sep 2019; 5:237-245 | PMID: 31236571
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Impact:
Abstract

Impact of Reduced-Dose Prasugrel vs. Standard-Dose Clopidogrel on In-Hospital Outcomes of Percutaneous Coronary Intervention in 62,737 Patients with Acute Coronary Syndromes: A Nationwide Registry Study in Japan.

Akita K, Inohara T, Yamaji K, Kohsaka S, ... Nakamura M, Maekawa Y
Aims
In Japan, reduced-dose prasugrel (loading/maintenance dose, 20/3.75 mg) has been approved for use in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI), because of the higher bleeding risk among East Asians. However, its safety in the real-world population has not been investigated. We aimed to evaluate the effectiveness and safety of reduced-dose prasugrel vs. standard-dose clopidogrel in ACS patients undergoing PCI.
Methods and results
ACS patients who underwent PCI in 2016, who were treated with either reduced-dose prasugrel or standard-dose clopidogrel in addition to aspirin, were identified from the nationwide Japanese PCI registry. The primary outcome was in-hospital mortality following PCI. Secondary outcomes included stent thrombosis and bleeding complication after PCI. Among 62,737 ACS patients who underwent PCI at any of 986 participating centres across Japan (clopidogrel, 31.9%; prasugrel, 68.1%), we identified 12,016 propensity score-matched pairs (24,032 patients; age, 69.4±12.2 years; female, 24.9%; ST-elevation myocardial infarction, 42.3%). Compared with standard-dose clopidogrel, reduced-dose prasugrel was associated with increased risk of bleeding (odds ratio [OR], 1.65; 95% CI, 1.10-2.51; p = 0.016), but both had similar rates of mortality (OR, 1.11; 95% CI, 0.89-1.38; p = 0.371) and stent thrombosis (OR, 1.29; 95% CI, 0.73-2.30; p = 0.387) as well as similar falsification endpoints of cardiac tamponade and emergent operation.
Conclusion
In Japanese ACS patients undergoing PCI, the risk of bleeding is higher when using reduced-dose prasugrel than when using standard-dose clopidogrel, but there is no significant difference in in-hospital mortality and incidence of stent thrombosis between the two antiplatelet regimens.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 07 Oct 2019; epub ahead of print
Akita K, Inohara T, Yamaji K, Kohsaka S, ... Nakamura M, Maekawa Y
Eur Heart J Cardiovasc Pharmacother: 07 Oct 2019; epub ahead of print | PMID: 31593213
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Impact:
Abstract

Resistant hypertension: new insights and therapeutic perspectives.

Ruilope LM, Rodríguez-Sánchez E, Navarro-García JA, Segura J, ... Lucia A, Ruiz-Hurtado G

Resistant hypertension (RH) is a concept that currently goes beyond the classical definition of blood pressure (BP) ≥140/90 mmHg in subjects receiving three or more drugs of different classes at maximally tolerated doses. Here we review the clinical relevance of RH and the different types of RH-associated phenotypes, namely refractory hypertension, controlled resistant hypertension, and masked uncontrolled hypertension. We also discuss current drug strategies and future treatments for these high-risk phenotypes.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 08 Oct 2019; epub ahead of print
Ruilope LM, Rodríguez-Sánchez E, Navarro-García JA, Segura J, ... Lucia A, Ruiz-Hurtado G
Eur Heart J Cardiovasc Pharmacother: 08 Oct 2019; epub ahead of print | PMID: 31598644
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Impact:
Abstract

External applicability of the COMPASS trial: the Western Denmark Heart Registry.

Würtz M, Olesen KKW, Thim T, Kristensen SD, Eikelboom JW, Maeng M
Aims
In the COMPASS trial, combined aspirin and rivaroxaban treatment reduced ischaemic events in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). We estimated the proportion of COMPASS eligible patients among unselected patients undergoing coronary angiography (CAG) and compared outcome rates among COMPASS eligible and non-eligible patients.
Methods and results
We applied the COMPASS study criteria on patients undergoing CAG in Western Denmark (2004-11). Both COMPASS eligible and non-eligible patients had CAD/PAD and met no exclusion criteria, but only COMPASS eligible patients met the inclusion criteria. We assessed the COMPASS primary endpoint of cardiovascular death, ischaemic stroke, haemorrhagic stroke, or myocardial infarction (MI). We computed event rates and adjusted incidence rate ratios (aIRRs). Of 80 071 patients undergoing CAG, 27 939 did not have CAD or PAD and were not considered. Of the 52 132 patients remaining, 11 930 were COMPASS eligible. Rates of the primary endpoint were 4.8 (95% confidence interval 4.6-5.0) events per 100 person-years among COMPASS eligible patients and 2.3 (2.2-2.4) among COMPASS non-eligible patients [aIRR 1.7 (1.6-1.9)]. COMPASS eligible patients also had higher risks of cardiovascular death [aIRR 2.5 (2.1-3.0)], ischaemic stroke [aIRR 1.4 (1.2-1.6)], and MI [aIRR 1.9 (1.7-2.1)].
Conclusion
In this all-comers CAG cohort, 15% were eligible for combined aspirin and rivaroxaban treatment. COMPASS eligible patients had up to 2.5-fold higher rates of cardiovascular events than non-eligible patients. The higher incidence of ischaemic events in COMPASS eligible patients highlights an unmet need for additional preventive measures.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 30 Sep 2019; 5:192-199
Würtz M, Olesen KKW, Thim T, Kristensen SD, Eikelboom JW, Maeng M
Eur Heart J Cardiovasc Pharmacother: 30 Sep 2019; 5:192-199 | PMID: 30916315
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Impact:
Abstract

Effectiveness and safety of rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation and coronary or peripheral artery disease.

Coleman CI, Baker WL, Meinecke AK, Eriksson D, ... Bunz TJ, Alberts MJ
Aims
There are scarce data evaluating the effectiveness and safety of rivaroxaban vs. warfarin in non-valvular atrial fibrillation (NVAF) patients with concomitant coronary artery disease (CAD) and/or peripheral artery disease (PAD) treated in routine practice.
Methods and results
Using MarketScan data from January 2012 to December 2017, we identified oral anticoagulant (OAC)-naïve NVAF patients receiving rivaroxaban (15-20 mg once daily) or warfarin, with comorbid CAD and/or PAD and ≥12 months of insurance coverage before OAC initiation. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weights based on propensity scores (standardized differences <0.1 achieved for all covariates after adjustment). Endpoints included a composite of major thrombotic vascular events (MTVEs) (including ischaemic stroke, myocardial infarction, or need for lower limb revascularization/major amputation) and major bleeding. Patients were followed until an event-of-interest, discontinuation/switch of index OAC, insurance disenrolment, or end-of-data availability. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression. We identified 3257 rivaroxaban (30.4% received a 15 mg dose) and 5046 warfarin users with NVAF and comorbid CAD and/or PAD. Rivaroxaban was associated with a 32% (95% CI = 8-50%) reduction in the composite of MTVE. No significant difference in major bleeding was observed (HR = 1.13, 95% CI = 0.84-1.52). No statistical interactions were noted in subgroup analyses performed on the MTVE (P-interaction ≥ 0.35 for all) or major bleeding endpoints (P-interaction ≥ 0.09 for all).
Conclusion
Among patients with NVAF and comorbid CAD and/or PAD, rivaroxaban use was associated with a reduced risk of MTVEs vs. warfarin, without significantly increasing major bleeding risk.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 05 Sep 2019; epub ahead of print
Coleman CI, Baker WL, Meinecke AK, Eriksson D, ... Bunz TJ, Alberts MJ
Eur Heart J Cardiovasc Pharmacother: 05 Sep 2019; epub ahead of print | PMID: 31549153
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Impact:
Abstract

Platelet inhibition with standard vs. lower maintenance dose of ticagrelor early after myocardial infarction (ELECTRA): a randomized, open-label, active-controlled pharmacodynamic and pharmacokinetic study.

Kubica J, Adamski P, Buszko K, Barańska M, ... Alexopoulos D, Navarese EP
Aims
Currently available data indicate that reduction of ticagrelor maintenance dose (MD) 1-3 years after acute myocardial infarction (AMI) not only provides sufficient platelet inhibition but also can improve ticagrelor\'s safety profile. The aim of this study was to compare the antiplatelet effect of reduced and standard ticagrelor MD in stable patients beginning 1 month after AMI.
Methods and results
In a single-centre, randomized, open-label, active-controlled trial, on Day 30 following AMI, 52 patients (26 in each study arm) were assigned in a 1:1 ratio to receive either reduced (60 mg b.i.d) or standard (90 mg b.i.d) ticagrelor MD for the following 2 weeks. On Day 45 after AMI the antiplatelet effect of ticagrelor was evaluated with the VASP assay and Multiplate, and there were no significant differences in platelet inhibition between patients on reduced vs. standard MD [VASP: 10.4 (5.6-22.2) vs. 14.1 (9.4-22.1) platelet reactivity index; P = 0.30; Multiplate: 30.0 (24.0-39.0) vs. 26.5 (22.0-35.0) U; P = 0.26]. Likewise, no differences were found regarding the prevalence of on-ticagrelor high platelet reactivity between patients on ticagrelor 60 mg b.i.d vs. 90 mg b.i.d (VASP: 4% vs. 8%; P = 0.67; Multiplate: 15% vs. 8%; P = 0.54). Administration of reduced MD resulted in proportionally lower plasma concentrations of ticagrelor and its active metabolite on Day 45 after AMI.
Conclusion
These results suggest that lowering ticagrelor MD 1 month after AMI confers an adequate antiplatelet effect that is comparable to the standard dose. The tested strategy warrants further research to assess its clinical efficacy and safety.
Clinicaltrials.gov identifier
NCT03251859.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 30 Jun 2019; 5:139-148
Kubica J, Adamski P, Buszko K, Barańska M, ... Alexopoulos D, Navarese EP
Eur Heart J Cardiovasc Pharmacother: 30 Jun 2019; 5:139-148 | PMID: 30689800
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Impact:
Abstract

Differential effects on out-of-hospital cardiac arrest of dihydropyridines: real-world data from population-based cohorts across two European countries.

Eroglu TE, Mohr GH, Blom MT, Verkerk AO, ... Gislason GH, Tan HL
Aims
Various drugs increase the risk of out-of-hospital cardiac arrest (OHCA) in the general population by impacting cardiac ion channels, thereby causing ventricular tachycardia/fibrillation (VT/VF). Dihydropyridines block L-type calcium channels, but their association with OHCA risk is unknown. We aimed to study whether nifedipine and/or amlodipine, often-used dihydropyridines, are associated with increased OHCA risk, and how these drugs impact on cardiac electrophysiology.
Methods and results
We conducted a case-control study with VT/VF-documented OHCA cases with presumed cardiac cause from ongoing population-based OHCA registries in the Netherlands and Denmark, and age/sex/index date-matched non-OHCA controls (Netherlands: PHARMO Database Network, Denmark: Danish Civil Registration System). We included 2503 OHCA cases, 10 543 non-OHCA controls in Netherlands, and 8101 OHCA cases, 40 505 non-OHCA controls in Denmark. To examine drug effects on cardiac electrophysiology, we performed single-cell patch-clamp studies in human-induced pluripotent stem cell-derived cardiomyocytes. Use of high-dose nifedipine (≥60 mg/day), but not low-dose nifedipine (<60 mg/day) or amlodipine (any-dose), was associated with higher OHCA risk than non-use of dihydropyridines [Netherlands: adjusted odds ratios (ORadj) 1.45 (95% confidence interval 1.02-2.07), Denmark: 1.96 (1.18-3.25)] or use of amlodipine [Netherlands: 2.31 (1.54-3.47), Denmark: 2.20 (1.32-3.67)]. Out-of-hospital cardiac arrest risk of (high-dose) nifedipine use was not further increased in patients using nitrates, or with a history of ischaemic heart disease. Nifedipine and amlodipine blocked L-type calcium channels at similar concentrations, but, at clinically used concentrations, nifedipine caused more L-type calcium current block, resulting in more action potential shortening.
Conclusion
High-dose nifedipine, but not low-dose nifedipine or any-dose amlodipine, is associated with increased OHCA risk in the general population. Careful titration of nifedipine dose should be considered.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 09 Aug 2019; epub ahead of print
Eroglu TE, Mohr GH, Blom MT, Verkerk AO, ... Gislason GH, Tan HL
Eur Heart J Cardiovasc Pharmacother: 09 Aug 2019; epub ahead of print | PMID: 31504369
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Impact:
Abstract

Efficacy and safety with ticagrelor in patients with prior myocardial infarction in the approved European label: insights from PEGASUS-TIMI 54.

Dellborg M, Bonaca MP, Storey RF, Steg PG, ... Braunwald E, Sabatine MS
Aims
In PEGASUS-TIMI 54, ticagrelor significantly reduced the risk of the composite of major adverse cardiovascular (CV) events by 15-16% in stable patients with a prior myocardial infarction (MI) 1-3 years earlier. We report the efficacy and safety in the subpopulation recommended for treatment in the European (EU) label, i.e. treatment with 60 mg b.i.d. initiated up to 2 years from the MI, or within 1 year after stopping previous adenosine diphosphate receptor inhibitor treatment.
Methods and results
Of the 21 162 patients enrolled in PEGASUS-TIMI 54, 10 779 patients were included in the primary analysis for this study, randomized to ticagrelor 60 mg (n = 5388) or matching placebo (n = 5391). The cumulative proportions of patients with events at 36 months were calculated by the Kaplan-Meier (KM) method. The composite of CV death, MI, or stroke occurred less frequently in the ticagrelor group (7.9% KM rate vs. 9.6%), hazard ratio (HR) 0.80 [95% confidence interval (CI) 0.70-0.91; P = 0.001]. Ticagrelor also reduced the risk of all-cause mortality, HR 0.80 (0.67-0.96; P = 0.018). Thrombolysis in myocardial infarction major bleeding was more frequent in the ticagrelor group 2.5% vs. 1.1%; HR 2.36 (1.65-3.39; P < 0.001). The corresponding HR for fatal or intracranial bleeding was 1.17 (0.68-2.01; P = 0.58).
Conclusion
In PEGASUS-TIMI 54, treatment with ticagrelor 60 mg as recommended in the EU label, was associated with a relative risk reduction of 20% in CV death, MI, or stroke. Thrombolysis in myocardial infarction major bleeding was increased, but fatal or intracranial bleeding was similar to placebo. There appears to be a favourable benefit-risk ratio for long-term ticagrelor 60 mg in this population.
Clinical trial registration
http://www.clinicaltrials.gov NCT01225562.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 30 Sep 2019; 5:200-206
Dellborg M, Bonaca MP, Storey RF, Steg PG, ... Braunwald E, Sabatine MS
Eur Heart J Cardiovasc Pharmacother: 30 Sep 2019; 5:200-206 | PMID: 31218354
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Impact:
Abstract

Clinical use of cangrelor: nationwide experience from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR).

Grimfjärd P, Lagerqvist B, Erlinge D, Varenhorst C, James S
Aims
This nationwide study aimed to analyse the first 2 years of routine clinical use of cangrelor in all Swedish patients undergoing percutaneous coronary intervention (PCI).
Methods and results
This observational Swedish Coronary Angiography and Angioplasty Registry (SCAAR) study identified 915 cangrelor-treated patients. As 899 were ST-segment elevation myocardial infarction (STEMI)-patients undergoing primary PCI, we decided to exclude all non-STEMI patients (n = 16) from the following analysis. We then identified all primary PCI patients, January 2016 to January 2018 (n = 10 816). Excluding hospitals without cangrelor use, tailoring time frames from first cangrelor use per hospital, patients treated with cangrelor (n = 899) were compared with those without cangrelor treatment (n = 4614). A separate analysis was performed for cardiac arrest STEMI patients (n = 273). Cangrelor-use in primary PCI varied greatly between hospitals (4-36%, mean 16%). At variance with randomized trials, cangrelor was used nearly exclusively in STEMI, often with cardiac arrest (19%). Cangrelor was combined with ticagrelor in two-thirds of patients, among which >50% was prehospital. Cangrelor was used more frequently in high-risk patients: left main PCI, thrombus aspiration, and cardiac arrest. Despite cangrelor being used in more high-risk patients, crude definite stent thrombosis rates at 30 days were low and similar in cangrelor (0.7%) and non-cangrelor treated patients (0.8%).
Conclusion
Cangrelor was used nearly exclusively in primary PCI STEMI patients, predominantly with ticagrelor. Despite being used in very high-risk patients, often with cardiac arrest, cangrelor treatment was associated with low stent thrombosis rates.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 30 Jun 2019; 5:151-157
Grimfjärd P, Lagerqvist B, Erlinge D, Varenhorst C, James S
Eur Heart J Cardiovasc Pharmacother: 30 Jun 2019; 5:151-157 | PMID: 30698669
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Impact:
Abstract

Pharmacogenomic Polygenic Response Score Predicts Ischemic Events and Cardiovascular Mortality in Clopidogrel-Treated Patients.

Lewis JP, Backman JD, Reny JL, Bergmeijer TO, ... Klein TE, Shuldiner AR
Aims
Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events remains controversial.
Methods and results
We assessed the impact of 31 candidate gene polymorphisms on ADP-stimulated platelet reactivity in 3,391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on cardiovascular events (CVE) was tested in 2,134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8x10-54; CES1 G143E, P = 1.3x10-16; CYP2C19*17, P = 9.5x10-10; CYP2B6 1294 + 53C>T, P = 3.0x10-4; CYP2B6 516G>T, P = 1.0x10-3; CYP2C9*2, P = 1.2x10-3; and CYP2C9*3, P = 1.5x10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried 8 or more risk alleles were significantly more likely to experience CVEs (OR = 1.78, 95%CI 1.14-2.76, P = 0.01) and cardiovascular death (OR = 4.39, 95%CI 1.35-14.27, P = 0.01) compared to patients who carried 6 or fewer of these alleles.
Conclusion
Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 02 Sep 2019; epub ahead of print
Lewis JP, Backman JD, Reny JL, Bergmeijer TO, ... Klein TE, Shuldiner AR
Eur Heart J Cardiovasc Pharmacother: 02 Sep 2019; epub ahead of print | PMID: 31504375
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Impact:
Abstract

Intensive blood pressure lowering in different age categories: insights from the Systolic Blood Pressure Intervention Trial.

Byrne C, Pareek M, Vaduganathan M, Biering-Sørensen T, ... Olsen MH, Bhatt DL
Aims
The 2018 ESC/ESH guidelines for hypertension recommend differential management of patients who are <65, 65-79, and ≥80 years of age. However, it is unclear whether intensive blood pressure lowering is well-tolerated and modifies risk uniformly across the age spectrum.
Methods and results
SPRINT randomized 9,361 high-risk adults without diabetes and age ≥50 years with systolic blood pressure 130-180 mmHg to either intensive or standard antihypertensive treatment. The primary efficacy endpoint was the composite of acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. The primary safety endpoint was composite serious adverse events. We assessed whether age modified the efficacy and safety of intensive versus standard blood pressure lowering using Cox proportional-hazards regression and restricted cubic splines. In all, 3,805 (41%), 4,390 (47%), and 1,166 (12%) were <65, 65-79, and ≥80 years. Mean age was similar between the two study groups (intensive group 67.9±9.4 years versus standard group 67.9±9.5 years; P = 0.94). Median follow-up was 3.3 years. In multivariable models, age was linearly associated with the risk of stroke (P < 0.001) and non-linearly associated with the risk of primary efficacy events, death from cardiovascular causes, death from any cause, heart failure, and serious adverse events (P < 0.001). The safety and efficacy of intensive blood pressure lowering was not modified by age, whether tested continuously or categorically (P > 0.05).
Conclusion
In SPRINT, the benefits and risks of intensive blood pressure lowering did not differ according to the age categories proposed by the ESC/ESH guidelines for hypertension.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 13 Sep 2019; epub ahead of print
Byrne C, Pareek M, Vaduganathan M, Biering-Sørensen T, ... Olsen MH, Bhatt DL
Eur Heart J Cardiovasc Pharmacother: 13 Sep 2019; epub ahead of print | PMID: 31529024
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Impact:
Abstract

Anti-Thrombotic Strategies in Elderly Patients Receiving Platelet Inhibitors.

Schäfer A, Flierl U, Bauersachs J

Acetyl-salicylic acid (ASA) is the basic anti-thrombotic therapy used for single anti-platelet therapy (SAPT) in primary as well as secondary prevention of atherosclerotic disease. Dual anti-platelet therapy (DAPT) is the cornerstone of maintenance medication following elective percutaneous coronary intervention or acute coronary syndromes (ST elevation myocardial infarction, non-ST elevation myocardial infarction, unstable angina). DAPT duration has been frequently discussed. Currently, guideline recommendations strengthen the importance of individualised treatment to reduce bleeding risk based on clinical predictors, of which older age is an important one. Patients aged ≥75 years are often underrepresented in randomised clinical trials, but present a patient cohort deemed both at heightened ischaemic as well as bleeding risk. We aimed to summarise the evidence or the lack of evidence for anti-platelet treatment strategies in patients aged ≥75 years including combinations with anticoagulants in secondary prevention or coronary interventions in elderly patients with atrial fibrillation. This review article represents the authors interpretation of available data and is not discussed by a formal task force; it is intended to point out missing evidence and to provide age-specific data for individualised decision making, which is currently encouraged by the guidelines.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 05 Aug 2019; epub ahead of print
Schäfer A, Flierl U, Bauersachs J
Eur Heart J Cardiovasc Pharmacother: 05 Aug 2019; epub ahead of print | PMID: 31384933
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Impact:
Abstract

Antithrombotic Therapy and Major Adverse Limb Events in Patients With Chronic Lower Extremity Arterial Disease: Systematic Review and Meta-analysis from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy in Collaboration with the European Society of Cardiology Working Group on Aorta & Peripheral Vascular Diseases.

Savarese G, Reiner MF, Uijl A, D Amario D, ... Aboyans V, Lewis BS
Introduction
The role and selection of antithrombotic therapy to improve limb outcomes in chronic lower extremity artery disease (LEAD) is still debated. We conducted a meta-analysis to examine the efficacy and safety of anti-thrombotic and more intense antithrombotic therapy on limb outcomes and limb salvage in patients with chronic LEAD.
Methods
Study inclusion criteria were: enrollment of patients with LEAD, randomized allocation to more vs. less intense antithrombotic therapy [more vs. less intense single antiplatelet therapy (SAPT); dual antiplatelet therapy (DAPT) vs. SAPT; dual antithrombotic therapy vs. SAPT or oral anticoagulant]; enrolment of ≥ 200 patients; reporting of at least one of following outcomes: limb amputation or revascularization. Seven randomized studies enrolling 30\'447 patients were included.
Results
Over a median follow-up of 24 months, more vs. less intense antithrombotic therapy or placebo significantly reduced the risk of limb revascularization (relative risk [RR]: 0.89; 95% confidence interval [CI]: 0.83 - 0.94) and limb amputation (RR: 0.63, 95% confidence interval [CI]: 0.46-0.86), as well as stroke (RR: 0.82, 95% CI: 0.70-0.97). There was no statistically significant effect on the risk of myocardial infarction (RR: 0.98, 95% CI: 0.87-1.11), all-cause (RR: 0.93, 95% CI: 0.86-1.01) and cardiovascular death (RR: 0.97, 95% CI: 0.86-1.08). Risk of major bleeding increased (RR: 1.23, 95% CI: 1.04-1.44).
Conclusion
In patients with LEAD, more intense antithrombotic therapy reduces risk of limb amputation and revascularization as well as stroke, with an increase in the risk of bleeding events.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 07 Aug 2019; epub ahead of print
Savarese G, Reiner MF, Uijl A, D Amario D, ... Aboyans V, Lewis BS
Eur Heart J Cardiovasc Pharmacother: 07 Aug 2019; epub ahead of print | PMID: 31392312
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Impact:
Abstract

Antithrombotic therapy in the early phase of NSTE-ACS: a systematic review and meta-analysis.

Galli M, Andreotti F, D\'Amario D, Vergallo R, ... Porto I, Crea F
Aims
Despite the increasing use of early invasive strategies in non-ST-elevation acute coronary syndromes (NSTE-ACS), optimal initial antithrombotic therapy (ATT) based on the safety/efficacy profile of all guideline-recommended combinations remains crucial for the early management of both medically and invasively treated NSTE-ACS patients.
Methods and results
Randomised controlled trials (RCTs) on ATT in NSTE-ACS/unstable angina reporting early (within 14 days) major adverse cardiovascular events (MACE) and major bleeding were selected. Overall, 3799 studies were screened, 117 clinical trials were assessed as potentially eligible, 20 trials were included in the study. According to treatment and type of intervention, 9 different meta-analyses were performed including a total of 88,748 patients. A significant reduction of trial-defined MACE was found for aspirin vs placebo (OR, 0.57; 95% CI, 0.34-0.96), heparin vs placebo (OR, 0.38; 95% CI, 0.15-0.97), aspirin+heparin vs placebo (OR, 0.32; 95% CI, 0.18-0.59), aspirin+heparin vs aspirin (OR, 0.57; 95% CI, 0.42-0.79), aspirin+LMWH vs aspirin+UFH (OR, 0.81; 95% CI, 0.69-0.95) and aspirin+ticagrelor/prasugrel+heparins vs aspirin+clopidogrel+heparins (OR, 0.76; 95% CI, 0.62-0.94). A significant decrease in major bleeding was found only for fondaparinux vs LMWH on the background of aspirin+clopidogrel (OR, 0.52; 95% CI, 0.44-0.62) despite a clear trend in increased bleeding for heparin compared to aspirin, aspirin+heparin compared to placebo, aspirin+heparin compared to aspirin, aspirin+P2Y12inhibitors+UFH/LMWH compared to aspirin+UFH/LMWH and aspirin+ticagrelor/prasugrel+heparins vs aspirin+clopidogrel+heparins.
Conclusion
To our knowledge, these findings are the first to report the safety and efficacy of all the various combinations of currently recommended ATT for the early management of NSTE-ACS, providing a comprehensive evidence-base to guide decisions depending on the patients\' bleeding risk and treatment strategy.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 26 Jul 2019; epub ahead of print
Galli M, Andreotti F, D'Amario D, Vergallo R, ... Porto I, Crea F
Eur Heart J Cardiovasc Pharmacother: 26 Jul 2019; epub ahead of print | PMID: 31350546
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Impact:
Abstract

Oral anticoagulation in patients with non-valvular atrial fibrillation and a CHA2DS2-VASc score of 1: a current opinion of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy and European Society of Cardiology Council on Stroke.

Sulzgruber P, Wassmann S, Semb AG, Doehner W, ... Agewall S, Niessner A

Oral anticoagulation in patients presenting with non-valvular atrial fibrillation and a CHA2DS2-VASc score of 1 (CHA2DS2-VASc of 2 in women) remains a challenging approach in clinical practice. Therapeutic decisions need to balance the individual benefit of reducing thromboembolic risk against the potential harm due to an increase in bleeding risk in this intermediate risk patient population. Within the current opinion statement of the European Society of Cardiology working group of cardiovascular pharmacotherapy and the European Society of Cardiology council on stroke the currently available evidence on the anti-thrombotic management in patients presenting with a CHA2DS2-VASc of 1 is summarized. Easily applicable tools for a personalized refinement of the individual thromboembolic risk in patients with atrial fibrillation and a CHA2DS2-VASc score of 1 that guide clinicians through the question whether to anticoagulate or not are provided.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 30 Jun 2019; 5:171-180
Sulzgruber P, Wassmann S, Semb AG, Doehner W, ... Agewall S, Niessner A
Eur Heart J Cardiovasc Pharmacother: 30 Jun 2019; 5:171-180 | PMID: 31119266
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Abstract

ESC Position Paper on statins adherence and implementation of new lipid-lowering medications: barriers to be overcome.

Drexel H, Coats AJS, Spoletini I, Bilato C, ... Filardi PP, Rosano GMC

Benefits and safety on statins have been well established over 20 years of research. Despite this, the vast majority of patients are not adequately treated and do not achieve the low-density lipoprotein cholesterol target levels. This is mainly due to poor adherence, which is associated with dangerous and sometimes fatal outcomes. To increase adherence and prevent worse outcomes, a combination therapy with lower dosage of statins and new lipid lowering drugs may be used. However, the implementation of new lipid lowering drugs in European countries is still at the beginning. For these reasons, aim of this position paper is to give an up-to-date indication from the European Society of Cardiology in order to discuss the barriers towards statins adherence and new lipid lowering drugs implementation in Europe.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 23 Dec 2019; epub ahead of print
Drexel H, Coats AJS, Spoletini I, Bilato C, ... Filardi PP, Rosano GMC
Eur Heart J Cardiovasc Pharmacother: 23 Dec 2019; epub ahead of print | PMID: 31873726
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Abstract

An observational study of INR control according to NICE criteria in patients with non-valvular atrial fibrillation-The SAIL Warfarin Out of Range Descriptors Study (SWORDS).

Harris DE, Thayer D, Wang T, Brooks C, ... Lister S, Halcox J
Aims
In patients with non-valvular atrial fibrillation (NVAF) prescribed warfarin, the UK National Institute of Health and Care Excellence (NICE) defines poor anticoagulation as a TTR of < 65%, any 2 INRs within a 6 month period of ≤ 1.5 (\"low\"), 2 INRs ≥5 within 6months, or any INR ≥ 8 (\"high\").Our objectives were to (i) quantify the number of patients with poor INR control and (ii) describe the demographic and clinical characteristics associated with poor INR control.
Method and results
Linked anonymised health record data for Wales (2006-2017) was used to evaluate patients prescribed warfarin who had at least 6 months of INR data.32,380 patients were included. In total, 13,913 (43.0%) patients had at least one of the NICE markers of poor INR control. Importantly, in the 24,123 (74.6%) of the cohort with an acceptable TTR (≥65%), 5,676 (23.5%) had either low or high INR readings at some point in their history. In a multivariable regression female gender, age (≥75), excess alcohol, diabetes heart failure, ischaemic heart disease and respiratory disease were independently associated with all markers of poor INR control.
Conclusion
Acceptable INR control according to NICE standards is poor. Of those with an acceptable TTR (>65%) one quarter still had unacceptably low or high INR levels according to NICE criteria. Thus, only using TTR to assess effectiveness with warfarin has the potential to miss a large number of patients with non-therapeutic INRs who are likely to be at increased risk.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 26 Nov 2019; epub ahead of print
Harris DE, Thayer D, Wang T, Brooks C, ... Lister S, Halcox J
Eur Heart J Cardiovasc Pharmacother: 26 Nov 2019; epub ahead of print | PMID: 31774502
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Abstract

New AI Prediction Model Using Serial PT-INR Measurements in AF Patients on VKAs: GARFIELD-AF.

Goto S, Goto S, Pieper KS, Bassand JP, ... Kakkar AK,
Background
Most clinical risk stratification models are based on measurement at a single time-point rather than serial measurements. Artificial intelligence (AI) is able to predict one-dimensional outcomes from multi-dimensional datasets. Using data from GARFIELD-AF registry, a new AI model was developed for predicting clinical outcomes in atrial fibrillation (AF) patients up to 1 year based on sequential measures of PT-INR within 30 days of enrolment.
Methods and results
Patients with newly diagnosed AF who were treated with vitamin K antagonists (VKA) and had at least 3 measurements of PT-INR taken over the first 30 days after prescription were analyzed. The AI model was constructed with multilayer neural network including long short-term memory (LSTM) and one-dimensional convolution layers. The neural network was trained using PT-INR measurements within days 0-30 after starting treatment and clinical outcomes over days 31-365 in a derivation cohort (cohorts 1-3; n = 3185). Accuracy of the AI model at predicting major bleed, stroke/SE, and death was assessed in a validation cohort (cohorts 4-5; n = 1523). The model\'s c-statistic for predicting major bleed, stroke/SE, and all-cause death was 0.75, 0.70, and 0.61, respectively.
Conclusions
Using serial PT-INR values collected within 1 month after starting VKA, the new AI model performed better than time in therapeutic range (TTR) at predicting clinical outcomes occurring up to 12 months thereafter. Serial PT-INR values contain important information that can be analyzed by computer to help predict adverse clinical outcomes.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 09 Dec 2019; epub ahead of print
Goto S, Goto S, Pieper KS, Bassand JP, ... Kakkar AK,
Eur Heart J Cardiovasc Pharmacother: 09 Dec 2019; epub ahead of print | PMID: 31821482
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Abstract

Differences in the risk of stroke, bleeding events, and mortality between female and male patients with atrial fibrillation during warfarin therapy.

Penttilä T, Lehto M, Niiranen J, Mehtälä J, ... Lassila R, Raatikainen P
Aims
Females with atrial fibrillation (AF) have been suggested to carry a higher risk for thromboembolic events than males. We compared the residual risk of stroke, bleeding events, and cardiovascular and all-cause mortality among female and male AF patients taking warfarin.
Methods and results
Data from several nationwide registries and laboratory databases were linked with the civil registration number of the patients. A total of 54 568 patients with data on the quality of warfarin treatment (time in therapeutic range) 60 days prior to the events were included (TTR60). Gender differences in the endpoints were reported for the whole population, pre-specified age groups, and different TTR60 groups. During the 3.2 ± 1.6 years follow-up, there were no differences in the adjusted risk of stroke [hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.91-1.03, P = 0.304] between the genders. Cardiovascular mortality (HR 0.82, 95% CI 0.78-0.88, P < 0.001) and all-cause mortality (HR 0.79, 95% CI 0.75-0.83, P < 0.001) were lower in women when compared with men. There were no differences in the risk of stroke, cardiovascular mortality, and all-cause mortality between the genders in the TTR60 categories except for those with TTR60 <50%. Bleeding events were less frequent in females (HR 0.52, 95% CI 0.49-0.56, P < 0.001).
Conclusion
There were no differences in the risk of stroke between female and male AF patients taking warfarin. Cardiovascular mortality, all-cause mortality, and risk of bleeding events were lower in females. Hence, female gender was not a risk marker for adverse outcomes in AF patients with proper warfarin therapy.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:29-36
Penttilä T, Lehto M, Niiranen J, Mehtälä J, ... Lassila R, Raatikainen P
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:29-36 | PMID: 30052822
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Abstract

Association Between Serum Potassium Levels and Short-Term Mortality in Patients With Atrial Fibrillation or Flutter Co-treated With Diuretics and Rate- or Rhythm-Controlling Drugs.

Hagengaard L, Søgaard P, Espersen M, Sessa M, ... Kragholm KH, Polcwiartek C
Aim
We investigated the association between potassium levels and 90-day all-cause mortality in atrial fibrillation or flutter (AF) patients co-treated with diuretics and rate- or rhythm-controlling drugs.
Methods and results
During 2000-2012, first-time AF patients treated with beta-blockers, amiodarone, sotalol, verapamil, and/or digoxin combined with any diuretic within 90 days post-AF discharge were included. Following co-treatment, a potassium measurement within 90 days after initiating diuretic treatment was required. Mortality risk associated with potassium <3.5, 3.5-3.7, 3.8-4.0, 4.5-4.7, 4.8-5.0, and >5.0 mmol/L (reference: 4.1-4.4 mmol/L) was assessed using Multivariable Cox regression. In total, 14,425 AF patients were included (median age: 78 years; women: 52%). Patients most often received beta-blocker monotherapy (29%), beta-blocker and digoxin combined (25%), digoxin monotherapy (24%), amiodarone monotherapy (3%), and verapamil monotherapy (3%). Increased 90-day mortality risk was associated with <3.5 mmol/L (HR 2.05, 95% CI: 1.68-2.50), 3.5-3.7 mmol/L (HR: 1.28, 95% CI 1.05-1.57), 4.5-4.7 mmol/L (HR: 1.20, 95% CI: 1.02-1.41), 4.8-5.0 mmol/L, (HR: 1.37, 95% CI: 1.14-1.66) and >5.0 mmol/L: (HR: 1.84, 95% CI: 1.53-2.21). Compared with beta-blocker monotherapy, rate- or rhythm-controlling drugs did not modify the association between potassium groups and mortality risk.
Conclusion
In addition to hypo- and hyperkalemia, low and high normal range potassium levels were associated with increased 90-day mortality risk in AF patients co-treated with diuretics and rate- or rhythm-controlling drugs. These associations were independent of rate- or rhythm-controlling drugs.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 01 Jul 2019; epub ahead of print
Hagengaard L, Søgaard P, Espersen M, Sessa M, ... Kragholm KH, Polcwiartek C
Eur Heart J Cardiovasc Pharmacother: 01 Jul 2019; epub ahead of print | PMID: 31263883
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Abstract

Relationship between degree of heparin anticoagulation and clinical outcome in patients receiving potent P2Y12-inhibitors with no planned GPI during primary percutaneous coronary intervention in acute myocardial infarction - a VALIDATE-SWEDEHEART substudy.

Sharma T, Rylance R, Karlsson S, Koul S, ... James S, Erlinge D
Background
Heparin is the preferred choice of anticoagulant in percutaneous coronary intervention (PCI) for acute myocardial infarction (MI). An established dosage of heparin has not yet been determined, but treatment may be optimized through monitoring of activating clotting time (ACT). The aim of this study was to determine the relationship between heparin dose or ACT with a composite outcome of death, MI or bleeding using data from the registry-based, randomized, controlled and open-label VALIDATE-SWEDEHEART-trial, although patients were not randomized to heparin dose in this sub-study.
Methods
Patients with MI undergoing PCI and receiving treatment with a potent P2Y12-inhibitor and anticoagulation with heparin, without the planned use of glycoprotein IIb/IIIa inhibitor (GPI), were enrolled in this substudy. The primary endpoint was a composite end point of death, MI and bleeding at 30 days. The individual components and stent thrombosis were analyzed separately. We divided patients into groups according to the initial dose of unfractionated heparin during PCI (<70U/kg, 70-100U/kg and >100U/kg) or ACT (ACT <250 sec, 250-350 sec and >350 sec) as well as investigating them as continuous variables in Cox proportional hazards models using univariable and multivariable analyses.
Results
No major differences were noted between heparin stratified in groups (p = 0.22) or heparin as a continuous variable in relation to the primary composite endpoint HR 1.0 CI (0.99-1.01) for heparin dose/kg. No differences were found between ACT stratified in groups (p = 0.453) or ACT in seconds HR 1.0 CI (0.99-1.00) regarding the primary endpoint. The individual components of death, MI, major bleeding and stent thrombosis were not significantly different across heparin doses or ACT levels either.
Conclusions
We found no association between heparin dose or ACT levels and death, MI bleeding complications or stent thrombosis. Therefore, there is no strong support for a specific heparin dose or mandatory ACT monitoring in patients treated with potent P2Y12-inhibitors with no planned GPI.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 14 May 2019; epub ahead of print
Sharma T, Rylance R, Karlsson S, Koul S, ... James S, Erlinge D
Eur Heart J Cardiovasc Pharmacother: 14 May 2019; epub ahead of print | PMID: 31093662
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Abstract

How to implement the recommendations of the 2018 ESC/ESH Hypertension Guidelines in a given patient: a step by step approach.

Coca A, Doménech M

All clinical guidelines release general recommendations based on the best available evidence on the issue, usually obtained from epidemiological studies, randomized clinical trials, or meta-analyses. However, the final data of these studies are averages of a given parameter from groups of patients whose clinical characteristics are not necessarily similar to those of a specific patient seen in daily practice. As the guidelines recommendations have to be implemented in patients, not in group of patients, the final decisions concerning an individual patient must be made by the attending physician, in consultation with the patient and caregiver, as appropriate. In this article, a clinical case of a patient with hypertension and other associated cardiovascular risk factors is discussed and managed following the recommendations of the 2018 ESC/ESH Hypertension Guidelines implemented in this specific patient.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 30 Jun 2019; 5:164-170
Coca A, Doménech M
Eur Heart J Cardiovasc Pharmacother: 30 Jun 2019; 5:164-170 | PMID: 30851109
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Abstract

Trends in cardiovascular and bleeding outcomes in acute coronary syndrome patients treated with or without proton-pump inhibitors during the introduction of novel P2Y12 inhibitors: a five-year experience from a single-centre observational registry.

Hoedemaker NPG, Damman P, Ottervanger JP, Dambrink JHE, ... de Winter RJ, van \'t Hof AWJ
Aims
Proton-pump inhibitors (PPIs) are commonly prescribed in acute coronary syndrome (ACS) patients on antiplatelet therapy. We studied PPI prescription in ACS patients in the era of novel P2Y12 inhibitors and assessed the association between PPI use and clinical outcomes.
Methods and results
Between 2010 and 2014, we included all consecutive ACS patients admitted to a Dutch tertiary hospital. The main outcome was PPI prescription at discharge. Additionally, we present 1-year mortality and 30-day cardiovascular and bleeding outcomes. Of 4595 ACS patients with known discharge medication, 63.9% received a PPI. PPI-treated patients were older (67.1 ± 12.5 vs. 63.0 ± 13.3, P < 0.001). PPI treatment at discharge increased from 34.7% in 2010 to 88.7% in 2014 (P < 0.001). Concurrently, ticagrelor prescription at discharge increased from 0.0% to 48.6% in 2014 (P < 0.001), while clopidogrel prescription decreased from 78.6% in 2010 to 28.7% in 2014 (P < 0.001). PPI treatment was associated with reductions in death or myocardial infarction (MI) [adjusted hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.10-0.76] and death, MI or stroke (adjusted HR 0.33, 95% CI 0.14-0.81) at 30-days post-discharge. However, this association was not present in subgroup analyses of patients treated with clopidogrel or ticagrelor.
Conclusion
In this single-centre registry, PPI prescription in ACS patients doubled between 2010 and 2014. PPI treatment at discharge was associated with a reduction in death, MI, or stroke at 30-days post-discharge, mainly driven by a reduction in MI. There were no differences gastrointestinal bleeding between patients treated with or without a PPI. PPI treatment may serve as a marker of improved therapies and outcome, rather than causing a reduction in cardiovascular events.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 30 Jun 2019; 5:127-138
Hoedemaker NPG, Damman P, Ottervanger JP, Dambrink JHE, ... de Winter RJ, van 't Hof AWJ
Eur Heart J Cardiovasc Pharmacother: 30 Jun 2019; 5:127-138 | PMID: 30084902
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Abstract

Safety and efficacy of non-vitamin K antagonist oral anticoagulants in elderly patients with atrial fibrillation.

Silverio A, Di Maio M, Prota C, De Angelis E, ... Capodanno D, Galasso G
Aims
The aim of the present meta-analysis was to evaluate the efficacy and safety of non-vitamin-K oral antagonists (NOACs) versus vitamin-K antagonists (VKAs) in elderly patients with atrial fibrillation (AF) and indirectly compare NOACs in this population.
Methods and results
MEDLINE, Cochrane, ISI Web of Sciences, and SCOPUS were searched for randomized or adjusted observational studies comparing NOACs versus VKAs for stroke prevention in AF patients≥75 years. The primary efficacy and safety outcomes of this meta-analysis were the composite of stroke and systemic embolism (SSE) and major bleedings, respectively. Other secondary outcomes were also analyzed.The analysis included 22 studies enrolling 440,281 AF patients≥75 years. The risk of SSE was significantly lower with NOACs versus VKAs (HR, 0.79; 95%CI, 0.70-0.89), whereas no differences were found for major bleedings (HR, 0.94; 95%CI, 0.85-1.05). NOACs reduced the risk of intracranial bleeding (HR, 0.46; 95%CI, 0.38-0.58), hemorrhagic stroke (HR, 0.61; 95%CI, 0.48-0.79) and fatal bleeding (HR, 0.46; 95%CI, 0.30-0.72) but increased gastrointestinal bleedings (HR, 1.46; 95%CI, 1.30-1.65), compared to VKAs.The adjusted indirect comparison showed no significant differences in term of SSE between NOAC agents. Conversely, the risk of major bleeding was higher for rivaroxaban versus apixaban (HR, 1.69; 95%CI, 1.39-2.08) and edoxaban (HR, 1.37; 95%CI, 1.14-1.67), and for dabigatran versus apixaban (HR, 1.47; 95%CI, 1.18-1.85).
Conclusion
In elderly patients with AF, NOACs are associated to a lower risk of SSE, intracranial bleeding, hemorrhagic stroke and fatal bleeding than VKAs, but increase gastrointestinal bleedings. In this analysis, the safety profile of individual NOAC agents was significantly different.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 11 Dec 2019; epub ahead of print
Silverio A, Di Maio M, Prota C, De Angelis E, ... Capodanno D, Galasso G
Eur Heart J Cardiovasc Pharmacother: 11 Dec 2019; epub ahead of print | PMID: 31830264
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Abstract

Lipid management in rheumatoid arthritis: a position paper by the Cardiovascular Pharmacotherapy Working Group of European Society of Cardiology.

Hollan I, Ronda N, Dessein P, Agewall S, ... Wassmann S, Meroni PL

Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity, partly due to alterations in lipoprotein quantity, quality and cell cholesterol trafficking. Although cardiovascular disease significantly contributes to mortality excess in RA, cardiovascular prevention has been largely insufficient. Because of limited evidence, optimal strategies for lipid management (LM) in RA have not been determined yet, and recommendations are largely based on expert opinions. In this position paper, we describe abnormalities in lipid metabolism in RA and introduce a new algorithm for estimation of cardiovascular risk (CVR) and LM in RA. The algorithm stratifies patients according to RA-related factors impacting CVR (such as RA activity and severity and medication) and therefore enables a more nuanced approach than other current methods. We propose strategies for monitoring of lipid parameters and treatment of dyslipidemia in RA (including lifestyle, statins and other lipid-modifying therapies, and disease modifying anti-rheumatic drugs). These opinion-based recommendations are meant to facilitate LM in RA until more evidence is available.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 08 Aug 2019; epub ahead of print
Hollan I, Ronda N, Dessein P, Agewall S, ... Wassmann S, Meroni PL
Eur Heart J Cardiovasc Pharmacother: 08 Aug 2019; epub ahead of print | PMID: 31397840
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Abstract

Antithrombotic treatment and major adverse cardiac events after bleeding in patients with myocardial infarction: a retrospective analysis of nationwide registry data.

Nabi H, Rørth R, Tajchman Mb DH, Holmvang L, ... Køber L, Sørensen R
Aims
The aim of this study was to describe the use of antithrombotic therapy following a bleeding event among patients with myocardial infarction (MI), and the associated risk of major adverse cardiac events (MACE).
Methods and results
Using Danish nationwide registries patients hospitalized with a bleeding event within 1 year after MI were identified. Antithrombotic treatment with aspirin, clopidogrel and/or vitamin K antagonists (VKA) was determined at the bleeding and at Day 90 and 180 post bleed. Based on guidelines, patients were stratified into four groups: expected, reduced, discontinued, or intensified treatment. Risk of MACE (ischemic stroke, MI, or death) within the first year was assessed by Cox proportional hazard models. A total of 3324 patients with a bleeding after MI were included. At day 90 post bleed 1052 (31.7%) received expected antitrombotic treatment, 1301 (39.2%) reduced, 164 (4.9%) intensified, and 807 (24.3%) no treatment. MACE occurred in 637 (19.2%) patients. With dual antiplatelet therapy (DAPT) as reference, adjusted hazard ratios for MACE were: aspirin 1.81 (1.06-3.09), clopidogrel 1.08 (0.64-1.82), VKA 1.08 (0.47-2.48), VKA+aspirin 1.97 (0.95- 4.07), VKA+clopidogrel 0.26 (0.03-1.91), triple 1.73 (0.50-5.95), no treatment 1.93 (1.11-3.36).
Conclusions
The majority of MI patients reduced or discontinued their antithrombotic therapy post-bleed. Patients in monotherapy with aspirin or no treatment post-bleed had a higher risk of MACE Further studies of optimal antithrombotic treatments after a bleed are needed.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 04 Jul 2019; epub ahead of print
Nabi H, Rørth R, Tajchman Mb DH, Holmvang L, ... Køber L, Sørensen R
Eur Heart J Cardiovasc Pharmacother: 04 Jul 2019; epub ahead of print | PMID: 31274145
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Abstract

Influence of intravenous fentanyl compared with morphine on ticagrelor absorption and platelet inhibition in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: rationale and design of the PERSEUS randomized trial.

Degrauwe S, Roffi M, Lauriers N, Muller O, ... Valgimigli M, Iglesias JF
Aims
Recent evidence demonstrates that intravenous morphine significantly reduces absorption and delays onset of action of oral P2Y12 receptor inhibitors in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). We aimed to assess the influence of intravenous fentanyl compared with morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients undergoing pPCI for STEMI.
Methods and results
Single-centre, prospective, open-label, randomized controlled study that will randomly assign in a 1:1 ratio patients with STEMI undergoing pPCI to receive intravenous fentanyl or morphine following a pre-hospital 180-mg loading dose of ticagrelor (ClinicalTrials.gov Identifier: NCT02531165). Pharmacokinetic and pharmacodynamic analyses will be performed at baseline and 1, 2, 4, 6, and 12 h post-loading dose. Pharmacodynamic assessments will include P2Y12 reaction units (PRU) measured by VerifyNow P2Y12. Pharmacokinetic assessments include determination of maximal observed plasma concentrations, time for maximal plasma concentration, and area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC0-t) for ticagrelor and AR-C124910XX. The primary endpoint is platelet reactivity assessed by PRU at 2 h post ticagrelor loading dose.
Conclusion
PERSEUS will provide randomized data regarding the impact of fentanyl administration, in patients with STEMI undergoing pPCI, on platelet inhibition and ticagrelor absorption and total exposure.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permiss[email protected]

Eur Heart J Cardiovasc Pharmacother: 30 Jun 2019; 5:158-163
Degrauwe S, Roffi M, Lauriers N, Muller O, ... Valgimigli M, Iglesias JF
Eur Heart J Cardiovasc Pharmacother: 30 Jun 2019; 5:158-163 | PMID: 30101278
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Abstract

Effectiveness and safety of edoxaban in patients with atrial fibrillation: data from the Danish nationwide cohort.

Nielsen PB, Larsen TB, Skjøth F, Søgaard M, Lip GYH
Aim
Edoxaban treatment for stroke prevention in atrial fibrillation (AF) has mainly been investigated in randomized controlled trials, and data reflecting clinical practice are limited. We ascertained the clinical effectiveness and safety of edoxaban 30mg and 60mg once daily among Danish patients with AF.
Methods and results
This was an observational study based on Danish nationwide registries collecting information for administrative purposes. From June 2016 through November 2018 we identified 3,405 patients initiating edoxaban. After exclusions, 2,285 AF patients were followed for the effectiveness outcome of thromboembolism (ischemic stroke and/or systemic embolism) and bleeding outcomes (composite of major bleeding, gastrointestinal bleeding, and intracranial hemorrhage), as well as bleeding requiring hospitalization. Population mean age was 75 years and 43% were female; 643 patients received the 30mg edoxaban dosage regimen and 1,642 initiated 60mg edoxaban. During follow-up, we observed 41 thromboembolic events and 89 bleeding events of which 40 events required hospitalization. Among patients with 30mg edoxaban the rate (per 100 person-years) of thromboembolism was 2.07 versus 1.62 for 60mg edoxaban. Rates of bleeding were similar for the two dosages at approximately 3.85. Bleeding requiring hospitalization occurred at a rate of 1.74 for 30mg edoxaban and 1.69 with 60mg edoxaban.
Conclusion
In this nationwide cohort of Caucasian AF patients treated with edoxaban for stroke prevention, the clinical effectiveness and safety was in line with data from the ENGAGE AF-TIMI 48 trial. Studies investigating comparative effectiveness and safety for edoxaban in comparison with other choices of antithrombotic treatment options are needed.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 26 Nov 2019; epub ahead of print
Nielsen PB, Larsen TB, Skjøth F, Søgaard M, Lip GYH
Eur Heart J Cardiovasc Pharmacother: 26 Nov 2019; epub ahead of print | PMID: 31774504
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Impact:
Abstract

Impact of Vitamin D on Cardiac structure and function in CKD patients with hypovitaminosis D, a randomised controlled trial and meta-analysis.

Banerjee D, Chitalia N, Ster IC, Appelbaum E, ... Kaski JC, Goldsmith D
Introduction
Vitamin D deficiency is associated with cardiovascular events in CKD yet the impact of supplementation is controversial. Previous active vitamin D supplementation studies did not show improvement in cardiac structure or function but the effect of native vitamin D supplementation in CKD patients with low vitamin D levels is unknown. We have addressed this question via both a randomised double-blind prospective study and a meta-analysis of three randomised placebo-controlled studies.
Methods and results
We conducted a randomised double-blind, placebo-controlled trial of vitamin D supplementation in stable, non-diabetic, CKD 3-4 patients with circulating vitamin D < 75nmol/L, who were receiving treatment with ACEi or ARB and had high-normal left ventricular (LV) mass. Patients were randomised to receive 6 directly-observed doses of 100,000 IU cholecalciferol (n = 25) or matched placebo (n = 23). The primary endpoint was change in LV Mass index (LVMI) over 52 weeks, as assessed by cardiac magnetic resonance imaging. Secondary endpoints included changes in LV ejection fraction; left and right ventricular volumes and left and right atrial area.Vitamin D concentration increased with the administration of cholecalciferol. The change in LVMI with cholecalciferol (median[interquartile-range], -0.25g[-7.20 to 5.30]) was no different from placebo (-4.30g[9.70 to 2.60]). There was no difference in changes of LV ejection fraction; left and right ventricular volumes and left and right atrial area. The meta-analysis of three 52-week, randomised placebo-controlled studies using active/native vitamin D supplementation showed no differences in LVMI measurements.
Conclusion
Vitamin D supplementation does not have beneficial effects on left ventricular mass in CKD patients.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 11 Dec 2019; epub ahead of print
Banerjee D, Chitalia N, Ster IC, Appelbaum E, ... Kaski JC, Goldsmith D
Eur Heart J Cardiovasc Pharmacother: 11 Dec 2019; epub ahead of print | PMID: 31830258
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Impact:
Abstract

Assessing Major Bleeding Risk in Atrial Fibrillation Patients Concurrently Taking Non-Vitamin K Antagonist Oral Anticoagulants and Antiepileptic Drugs.

Wang CL, Wu VC, Chang KH, Tu HT, ... Kuo CC, Chang SH
Aims
This study compared the risk of major bleeding between atrial fibrillation (AF) patients who took non-vitamin-K antagonist oral anticoagulants (NOACs) and antiepileptic drugs (AEDs) concurrently and those who took only NOACs.
Methods and results
We performed a retrospective cohort study using Taiwan National Health Insurance database and included AF patients who received NOAC prescriptions from June 1, 2012, to December 31, 2017. The major bleeding risks of person-quarters exposed to NOAC and 11 concurrent AEDs (carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, topiramate, valproic acid, and zonisamide) were compared with person-quarters exposed to NOAC alone. Adjusted incidence rate differences between NOAC with or without concurrent AEDs were estimated using Poisson regression models weighted by the inverse probability of treatment. Among 104319 patients (age 75.0±10.3 years; men, 56.2%), 8546 major bleeding events occurred during 731723 person-quarters with NOAC prescriptions. Concurrent AED use was found in 15.3% of NOAC-treated patients. Concurrent use of NOAC with valproic acid, phenytoin, or levetiracetam increased adjusted incidence rates per 1000 person-years of major bleeding more significantly than NOAC alone: 153.49 for NOAC plus valproic acid vs. 55.06 for NOAC alone (difference 98.43, 95% CI 82.37-114.49); 135.83 for NOAC plus phenytoin vs. 54.43 for NOAC alone (difference 81.4, 95% CI 60.14-102.66); and 132.96 for NOAC plus levetiracetam vs. 53.08 for NOAC alone (difference 79.88, 95% CI 64.47-95.30).
Conclusions
For AF patients, the concurrent use of NOACs and valproic acid, phenytoin, or levetiracetam was associated with a higher risk of major bleeding.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 05 Aug 2019; epub ahead of print
Wang CL, Wu VC, Chang KH, Tu HT, ... Kuo CC, Chang SH
Eur Heart J Cardiovasc Pharmacother: 05 Aug 2019; epub ahead of print | PMID: 31384926
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Impact:
Abstract

Is P2Y12 inhibitor therapy associated with an increased risk of cancer?

Kaufmann CC, Lyon AR, Wojta J, Huber K

Antiplatelet therapy is a mainstay of cardiovascular therapy and is well established in clinical routine. Recently, the potential risk of solid cancers with P2Y12 inhibitor therapy has been an issue of growing interest. The alleged association primarily originated from the findings of an US Food and Drug Administration (FDA) review of the randomized controlled TRITON-TIMI 38 trial and the following results of the DAPT trial. The higher risk of cancer was predominately observed with the newer, more potent P2Y12 inhibitors and in the setting of prolonged dual antiplatelet therapy (DAPT). Current European Society of Cardiology (ESC) Guidelines suggest consideration of prolonged DAPT beyond the recommended duration of 6 months in stable coronary artery disease and 12 months in acute coronary syndrome if ischaemic risk prevails over the risk of bleeding. Several trials, studies and meta-analyses have addressed the potential interplay of cancer and P2Y12 inhibition since then. The effect of P2Y12 inhibition on cancer has been investigated extensively in basic research as well. In this review, we summarize current available evidence of cancer risk with P2Y12 inhibitor therapy and discuss the resulting clinical implications.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:100-104
Kaufmann CC, Lyon AR, Wojta J, Huber K
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:100-104 | PMID: 30657876
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Impact:
Abstract

Neoatherosclerosis after drug-eluting stent implantation: a novel clinical and therapeutic challenge.

Borovac JA, D\'Amario D, Vergallo R, Porto I, ... Niccoli G, Crea F

The recognition that obstructive disease of the epicardial coronary arteries, causing ischaemic heart disease, can be treated with a percutaneous coronary intervention (PCI) has been a major discovery in cardiology in the last 40 years contributing, in particular, to the reduction of mortality associated to acute myocardial infarction (AMI). However, even in the era of drug-eluting stent (DES) implantation, a sizable proportion of patients who undergo PCI may develop late or very late post-implantation complications, that occur in the form of restenosis, neoatherosclerosis, and/or in-stent thrombosis. Such complications are clinically relevant since they can cause AMI and negatively impact on the outcome. The underlying pathophysiological mechanisms are complex but related to inhibition of neointimal proliferation by DES that, on the hand, reduces the rate of in-stent restenosis, but, on the other hand, causes dysfunctional vessel healing, persistent inflammation, platelet activation, and adverse immunological responses. Multiple approaches have been developed or are under evaluation to target DES-related complications including pharmacotherapy, procedure-related imaging methods, novel stent designs, and drug-delivery methods. The aim of this review is to provide an update on the latest preclinical, translational, and clinical pharmacotherapeutic developments in this setting that target novel cellular mechanisms and pathways that might contribute to neoatherosclerosis. Due to the importance of secondary prevention in the reduction of DES-associated complications, this review also provides a short overview of pharmacological agents that are established or currently being investigated in this regard.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:105-116
Borovac JA, D'Amario D, Vergallo R, Porto I, ... Niccoli G, Crea F
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:105-116 | PMID: 30285099
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Impact:
Abstract

Adherence to dabigatran etexilate in atrial fibrillation patients intended to undergo electrical cardioversion.

Comuth WJ, de Maat MPM, van de Kerkhof D, Malczynski J, ... Kristensen SD, Münster AB
Aims
Effective anticoagulation in patients undergoing electrical cardioversion (ECV) for symptomatic atrial fibrillation is important to prevent adverse events. High medication adherence is a requirement. In patients with newly diagnosed atrial fibrillation (n = 169) who were intended to undergo ECV, the aim of this study was to measure self-reported short- and long-term adherence, evaluate whether dabigatran plasma concentrations reflect adherence, measure treatment satisfaction and assess whether adherence and treatment satisfaction are correlated.
Methods and results
Plasma concentrations (liquid-chromatography tandem mass spectrometry), the 8-point Morisky Medication Adherence Scale (MMAS-8) and the Anti-Clot Treatment Scale (ACTS) were measured after 3 weeks and 7 weeks of treatment. Combined mean peak (1-3 h after intake) and trough (10-16 h after intake) plasma concentrations were 175 (SD 109) ng/mL and 75 (SD 45) ng/mL, respectively. There was no relationship between short-term adherence (last 3 days) or long-term adherence (last 3-4 weeks) and plasma concentrations, unless the last intake was more than 48 h ago. After 7 weeks high, moderate, and low adherence, according to the MMAS-8, was seen in 74%, 21%, and 5% of patients, respectively. Treatment satisfaction was high (median ACTS score 68.5, range 46-75 points). Treatment satisfaction and adherence were not correlated.
Conclusion
The percentage of patients in the high adherence group (74%) was lower than expected, which is a matter of concern. Dabigatran plasma concentrations could not detect short- or long-term non-adherence, unless the drug was last taken more than 48 h ago. Treatment satisfaction did not correlate with adherence.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:91-99
Comuth WJ, de Maat MPM, van de Kerkhof D, Malczynski J, ... Kristensen SD, Münster AB
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:91-99 | PMID: 30608563
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Impact:
Abstract

Comparative safety and effectiveness of dabigatran vs. rivaroxaban and apixaban in patients with non-valvular atrial fibrillation: a retrospective study from a large healthcare system.

Villines TC, Ahmad A, Petrini M, Tang W, ... Oh K, Schwartzman E
Aims
We used the US Department of Defense Military Health System database to compare the safety and effectiveness of direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation (NVAF) initiating dabigatran vs. rivaroxaban or apixaban.
Methods and results
Two cohorts of adults with NVAF, newly initiated on standard-dose DOAC, were identified based on clinical approval dates: July 2011-June 2016 for dabigatran (150 mg b.i.d.) or rivaroxaban (20 mg QD) and January 2013-June 2016 for dabigatran (150 mg b.i.d.) or apixaban (5 mg b.i.d.). Propensity score matching (1:1) identified two well-balanced cohorts (dabigatran vs. rivaroxaban n = 12 763 per treatment group; dabigatran vs. apixaban n = 4802 per treatment group). In both cohorts, baseline characteristics and follow-up duration were similar between treatment groups. Patients newly initiating dabigatran had significantly lower risk of major bleeding vs. rivaroxaban [2.08% vs. 2.53%; hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.70-0.97; P = 0.018], while stroke risk was similar (0.60% vs. 0.78%; HR 0.77, 95% CI 0.57-1.04; P = 0.084). The dabigatran vs. apixaban cohort analysis found no differences in risk of major bleeding (1.60% vs. 1.21%; HR 1.37, 95% CI 0.97-1.94; P = 0.070) or stroke (0.44% vs. 0.35%; HR 1.26, 95% CI 0.66-2.39; P = 0.489).
Conclusion
Among NVAF patients newly initiated on standard-dose DOAC therapy in this study, dabigatran was associated with significantly lower major bleeding risk vs. rivaroxaban, and no significant difference in stroke risk. For dabigatran vs. apixaban, the reduced sample size limited the ability to draw definitive conclusions.

© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:80-90
Villines TC, Ahmad A, Petrini M, Tang W, ... Oh K, Schwartzman E
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:80-90 | PMID: 30500885
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Impact:
Abstract

Effect of oral β-blocker treatment on mortality in contemporary post-myocardial infarction patients: a systematic review and meta-analysis.

Dahl Aarvik M, Sandven I, Dondo TB, Gale CP, ... Atar D, Otterstad JE
Aims
Guidelines concerning β-blocker treatment following acute myocardial infarction (AMI) are based on studies undertaken before the implementation of reperfusion and secondary prevention therapies. We aimed to estimate the effect of oral β-blockers on mortality in contemporary post-AMI patients with low prevalence of heart failure and/or reduced left ventricular ejection fraction.
Methods and results
A random effects model was used to synthetize results of 16 observational studies published between 1 January 2000 and 30 October 2017. Publication bias was evaluated, and heterogeneity between studies examined by subgroup and random effects meta-regression analyses considering patient-related and study-level variables. The pooled estimate showed that β-blocker treatment [among 164 408 (86.8%) patients, with median follow-up time of 2.7 years] was associated with a 26% reduction in all-cause mortality [rate ratio (RR) 0.74, 95% confidence interval (CI) 0.64-0.85] with moderate heterogeneity (I2 = 67.4%). The patient-level variable mean age of the cohort explained 31.5% of between study heterogeneity. There was presence of publication bias, or small study effect, and when controlling for bias by the trim and fill simulation method, the effect disappeared (adjusted RR 0.90, 95% CI 0.77-1.04). Also, small study effect was demonstrated by a cumulative meta-analysis starting with the largest study showing no effect, with increasing effect as the smaller studies were accumulated.
Conclusion
Evidence from this study suggests that there is no association between β-blockers and all-cause mortality. A possible beneficial effect in AMI survivors needs to be tested by large randomized clinical trials.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:12-20
Dahl Aarvik M, Sandven I, Dondo TB, Gale CP, ... Atar D, Otterstad JE
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:12-20 | PMID: 30192930
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Impact:
Abstract

ESC Council on hypertension position document on the management of hypertensive emergencies.

van den Born BH, Lip GYH, Brguljan-Hitij J, Cremer A, ... Gosse P, Williams B

Hypertensive emergencies are those situations where very high blood pressure (BP) values are associated with acute organ damage, and therefore, require immediate, but careful, BP reduction. The type of acute organ damage is the principal determinant of: (i) the drug of choice, (ii) the target BP, and (iii) the timeframe in which BP should be lowered. Key target organs are the heart, retina, brain, kidneys, and large arteries. Patients who lack acute hypertension-mediated end organ damage do not have a hypertensive emergency and can usually be treated with oral BP-lowering agents and usually discharged after a brief period of observation.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:37-46
van den Born BH, Lip GYH, Brguljan-Hitij J, Cremer A, ... Gosse P, Williams B
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:37-46 | PMID: 30165588
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Impact:
Abstract

Effectiveness and safety of rivaroxaban vs. warfarin in non-valvular atrial fibrillation patients with a non-sex-related CHA2DS2-VASc score of 1.

Coleman CI, Turpie AGG, Bunz TJ, Eriksson D, Sood NA, Baker WL
Aims
To compare the effectiveness and safety of standard-dose rivaroxaban (20 mg o.d.) and warfarin in non-valvular atrial fibrillation (NVAF) patients with a non-sex-related CHA2DS2-VASc score of 1.
Methods and results
Analysis of United States Truven MarketScan claims from November 2011 to December 2016 for anticoagulant-naïve NVAF patients with a single non-sex-related stroke risk factor assigned 1-point in the CHA2DS2-VASc score and ≥12-months of continuous medical/prescription insurance coverage prior to the qualifying oral anticoagulant dispensing. Standard-dose rivaroxaban users were 1:1 propensity score-matched to warfarin users. Patients were followed until outcome occurrence, insurance disenrollment, or end of data availability. Primary outcomes included stroke or systemic embolism and major bleeding and were compared using Cox regression and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). In all, 3319 rivaroxaban users were 1:1 propensity score-matched to 3319 warfarin users. Median (interquartile range) duration of follow-up was 1.6 (0.7, 2) years and the most common qualifying stroke risk factor was hypertension (n = 4532, 68.3%). Rivaroxaban was associated with a significant reduction in the 1-year stroke or systemic embolism vs. warfarin (HR 0.41, 95% CI 0.17-0.98), with no significant difference in overall major bleeding (HR 0.74, 95% CI 0.44-1.26) or major bleeding subtypes (HR ranging from 0.33 to 0.78, P > 0.05 for all). Similar results were seen after extending follow-up to 2 years.
Conclusions
Rivaroxaban may lower the rate of stroke or systemic embolism vs. warfarin in NVAF patients with a non-sex-related CHA2DS2-VASc score of 1 without impacting major bleeding.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:64-69
Coleman CI, Turpie AGG, Bunz TJ, Eriksson D, Sood NA, Baker WL
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:64-69 | PMID: 30020424
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Impact:
Abstract

Heart rate, beta-blocker use, and outcomes of heart failure with reduced ejection fraction.

Ibrahim NE, Gaggin HK, Turchin A, Patel HK, ... Cannon CP, Januzzi JL
Aims
High resting heart rate (HR ≥70 b.p.m.) is associated with worse clinical outcomes in heart failure with reduced ejection fraction (HFrEF). Heart rate, guideline-directed medical therapy (GDMT) with beta-blocker (BB), and cardiovascular outcomes were evaluated in a large integrated health network.
Methods and results
Using electronic health records we examined patients with chronic HFrEF (ejection fraction ≤35%) in sinus rhythm with at least 1 year of follow-up and available serial HR and medication data between 1 January 2000 and 31 December 2014. Among 6071 patients followed for median of 1330 days across 73 586 total visits, median HR remained stable over time with 61.2% of the follow-up period with HR  ≥70 b.p.m. At baseline, 27.9% of patients were on ≥ 50% GDMT target BB dose, 16.2% subjects at baseline, and 19.4% at the end of follow-up had HR ≥70 b.p.m. despite receiving ≥50% of target BB dose. In adjusted analyses, baseline HR was associated with all-cause mortality/heart failure (HF) hospitalization (hazard ratio 1.28 per 15 b.p.m. Heart rate increase; P < 0.001). In comparison, hazard ratio for BB dose was 0.97 (per 77.2 mg increase; P = 0.36). When evaluating patients based on HR and BB dose there was a significant difference in the cumulative hazard for all-cause mortality or HF hospitalization (P < 0.001). For HF hospitalization, hazard appeared to be more closely associated with HR rather than BB dose (P = 0.01).
Conclusion
In a real-world analysis, high resting HR was common in HFrEF patients and associated with adverse outcomes. Opportunities exist to improve GDMT and achieve HR control.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:3-11
Ibrahim NE, Gaggin HK, Turchin A, Patel HK, ... Cannon CP, Januzzi JL
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:3-11 | PMID: 29490032
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Impact:
Abstract

P2Y12 inhibitors in acute coronary syndrome patients with renal dysfunction: an analysis from the RENAMI and BleeMACS projects.

De Filippo O, D\'Ascenzo F, Raposeiras-Roubin S, Abu-Assi E, ... Rinaldi M, De Ferrari GM
Aims
Aim of the present study was to establish the safety and efficacy profile of prasugrel and ticagrelor in real-life acute coronary syndrome (ACS) patients with renal dysfunction.
Methods and results
All consecutive patients from RENAMI and BLEEMACS registries were stratified according to estimated glomerular filtration rate (eGFR) lower or greater than 60mL/min/1.73m2. Death and myocardial infarction (MI) were the primary efficacy endpoints. Major bleedings (MB), defined as Bleeding Academic Research Consortium bleeding types 3 to 5, constituted the safety endpoint.19255 patients were enrolled. Mean age was 63 ± 12; 14892 (77.3%) were males. 2490 (12.9%) patients had chronic kidney disease (CKD), defined as eGFR<60mL/min/1.73m2. Mean follow-up was 13±5 months. Mortality was significantly higher in CKD patients (9.4% vs 2.6%, p < 0.0001), as well as the incidence of reinfarction (5.8% vs 2.9%, p < 0.0001) and MB (5.7% vs 3%, p < 0.0001). At Cox multivariable analysis, potent P2Y12 inhibitors significantly reduced the mortality rate (HR 0.82, 95% CI 0.54-0.96, p = 0.006) and the risk of reinfarction (HR 0.53, 95% CI 0.30-0.95, p = 0.033) in CKD patients as compared to clopidogrel. The reduction of risk of re-infarction was confirmed in patients with preserved renal function. Potent P2Y12 inhibitors did not increase the risk of MB in CKD patients (HR 1.00, 95% CI 0.59-1.68, p = 0.985).
Conclusion
In ACS patients with CKD, prasugrel and ticagrelor are associated with lower risk of death and recurrent MI without increasing the risk of MB.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 11 Jan 2019; epub ahead of print
De Filippo O, D'Ascenzo F, Raposeiras-Roubin S, Abu-Assi E, ... Rinaldi M, De Ferrari GM
Eur Heart J Cardiovasc Pharmacother: 11 Jan 2019; epub ahead of print | PMID: 31511896
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Impact:
Abstract

Time to epinephrine and survival after paediatric out-of-hospital cardiac arrest.

Fukuda T, Kondo Y, Hayashida K, Sekiguchi H, Kukita I
Aims
Delay in administration of epinephrine is associated with decreased survival among children with in-hospital cardiac arrest with an initial non-shockable rhythm. Whether this association is applicable to paediatric out-of-hospital cardiac arrest (OHCA) population remains unknown. We aimed to determine whether time to epinephrine administration is associated with outcomes in paediatric OHCA.
Methods and results
This was a nation-wide population-based study of paediatric OHCA in Japan from 2005 to 2012 based on data from the All-Japan Utstein Registry. We included paediatric OHCA patients (aged between 1 and 17 years) who received at least one dose of epinephrine. The primary outcome was 30-day survival. A total of 225 patients were included in the final cohort. Among the 225 patients, 23 (10.2%) survived 30 days after OHCA. The median time from emergency call to first epinephrine administration was 26 min [interquartile range, 20-32; range, 9-128; mean (standard deviation), 28.7 (15.5) min]. Longer time to epinephrine administration was associated with decreased chance of survival: 50.0, 41.2, 13.0, 11.6, 3.9, and 3.1%, respectively, when time to epinephrine was treated as a categorical variable categorized into ≤10, 11-15, 16-20, 21-25, 26-30, or > 30 min (P for trend <0.0001), and adjusted odds ratio 0.90 (95% confidence interval 0.82-0.96, P = 0.0011) when time to epinephrine was treated as a linear and continuous variable in a multivariable logistic regression model. Similar trends were observed for prehospital return of spontaneous circulation (P = 0.0032) and neurologically favourable survival (P = 0.0014).
Conclusions
Among paediatric OHCA patients, delayed administration of epinephrine was associated with a decreased chance of favourable outcomes.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:144-151
Fukuda T, Kondo Y, Hayashida K, Sekiguchi H, Kukita I
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:144-151 | PMID: 29036580
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Impact:
Abstract

Hypertension and cardiac arrhythmias: executive summary of a consensus document from the European Heart Rhythm Association (EHRA) and ESC Council on Hypertension, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE).

Lip GYH, Coca A, Kahan T, Boriani G, ... En Chiang C, Williams B

Hypertension (HTN) is a common cardiovascular risk factor leading to heart failure (HF), coronary artery disease (CAD), stroke, peripheral artery disease and chronic renal failure. Hypertensive heart disease can manifest as many types of cardiac arrhythmias, most commonly being atrial fibrillation (AF). Both supraventricular and ventricular arrhythmias may occur in HTN patients, especially in those with left ventricular hypertrophy (LVH), CAD, or HF. In addition, high doses of thiazide diuretics commonly used to treat HTN, may result in electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia), contributing further to arrhythmias, while effective blood pressure control may prevent the development of the arrhythmias such as AF. In recognizing this close relationship between HTN and arrhythmias, the European Heart Rhythm Association (EHRA) and the European Society of Cardiology (ESC) Council on Hypertension convened a Task Force, with representation from the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE), with the remit of comprehensively reviewing the available evidence and publishing a joint consensus document on HTN and cardiac arrhythmias, and providing up-to-date consensus recommendations for use in clinical practice. The ultimate judgment on the care of a specific patient must be made by the healthcare provider and the patient in light of all individual factors presented. This is an executive summary of the full document co-published by EHRA in EP-Europace.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:235-250
Lip GYH, Coca A, Kahan T, Boriani G, ... En Chiang C, Williams B
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:235-250 | PMID: 28541499
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Impact:
Abstract

Baseline low-density lipoprotein cholesterol to predict the extent of cardiovascular benefit from lipid-lowering therapies: a review.

Navarese EP, Andreotti F, Raggi P, Kolodziejczak M, ... Gurbel PA, Brouwer MA

Lipid-lowering therapies have been shown to improve cardiovascular outcome in a wide range of patients. The current guidelines recommend a graded approach to reduction in low-density lipoprotein cholesterol (LDL-C) proportional to the patient\'s risk, with the goal of achieving either a certain magnitude of reduction or a specific threshold of final LDL-C. Recent findings from a meta-analysis of numerous randomized trials suggest that more attention should be given to the baseline LDL-C of an individual patient. In this review, we discuss how the baseline LDL-C level may provide a means to better understand the results of recent cardiovascular outcome trials and the expected benefits of lipid-lowering therapies. The exact quantification of the clinical benefit associate with an intensified lipid-lowering therapy depends on the baseline LDL-C. Mortality is reduced in a log-linear fashion only when LDL-C > 100 mg/dL.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:47-54
Navarese EP, Andreotti F, Raggi P, Kolodziejczak M, ... Gurbel PA, Brouwer MA
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:47-54 | PMID: 30247574
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Impact:
Abstract

Outcomes associated with non-recommended dosing of rivaroxaban: results from the XANTUS study.

Amarenco P, Haas S, Hess S, Kirchhof P, ... Turpie AGG, Camm AJ
Aims
In Europe, the approved rivaroxaban dose for stroke prevention in patients with atrial fibrillation (AF) is 20 mg once daily (o.d.), with 15 mg o.d. recommended in patients with creatinine clearance (CrCl) 15-49 mL/min. Non-recommended doses are prescribed in real-world practice. This analysis of the XANTUS study assessed outcomes associated with non-recommended dosing and patient characteristics that may have impacted dose choice.
Methods and results
Baseline characteristics and 1 year outcomes were compared in 4464/6784 patients with known CrCl, receiving recommended or non-recommended rivaroxaban doses; 3608 (80.8%) patients received recommended doses (mean CHADS2 score 1.9) and 856 (19.2%) non-recommended doses (mean CHADS2 score 2.5). Incidence rate (events/100 patient-years) for the composite of treatment-emergent adjudicated major bleeding, stroke/systemic embolism, and death was 7.5 [95% confidence interval (CI) 5.7-9.8] and 4.8 (95% CI 4.1-5.7) with non-recommended and recommended doses, respectively [hazard ratio (HR) 1.55, 95% CI 1.2-2.1; P = 0.004]. Incidence rates for the components of the composite were 3.7 and 2.6, 1.4 and 0.9, and 3.5 and 1.9, respectively. Adjustment for baseline characteristics showed similar rates of the composite outcome (HR 1.06, 95% CI 0.77-1.45; P = 0.719). Multivariable analysis identified age, anaemia, congestive heart failure, diabetes mellitus, CrCl, lower body weight, AF type, and vascular disease as predictors of non-recommended dosing.
Conclusion
Non-recommended rivaroxaban dosing was associated with less favourable outcomes, possibly due to baseline characteristics, in addition to renal function, that may also affect physicians\' dosing decisions.
Trial registration number
Clinicaltrials.gov: NCT01606995.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:70-79
Amarenco P, Haas S, Hess S, Kirchhof P, ... Turpie AGG, Camm AJ
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:70-79 | PMID: 30423165
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Impact:
Abstract

A randomized, double-blind, placebo-controlled trial assessing the efficacy of S66913 in patients with paroxysmal atrial fibrillation.

Camm AJ, Dorian P, Hohnloser SH, Kowey PR, ... de Melis M, Sanders P
Aims
Antiarrhythmic drugs (AADs) for the treatment of atrial fibrillation (AF) are associated with limited efficacy and adverse effects. Inhibition of the atrial current IKur, absent from the ventricle, is expected to be antiarrhythmic, without adverse cardiac effects, particularly ventricular pro-arrhythmic effects.
Methods and results
A randomized clinical trial in symptomatic paroxysmal AF patients being considered for ablation. The primary endpoint was AF burden (AFB) as measured by insertable continuous monitoring (ICM) devices. Screened patients had an ICM implanted and were included if AFB was between 1% and 70% after 4 weeks of recording. They were randomly allocated to 4-week treatment of a selective IKur inhibitor S66913 (5 mg, 25 mg, or 100 mg orally per day) or placebo. The study was to enroll 160 patients. The study was terminated prematurely, due to non-study related preclinical safety concerns, after 58 patients had been enrolled. The median AFB ranged from 4.3% to 10.3% at baseline in the four treatment groups. S66913 had no significant effect on AFB or on AFB plus atrial tachycardia (AT) burden, at any dosage; nor on any secondary endpoints including the number and duration of AT or AF episodes, and symptoms. The drug was well tolerated with no safety concern during the treatment or the extended clinical follow-up.
Conclusions
DIAGRAF-IKUR was the first study to show that using ICM to assess the effect of an AAD is feasible. The selective IKur inhibitor S66913 was safe but had no clinically meaningful effect at the time of early termination of the study.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:21-28
Camm AJ, Dorian P, Hohnloser SH, Kowey PR, ... de Melis M, Sanders P
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2018; 5:21-28 | PMID: 30052825
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Impact:
Abstract

Smoking and Outcomes Following Guided De-escalation of Antiplatelet Treatment in Acute Coronary Syndrome Patients: A Substudy from the Randomized TROPICAL-ACS Trial.

Orban M, Trenk D, Geisler T, Rieber J, ... Hein R,
Aims
Prior analyses disclosed variations in antiplatelet drug response and clinical outcomes between smokers and non-smokers, thus the safety and efficacy of any dual antiplatelet therapy (DAPT) de-escalation strategy may differ in relation to smoking status. Hence, we assessed the impact of smoking on clinical outcomes and ADP-induced platelet aggregation following guided de-escalation of DAPT in invasively managed ACS patients.
Methods and results
The multicenter TROPICAL-ACS trial randomized 2610 biomarker-positive ACS patients 1:1 to standard treatment with prasugrel for 12 months (control group) or a platelet function testing guided de-escalation of DAPT. Current smokers (n = 1182) showed comparable event rates between study groups (6.6% vs. 6.6%; HR 1.0, 95% CI 0.64-1.56, P > 0.99). In non-smokers (n = 1428) a guided DAPT de-escalation was associated with a lower 1-year incidence of the primary endpoint (cardiovascular death, myocardial infarction, stroke, or bleeding ≥ grade 2 according to BARC criteria) compared to control group patients (7.9% vs. 11.0%; HR 0.71, 95% CI 0.50-0.99, P = 0.048). This reduction was mainly driven by a lower rate of BARC ≥ grade 2 bleedings (5.2% vs. 7.7%; HR 0.68, 95% CI 0.45-1.03, P = 0.066). There was no significant interaction of smoking status with treatment effects of guided DAPT de-escalation (Pint=0.23). ADP-induced platelet aggregation values were higher in current smokers (median 28U, IQR [20-40]) vs. non-smoker (median 24U [16-25], P < 0.0001) in the control group as well as in current smokers (median 42U, IQR [27-68] vs. non-smoker (median 37U, IQR [25-55], P < 0.001) in the monitoring group.
Conclusions
Guided DAPT de-escalation appears to be equally safe and effective in smokers and non-smokers. Regardless of smoking status and especially for those patients deemed unsuitable for one year of potent platelet inhibition this DAPT strategy might be used as an alternative antiplatelet treatment regimen.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 18 Dec 2019; epub ahead of print
Orban M, Trenk D, Geisler T, Rieber J, ... Hein R,
Eur Heart J Cardiovasc Pharmacother: 18 Dec 2019; epub ahead of print | PMID: 31855244
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Impact:
Abstract

Non-Vitamin K Antagonist Oral Anticoagulants and Warfarin in Atrial Fibrillation Patients with Concomitant Peripheral Artery Disease.

Lee HF, See LC, Li PR, Liu JR, ... Chan YH, Lip GYH
Aims
To investigate the effectiveness, safety, and outcomes of lower limb events for non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin among atrial fibrillation (AF) patients with concomitant peripheral artery disease (PAD).
Methods
In this nationwide retrospective cohort study collected from Taiwan National Health Insurance Research Database, a total of 5,768 and 2,034 consecutive AF patients with PAD patients taking NOACs or warfarin were identified from June 1, 2012, to December 31, 2017, respectively. We used propensity-score stabilized weighting to balance covariates across study groups.
Results
In the cohort, there were 89% patients taking low-dose NOAC (dabigatran 110mg twice daily, rivaroxaban 10-15mg daily, apixaban 2.5mg twice daily, or edoxaban 30mg daily). NOAC was associated with a comparable risk of ischemic stroke, and a lower risk of acute myocardial infarction (AMI) (hazard ratio [HR]:0.61; 95% confidence interval CI:[0.42-0.87]; P=0.007), lower extremity thromboembolism (HR:0.56; 95%CI:[0.44-0.72]; P<0.0001), revascularization procedure (HR:0.58; 95%CI:[0.47-0.72]; P<0.0001), lower limb amputation (HR:0.32; 95%CI:[0.23-0.46]; P<0.0001), and all major bleeding (HR:0.64; 95%CI:[0.50-0.80]; P=0.0001) than warfarin after weighting. The advantage of NOACs over warfarin persisted in high risk subgroups including patients of ≥ 75 years of age, diabetes, renal impairment, or use of concomitant antiplatelet agent.
Conclusions
This population-based study indicated that NOACs were associated with a comparable risk of ischemic stroke, and a significantly lower risk of major adverse limb events and major bleeding than warfarin among AF patients with concomitant PAD. Therefore, thromboprophylaxis with NOACs may be considered for such patients.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 27 Nov 2019; epub ahead of print
Lee HF, See LC, Li PR, Liu JR, ... Chan YH, Lip GYH
Eur Heart J Cardiovasc Pharmacother: 27 Nov 2019; epub ahead of print | PMID: 31778146
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Impact:
Abstract

Plaque imaging to refine indications for emerging lipid-lowering drugs.

Alkhalil M, Chai JT, Choudhury RP

Statins have been effective in reducing adverse cardiovascular events. Their benefits have been proportional to the level of plasma LDL-cholesterol reduction and seem to extend to patients with \'normal\' levels of cholesterol at outset. Statins are also inexpensive and have a favourable side-effect profile. As a result, they are used widely (almost indiscriminately) in patients with atherosclerotic vascular disease, and in those at risk of disease. Next generation lipid-modifying drugs seem unlikely to offer the same simplicity of application. The recent trials of new classes of lipid modifying drugs underline the need for a risk stratification tool which is not based on patients\' category of diagnosis (for example, post-myocardial infarction) but based on the characterization of disease in that individual patient. Mechanistic staging, a process that matches the target of the drug action with an identifiable disease characteristic, may offer an opportunity to achieve more precise intervention. The upshots of this targeted approach will be greater efficacy, requiring smaller clinical trials to demonstrate effectiveness; a reduced number needed to treat to yield benefits and more cost-effective prescribing. This will be important, as purchasers require ever more rigorous demonstration of both efficacy and cost-effectiveness. In this context, we will discuss available pharmacological strategies of lipid reduction in anti-atherosclerotic treatment and how plaque imaging techniques may provide an ideal method in stratifying patients for new lipid-modifying drugs.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 30 Dec 2016; 3:58-67
Alkhalil M, Chai JT, Choudhury RP
Eur Heart J Cardiovasc Pharmacother: 30 Dec 2016; 3:58-67 | PMID: 27816944
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Impact:
Abstract

Non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and valvular heart disease: systematic review and meta-analysis.

Caldeira D, David C, Costa J, Ferreira JJ, Pinto FJ

The non-vitamin K antagonist oral anticoagulants (NOACs) were approved for non-valvular atrial fibrillation (AF) but this term may be misnomer. Thus, the term non-mechanical and rheumatic mitral valvular (non-MARM) AF was proposed to exclude patients with valvular heart disease (VHD) without contraindications for NOACs. We aimed to review the efficacy and safety of NOACs in patients with AF and VHD compared to Vitamin K Antagonists (VKA). We performed a systematic review with meta-analysis (PROSPERO CRD42015024837) including data from randomized controlled trials (RCTs) retrieved in November 2016. The efficacy and safety data were pooled using random-effects meta-analyses using the hazard ratio (HR) with the 95% confidence interval (95%CI). Trial sequential analysis (TSA) was performed in statistical significant results to evaluate whether cumulative sample size was powered for the obtained effect. In 5 RCTs (with 12 653 VHD AF patients), NOACs significantly reduced the risk of stroke and systemic embolism (HR 0.73, 95%CI:0.60-0.90; TSA showed estimate was robust - O\'Brien-Fleming α-spending boundary crossed before reaching the estimated information size) and intracranial hemorrhage (HR 0.45, 95%CI:0.24-0.87) compared with VKA. Major bleeding risk was not significantly different. In patients with bioprosthesis (3 trials-280 patients) the risks of thromboembolism (HR 0.65, 95%CI:0.20-2.08) and major bleeding (HR 0.94, 95%CI:0.28-3.18) with NOACs were similar to VKA. NOACs are efficacious and safe in patients with non-MARM VHD AF, showing significant reduction in the risk of stroke and systemic embolism and intracranial hemorrage compared with VKA.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:111-118
Caldeira D, David C, Costa J, Ferreira JJ, Pinto FJ
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:111-118 | PMID: 28950374
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Impact:
Abstract

Adherence to dual antiplatelet therapy with ticagrelor in patients with acute coronary syndromes treated with percutaneous coronary intervention in real life. Results of the REAL-TICA registry.

Zeymer U, Cully M, Hochadel M
Aims
Little is known about the adherence to dual antiplatelet therapy with ticagrelor and reasons for discontinuation in real life. Therefore, we evaluated the 12-month course of patients with acute coronary syndromes (ACS) treated with percutaneous coronary intervention (PCI) and ticagrelor during the acute phase.
Methods and results
A total of 614 patients included into the prospective ALKK-PCI Registry between 2014 and 2015 surviving for at least 12 months after discharge provided informations about duration of ticagrelor therapy. In total, 133 patients (21.7%) discontinued ticagrelor prematurely: nine patients before discharge and 124 (20.2%) at a mean 131 days after PCI. Independent baseline predictors for early discontinuation were age >75 years, atrial fibrillation, and prior stroke. Side effects such as dypnoea or bradycardias and bleeding leading to a premature discontinuation of ticagrelor were reported in less than 3% and less than 2% of the total patient population, respectively. In 50% of patients, there was no replacement with another platelet inhibitor after early discontinuation of ticagrelor, while in 28.2% it was replaced by clopidogrel. Bleeding events were observed more often (10.4% vs. 2.7%, P < 0.001) and coronary artery bypass grafting (CABG) (5.3% vs. 0, 4%, P < 0.001) was performed more often in patients with early discontinuation.
Conclusion
In this real-life experience of ticagrelor in patients with ACS 22% of patients discontinued ticagrelor early. Side effects were the cause for discontinuation in only 3%, while age >75 years, prior stroke, atrial fibrillation, CABG, and bleeding during follow-up were associated with premature discontinuation.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:205-210
Zeymer U, Cully M, Hochadel M
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:205-210 | PMID: 29878086
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Impact:
Abstract

Trends in optimal medical therapy prescription and mortality after admission for acute coronary syndrome: a 9-year experience in a real-world setting.

Hoedemaker NPG, Damman P, Ottervanger JP, Dambrink JHE, ... de Winter RJ, van \'t Hof AWJ
Aims
Optimal medical therapy (OMT) is recommended in acute coronary syndrome (ACS) patients. Few studies present temporal trends of OMT prescription and its impact on outcomes in a real-world setting. We aimed to evaluate OMT prescription in a real-world ACS population and its relation to mortality during almost a decade.
Methods and results
Consecutive ST-elevation myocardial infarction and non-ST-elevation myocardial infarction (NSTEMI) patients (n = 9202) admitted to a single Dutch tertiary hospital between 2006 and 2014 were included and followed for drug prescription and mortality up to 1 year. Optimal medical therapy was defined as prescription of aspirin, P2Y12inhibitors, statin, beta-blockers, and angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB). Optimal medical therapy prescription was 43.7% at discharge, 46.6% at 30-days, and 25.5% at 1-year. Optimal medical therapy prescription at discharge was lower among NSTEMI patients (34.5% vs. 49.2%, P < 0.001). Optimal medical therapy prescription at discharge, 30-days and 1-year and mortality outcomes did not change during the study period. After adjustment for baseline and admission characteristics, OMT at discharge was associated with a reduction in mortality in patients who survived hospitalization for the index event [adjusted hazard ratio: 0.66, 95% confidence interval (0.46-0.93)].
Conclusions
In this single-centre observational registry with >9000 patients reflecting almost a decade of ACS care, <50% of patients were on OMT at discharge. Prescription of OMT and mortality outcomes remained stable during the study period. After adjustment, OMT prescription at discharge was associated with reduced mortality in ACS survivors. Further contemporary randomized studies are warranted to determine the role of beta-blockers and ACEi/ARBs in ACS patients with preserved left ventricular ejection fraction.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:102-110
Hoedemaker NPG, Damman P, Ottervanger JP, Dambrink JHE, ... de Winter RJ, van 't Hof AWJ
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:102-110 | PMID: 29394340
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Impact:
Abstract

Rationale and Design of the Effectiveness of LowEr maintenanCe dose of TicagRelor early After myocardial infarction (ELECTRA) pilot study.

Kubica J, Adamski P, Buszko K, Kubica A, ... Paciorek P, Navarese EP
Aims
The degree and time course of platelet inhibition using ticagrelor can vary during the acute phase and the following stable period after acute myocardial infarction (AMI). The optimal level of platelet inhibition during the various stages of AMI remains an open question. The aim of the current study is to compare the antiplatelet efficacy of two ticagrelor maintenance dose regimens (60 mg b.i.d. vs. 90 mg b.i.d.) in stable patients following an initial strategy with ticagrelor 90 mg b.i.d. during the first month after AMI.
Methods and results
The Effectiveness of LowEr maintenanCe dose of TicagRelor early After myocardial infarction (ELECTRA) pilot study is a phase III, single-centre, randomized, open-label, pharmacokinetic/pharmacodynamic trial. The study population will include 50 patients with AMI treated with percutaneous coronary intervention. At Day 30 post-AMI, all trial participants will be randomly assigned in 1:1 ratio to receive either reduced (60 mg b.i.d.) or standard (90 mg b.i.d.) maintenance ticagrelor dose until Day 45 post-AMI. Platelet function testing in each patient will be performed using up to two different methods (the VASP assay and multiple electrode aggregometry). Pharmacokinetics of ticagrelor and its active metabolite (AR-C124910XX) will be assessed by liquid chromatography mass spectrometry.
Conclusion
A de-escalation strategy with reduced dose of ticagrelor (60 mg b.i.d.) following an initial standard dose (90 mg b.i.d.) during the first month after AMI may provide equally effective platelet inhibition as compared to maintenance with the standard ticagrelor dose.
Clinicaltrials. gov identifier
NCT03251859.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:152-157
Kubica J, Adamski P, Buszko K, Kubica A, ... Paciorek P, Navarese EP
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:152-157 | PMID: 29040445
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Impact:
Abstract

Temporal trends in acute myocardial infarction presentation and association with use of cardioprotective drugs: a nationwide registry-based study.

Smedegaard L, Charlot MG, Gislason GH, Hansen PR
Aim
The present study aimed to investigate temporal trends in myocardial infarction (MI) presentation with or without ST-segment elevation and the association with the use of cardioprotective drugs prior to admission.
Methods and results
Using individual-level linkage of data from Danish nationwide registries, we identified all patients 30 years or older admitted with a first-time MI in the period 2003-2012, and their use of cardioprotective drugs 6 months prior to admission. We calculated incidence rates per 100 000 person-years (IRs) of ST-segment elevation MI (STEMI) and non-STEMI (NSTEMI). We identified 22 247 patients admitted with STEMI and 50 403 with NSTEMI. IRs for NSTEMI decreased by 35% from 194 in 2003 to 126 in 2012, whereas IRs for STEMI peaked in 2007 and subsequently declined from 71 to 65. Preadmission use of cardioprotective drugs increased in both groups from 2003 to 2012. Patients admitted with STEMI had odds ratio (OR) 0.64 [95% confidence interval (CI) 0.61-0.67] for preadmission use of aspirin compared with patients admitted with NSTEMI. Corresponding ORs were 0.82 (CI 0.78-0.87) for statins, 0.87 (CI 0.82-0.91) for beta-blockers, 0.89 (CI 0.85-0.92) for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 0.52 (CI 0.44-0.61) for thienopyridines. Also, 30-day and 1-year mortality declined in patients both admitted with STEMI and NSTEMI.
Conclusion
The IRs of MI declined between 2003 and 2012, primarily driven by a 35% reduction in IRs for NSTEMI whereas IRs for STEMI declined after 2007. Preadmission use of cardioprotective drugs increased markedly and was associated with lower ORs of presenting with STEMI than NSTEMI.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:93-101
Smedegaard L, Charlot MG, Gislason GH, Hansen PR
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:93-101 | PMID: 28510644
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Impact:
Abstract

Comparative effectiveness of enalapril, lisinopril, and ramipril in the treatment of patients with chronic heart failure: a propensity score-matched cohort study.

Fröhlich H, Henning F, Täger T, Schellberg D, ... Frankenstein L, Clark AL
Aims
Angiotensin-converting enzyme inhibitors (ACEIs) are recommended as first-line therapy in patients with heart failure with reduced ejection fraction (HFrEF). The comparative effectiveness of different ACEIs is not known.
Methods and results
A total of 4723 outpatients with stable HFrEF prescribed enalapril, lisinopril, or ramipril were identified from three registries in Norway, England, and Germany. In three separate matching procedures, patients were individually matched with respect to both dose equivalents and their respective propensity scores for ACEI treatment. During a follow-up of 21 939 patient-years, 360 (49.5%), 337 (52.4%), and 1119 (33.4%) patients died among those prescribed enalapril, lisinopril, and ramipril, respectively. In univariable analysis of the general sample, enalapril and lisinopril were both associated with higher mortality when compared with ramipril treatment [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.30-1.65, P < 0.001 and HR 1.38, 95% CI 1.22-1.56, P < 0.001, respectively). Patients prescribed enalapril or lisinopril had similar mortality (HR 1.06, 95% CI 0.92-1.24, P = 0.41). However, there was no significant association between ACEI choice and all-cause mortality in any of the matched samples (HR 1.07, 95% CI 0.91-1.25, P = 0.40; HR 1.12, 95% CI 0.96-1.32, P = 0.16; and HR 1.10, 95% CI 0.93-1.31, P = 0.25 for enalapril vs. ramipril, lisinopril vs. ramipril, and enalapril vs. lisinopril, respectively). Results were confirmed in subgroup analyses with respect to age, sex, left ventricular ejection fraction, New York Class Association functional class, cause of HFrEF, rhythm, and systolic blood pressure.
Conclusion
Our results suggest that enalapril, lisinopril, and ramipril are equally effective in the treatment of patients with HFrEF when given at equivalent doses.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:82-92
Fröhlich H, Henning F, Täger T, Schellberg D, ... Frankenstein L, Clark AL
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:82-92 | PMID: 28475676
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Impact:
Abstract

Coronary artery disease severity and long-term cardiovascular risk in patients with myocardial infarction: a Danish nationwide register-based cohort study.

Özcan C, Deleskog A, Schjerning Olsen AM, Nordahl Christensen H, Lock Hansen M, Hilmar Gislason G
Aim
Long-term prognostic impact of coronary artery disease (CAD) severity in stable post-myocardial infarction (MI) patients is not well known. We examined the impact of CAD severity and co-morbidity on the long-term (1 year and beyond) risk of cardiovascular events post-MI.
Methods and results
From nationwide administrative and clinical registers, we identified 55 747 MI patients, during 2004-2010, who had not experienced subsequent MI, stroke, or death within 7 days post-discharge. The risk for primary composite endpoint (MI, stroke, or cardiovascular death) was estimated for the first 365 days after MI (index MI) and from day 366 to study completion (stable post-MI population), corresponding to a mean follow-up of 3.6 (2.2) years. Risk was assessed using cumulative incidence, multivariable adjusted logistic regression and Cox proportional-hazards models. The 1-year cumulative incidence for primary endpoint was 20.0% [95% confidence interval (CI), (19.6-20.3)]. Correspondingly, the 4-year cumulative incidence for primary endpoint was 21.0% (95% CI, 20.6-21.4) in patients without events on the first year. In multivariable models with no significant stenosis as reference, CAD severity was the most important risk factor for cardiovascular events the first 365 days [left main stenosis (LMS): odds ratio and 95% CI, 4.37, 3.69-5.17; 3-vessel disease (VD), 4.18, 3.66-4.77; 2-VD, 3.23, 2.81-3.72; 1-VD, 2.12,-1.85-2.43] and remained from day 366 to study completion [LMS: hazard ratio and 95% CI, 1.91, 1.64-2.22; 3-VD, 1.85,1.65-2.07; 2-VD, 1.55, 1.38-1.74; 1-VD, 1.30, 1.16-1.45].
Conclusion
Despite contemporary treatment at baseline, stable post-MI patients\' 4-year outcome was similar to 1-year outcome after MI, and CAD severity remained a critical risk factor the first year and thereafter.

© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:25-35
Özcan C, Deleskog A, Schjerning Olsen AM, Nordahl Christensen H, Lock Hansen M, Hilmar Gislason G
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:25-35 | PMID: 28444162
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Impact:
Abstract

The relevance of depressive symptoms for the outcome of patients receiving vitamin K-antagonists: Results from the thrombEVAL cohort study.

Michal M, Eggebrecht L, Göbel S, Panova-Noeva M, ... Wild PS, Prochaska JH
Aims
Although depressive symptoms are highly prevalent in patients receiving oral anticoagulation (OAC), the relevance of depression for the outcome of anticoagulated individuals is unknown.
Methods and results
We analyzed data from the multi-center cohort study thrombEVAL (NCT01809015), investigating the efficacy of OAC with vitamin K-antagonists. There was an independent study monitoring, and an independent review panel assessed the endpoints. Out of n = 1,558 participants, information about depressive symptoms, as measured by the two-item screener PHQ-2, was available in n = 1,405 individuals. The mean follow-up period was 28.04 months, with a standard deviation of 11.52 months. In multivariable Cox regression analysis, baseline PHQ-2 sum score was a strong and robust predictor of clinically-relevant bleeding (hazard ratio (HR) 1.13, 95% confidence interval 1.03-1.24; p = 0.011) and all-cause mortality (HR 1.18, 1.08-1.28; p = 0.001) independent of age, sex, high school graduation, partnership, clinical profile, intake of SSRI, and quality of OAC therapy. Individuals with clinically significant depressive symptoms (PHQ-2 ≥3) had a 57% increased risk for clinically relevant bleeding (fully adjusted HR 1.57, 1.08-2.28) and 54% greater risk for death (fully adjusted HR 1.54, 1.09-2.17). There was no association of depressive symptoms with thromboembolic events. For hospitalization, individuals with depressive symptoms (PHQ-2 ≥3) did not experience an elevated risk in the fully adjusted model (HR 1.08, 0.86, 1.35; p = 0.52).
Conclusions
Assessment of depression by the PHQ-2 provided independent long-term prognostic information beyond common biomedical risk factors. These findings highlight the need for targeting depressive symptoms in the management of patients receiving OAC therapy.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 09 Jan 2020; epub ahead of print
Michal M, Eggebrecht L, Göbel S, Panova-Noeva M, ... Wild PS, Prochaska JH
Eur Heart J Cardiovasc Pharmacother: 09 Jan 2020; epub ahead of print | PMID: 31922545
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Impact:
Abstract

Non-steroidal anti-inflammatory drug use is associated with increased risk of out-of-hospital cardiac arrest: a nationwide case-time-control study.

Sondergaard KB, Weeke P, Wissenberg M, Schjerning Olsen AM, ... Gislason GH, Folke F
Aims
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and have been associated with increased cardiovascular risk. Nonetheless, it remains unknown whether use of NSAIDs is associated with out-of-hospital cardiac arrest (OHCA).
Methods and results
From the nationwide Danish Cardiac Arrest Registry, all persons with OHCA during 2001-10 were identified. NSAID use 30 days before OHCA was categorized as follows: diclofenac, naproxen, ibuprofen, rofecoxib, celecoxib, and other. Risk of OHCA associated with use of NSAIDs was analysed by conditional logistic regression in case-time-control models matching four controls on sex and age per case to account for variation in drug utilization over time. We identified 28 947 persons with OHCA of whom 3376 were treated with an NSAID up to 30 days before OHCA. Ibuprofen and diclofenac were the most commonly used NSAIDs and represented 51.0% and 21.8% of total NSAID use, respectively. Use of diclofenac (odds ratio [OR], 1.50 [95% confidence interval (CI) 1.23-1.82]) and ibuprofen [OR, 1.31 (95% CI 1.14-1.51)] was associated with a significantly increased risk of OHCA. Use of naproxen [OR, 1.29 (95% CI 0.77-2.16)], celecoxib [OR, 1.13 (95% CI 0.74-1.70)], and rofecoxib (OR, 1.28 [95% CI 0.74-1.70)] was not significantly associated with increased risk of OHCA; however, these groups were characterized by few events.
Conclusion
Use of non-selective NSAIDs was associated with an increased early risk of OHCA. The result was driven by an increased risk of OHCA in ibuprofen and diclofenac users.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions, please email: journals[email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:100-107
Sondergaard KB, Weeke P, Wissenberg M, Schjerning Olsen AM, ... Gislason GH, Folke F
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:100-107 | PMID: 28025218
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Impact:
Abstract

Peripartum management of hypertension. A position paper of the ESC Council on Hypertension and the European Society of Hypertension.

Cífková R, Johnson MR, Kahan T, Brguljan J, ... Regitz-Zagrosek V, de Simone G

Hypertensive disorders are the most common medical complications in the peripartum period associated with a substantial increase in morbidity and mortality. Hypertension in the peripartum period may be due to the continuation of pre-existing or gestational hypertension, de novo development of pre-eclampsia or it may be also induced by some drugs used for analgesia or suppression of postpartum haemorrhage. Women with severe hypertension and hypertensive emergencies are at high risk of life threatening complications, therefore, despite the lack of evidence-based data, based on expert opinion, antihypertensive treatment is recommended. Labetalol intravenously and metyldopa orally are then the two most frequently used drugs. Short-acting oral nifedipine is suggested to be used only if other drugs or iv access are not available. Induction of labour is associated with improved maternal outcome and should be advised for women with gestational hypertension or mild pre-eclampsia at 37 weeks᾽ gestation. This position paper provides the first interdisciplinary approach to the management of hypertension in the peripartum period based on the best available evidence and expert consensus.

© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2019. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 15 Dec 2019; epub ahead of print
Cífková R, Johnson MR, Kahan T, Brguljan J, ... Regitz-Zagrosek V, de Simone G
Eur Heart J Cardiovasc Pharmacother: 15 Dec 2019; epub ahead of print | PMID: 31841131
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Impact:
Abstract

Effect of rapid desensitization on platelet inhibition and basophil activation in patients with aspirin hypersensitivity and coronary disease.

Manzo-Silberman S, Nicaise-Roland P, Neukirch C, Tubach F, ... Ajzenberg N, Steg PG
Aims
To determine antiplatelet efficacy after desensitization in patients with a history of aspirin hypersensitivity.
Methods and results
We conducted a case-control study to evaluate the efficacy of aspirin 1 day (D1) and 6-8 weeks (W6-8) after desensitization. We also assessed ex vivo basophil reactivity to aspirin after desensitization. Cases were patients with coronary artery disease (CAD) and documented history of aspirin hypersensitivity who underwent rapid successful oral desensitization to aspirin. Controls were patients with stable CAD without hypersensitivity and receiving aspirin. Among 56 cases, 27 received aspirin for acute coronary syndromes and 29 were treated for stable CAD. Aspirin was effective (defined as light transmission aggregometry induced by arachidonic acid ≤20%) at D1 in 86% of cases (P = 0.045 vs. controls) and in 95% at W6-8, vs. 100% of controls (P = 0.39). Urinary excretion of thromboxane B2 diminished substantially in cases (P < 0.0001, D0 vs. W6-8) but remained higher than in controls (P = 0.03). Platelet reactivity (defined by platelet P-selectin expression, activated glycoprotein IIb/IIIa inhibitors, and platelet-monocyte aggregates) was similar in cases between D0 and D1 but decreased at W6-8. Basophil activation (quantified by upregulation of CD203c in response to aspirin) was higher in cases at W6-8 than in controls (P = 0.0002).
Conclusion
Thus, following rapid desensitization, aspirin achieves rapid biological efficacy, which is slightly lower at D1, but becomes indistinguishable from chronically treated patients at W6-8. Persistent basophil activation several weeks after desensitization suggests infraclinical hypersensitivity and the need to continue aspirin to maintain desensitization.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:77-81
Manzo-Silberman S, Nicaise-Roland P, Neukirch C, Tubach F, ... Ajzenberg N, Steg PG
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:77-81 | PMID: 27533953
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Impact:
Abstract

A nationwide registry study to compare bleeding rates in patients with atrial fibrillation being prescribed oral anticoagulants.

Halvorsen S, Ghanima W, Fride Tvete I, Hoxmark C, ... Solli O, Jonasson C
Aims
We aimed to evaluate bleeding risk in clinical practice in patients with atrial fibrillation (AF) being prescribed dabigatran, rivaroxaban, or apixaban compared with warfarin.
Methods
Using nationwide registries (Norwegian Patient Registry and Norwegian Prescription Database), we identified AF patients with a first prescription of oral anticoagulants between January 2013 and June 2015. Patients were followed until discontinuation or switching of oral anticoagulants, death, or end of follow-up. The primary endpoint was major or clinically relevant non-major (CRNM) bleeding.
Results
In total 32 675 AF patients were identified (58% men, median age 74 years): 11 427 patients used warfarin, 7925 dabigatran, 6817 rivaroxaban, and 6506 apixaban. After a median follow-up of 173 days (25th, 75th percentile 84, 340), 2081 (6.37%) patients experienced a first major or CRNM bleeding. Using a Cox proportional hazard model adjusting for baseline characteristics, use of apixaban [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.61-0.80, P < 0.001] and dabigatran (HR 0.74, 95% CI 0.66-0.84, P < 0.001) were associated with a lower risk of major or CRNM bleeding compared with warfarin whereas use of rivaroxaban was not (HR: 1.05, 95% CI 0.94-1.17, P = 0.400). Use of dabigatran and rivaroxaban were associated with higher risk of gastrointestinal bleeding, whereas use of apixaban and dabigatran were associated with lower risk of intracranial bleeding, compared with warfarin.
Conclusion
In this nationwide cohort study in AF patients, apixaban and dabigatran were associated with a lower risk of major or CRNM bleeding compared with warfarin. The risk of gastrointestinal bleeding was higher with rivaroxaban and dabigatran compared with warfarin.

© The Author 2016. Published on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 30 Dec 2016; 3:28-36
Halvorsen S, Ghanima W, Fride Tvete I, Hoxmark C, ... Solli O, Jonasson C
Eur Heart J Cardiovasc Pharmacother: 30 Dec 2016; 3:28-36 | PMID: 27680880
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Impact:
Abstract

The quality of warfarin therapy and CHA2DS2-VASc score associate with the incidence of myocardial infarction and cardiovascular outcome in patients with atrial fibrillation: data from the nationwide FinWAF Registry.

Raatikainen MJP, Penttilä T, Korhonen P, Mehtälä J, Lassila R, Lehto M
Aims
The impact of the quality of warfarin therapy on cardiovascular outcomes excluding stroke is largely unknown. The aims of this study were to evaluate the association between the warfarin control and the incidence and outcome of myocardial infarction (MI) and to validate the predictive value of the CHA2DS2-VASc score for MI in atrial fibrillation (AF) patients taking warfarin.
Methods and results
The nationwide FinWAF Registry consists of 54 568 AF patients (mean age 73.31 ± 10.7 years, 52% men) taking warfarin. The quality of warfarin therapy was assessed continuously by calculating the time in therapeutic range within a 60-day window using the Rosendaal method (TTR60). Adjusted Cox proportional hazards models were prepared for the incidence of MI and cardiovascular mortality in six different TTR60 categories. During the 3.2 ± 1.6 years of follow-up, the annual incidence of MI (95% confidence interval) was 3.3% (3.0-3.5%), 2.9% (2.6-3.3%), 2.4% (2.1-2.7%), 1.9% (1.7-2.2%), 1.7% (1.5-2.0%), and 1.2% (1.1-1.3%) among patients with TTR60 <40%, 40-50%, 50-60%, 60-70%, 70-80%, and >80%, respectively. Well-managed warfarin therapy (TTR60 > 80%) was associated also with a lower cardiovascular mortality, whereas a high CHA2DS2-VASc score correlated with poor outcome.
Conclusion
Cardiovascular outcome was superior among AF patients with good warfarin control and in those with a low CHA2DS2-VASc score. The inverse association between the TTR60 and incidence of MI and cardiovascular mortality indicate that in AF patients the quality of warfarin therapy is critical not only for prevention of stroke but also with regard to cardiovascular outcome.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:211-219
Raatikainen MJP, Penttilä T, Korhonen P, Mehtälä J, Lassila R, Lehto M
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:211-219 | PMID: 29514184
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Impact:
Abstract

Antithrombotic therapy after myocardial infarction in patients with atrial fibrillation undergoing percutaneous coronary intervention.

Batra G, Friberg L, Erlinge D, James S, ... Wallentin L, Oldgren J
Aims
Optimal antithrombotic therapy after percutaneous coronary intervention (PCI) in patients with myocardial infarction (MI) and atrial fibrillation is uncertain. In this study, we compared antithrombotic regimes with regard to a composite cardiovascular outcome of all-cause mortality, MI or ischaemic stroke, and major bleeds.
Methods and results
Patients between October 2005 and December 2012 were identified in Swedish registries, n = 7116. Landmark 0-90 and 91-365 days of outcome were evaluated with Cox-regressions, with dual antiplatelet therapy as reference. At discharge, 16.2% received triple therapy (aspirin, clopidogrel, and warfarin), 1.9% aspirin plus warfarin, 7.3% clopidogrel plus warfarin, and 60.8% dual antiplatelets. For cardiovascular outcome, adjusted hazard ratio with 95% confidence interval (HR) for triple therapy was 0.86 (0.70-1.07) for 0-90 days and 0.78 (0.58-1.05) for 91-365 days. A HR of 2.16 (1.48-3.13) and 1.61 (0.98-2.66) during 0-90 and 91-365 days, respectively, was observed for major bleeds. For aspirin plus warfarin, HR 0.82 (0.54-1.26) and 0.62 (0.48-0.79) was observed for cardiovascular outcome and 1.30 (0.60-2.85) and 1.01 (0.63-1.62) for major bleeds during 0-90 and 91-365 days, respectively. For clopidogrel plus warfarin, HR of 0.90 (0.68-1.19) and 0.68 (0.49-0.95) was observed for cardiovascular outcome and 1.28 (0.71-2.32) and 1.08 (0.57-2.04) for major bleeds during 0-90 and 91-365 days, respectively.
Conclusion
Compared to dual antiplatelets, aspirin or clopidogrel plus warfarin therapy was associated with similar 0-90 days and lower 91-365 days of risk of the cardiovascular outcome, without higher risk of major bleeds. Triple therapy was associated with non-significant lower risk of cardiovascular outcome and higher risk of major bleeds.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:36-45
Batra G, Friberg L, Erlinge D, James S, ... Wallentin L, Oldgren J
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:36-45 | PMID: 29126156
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Impact:
Abstract

Modelling the cost-effectiveness of PCSK9 inhibitors vs. ezetimibe through LDL-C reductions in a Norwegian setting.

Korman M, Wisløff T
Aims
Despite the success of statins, there remains unmet clinical need in cardiovascular disease (CVD) prevention. New proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce low-density lipoprotein cholesterol (LDL-C) by 55-65%. Two PCSK9 inhibitors, evolocumab, and alirocumab, were approved for use in Norway but not yet for reimbursement through public national insurance. We aim to explore the cost-effectiveness of these compared with available treatments in a Norwegian setting.
Methods and results
A state transition Markov model was developed to model the cost-effectiveness of PCSK9 inhibitors for prevention of coronary heart disease, ischaemic strokes, and death among high-risk patient subpopulations in Norway, in both primary and secondary settings. Evolocumab and alirocumab are compared against ezetimibe and standard treatment. Risk of CVD is based on population incidence rates and adjusted according to baseline risk factors. Preventative effect of treatment was modelled according to absolute reduction in LDL-C. PCSK9 inhibitors were never found to be cost-effective in primary prevention. In secondary prevention they were cost-effective only for older, high-risk patients. The lowest cost-effectiveness ratios were for heterozygous familial hypercholesterolaemia patients and high-risk diabetics, with €63 200 and €68 400 per quality-adjusted life-year, respectively.
Conclusion
High lifetime costs of PCSK9 inhibitors may not be offset by estimated health gains for most eligible patients. PCSK9 inhibitors are found in the model only to be cost-effective in secondary prevention for older patients with high absolute risk of CVD. This picture is likely to change as price decreases. Future research is needed to determine the long-term preventative effects of PCSK9 inhibitors.

© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:15-22
Korman M, Wisløff T
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:15-22 | PMID: 28444187
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Impact:
Abstract

Reasons for disparity in statin adherence rates between clinical trials and real-world observations: a review.

Vonbank A, Drexel H, Agewall S, Lewis BS, ... Baumgartner I, Tamargo J

With statins, the reported rate of adverse events differs widely between randomized clinical trials (RCTs) and observations in clinical practice, the rates being 1-2% in RCTs vs. 10-20% in the so-called real world. One possible explanation is the claim that RCTs mostly use a run-in period with a statin. This would exclude intolerant patients from remaining in the trial and therefore favour a bias towards lower rates of intolerance. We here review data from RCTs with more than 1000 participants with and without a run-in period, which were included in the Cholesterol Treatment Trialists Collaboration. Two major conclusions arise: (i) the majority of RCTs did not have a test dose of a statin in the run-in phase. (ii) A test dose in the run-in phase was not associated with a significantly improved adherence rate within that trial when compared to trials without a test dose. Taken together, the RCTs of statins reviewed here do not suggest a bias towards an artificially higher adherence rate because of a run-in period with a test dose of the statin. Other possible explanations for the apparent disparity between RCTs and real-world observations are also included in this review albeit mostly not supported by scientific data.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:230-236
Vonbank A, Drexel H, Agewall S, Lewis BS, ... Baumgartner I, Tamargo J
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:230-236 | PMID: 30099530
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Impact:
Abstract

Safety and effectiveness of rivaroxaban and apixaban in patients with venous thromboembolism: a nationwide study.

Sindet-Pedersen C, Staerk L, Pallisgaard JL, Gerds TA, ... Gislason GH, Olesen JB
Aims
To investigate the risk of all-cause mortality, recurrent venous thromboembolism (VTE), and hospitalized bleeding in patients with VTE treated with either rivaroxaban or apixaban.
Methods and results
Using Danish nationwide registries, patients with VTE treated with rivaroxaban or apixaban in the period from 1 January 2015 to 30 June 2017 were identified. Standardized absolute risks were estimated based on outcome-specific Cox regression models, adjusted for potential confounders. A total of 8187 patients were included in the study, of which 1504 (18%) were treated with apixaban [50% males, median age 70 years; interquartile range (IQR) 56-80] and 6683 (82%) were treated with rivaroxaban (55% males, median age 67 years; IQR 53-76). The 180 days risk of all-cause mortality was 5.08% [95% confidence interval (95% CI) 4.08% to 6.08%)] in the apixaban group and 4.60% (95% CI 4.13% to 5.18%) in the rivaroxaban group [absolute risk difference: -0.48% (95% CI -1.49% to 0.72%)]. The 180 days risk of recurrent VTE was 2.16% (95% CI 1.49% to 2.88%) in the apixaban group and 2.22% (95% CI 1.89% to 2.52%) in the rivaroxaban group [absolute risk difference of 0.06% (95% CI -0.72% to 0.79%)]. The 180 days risk of hospitalized bleeding was 1.73% (95% CI 1.22% to 2.35%) for patients in the apixaban group and 1.89% (95% CI 1.56% to 2.20%) in the rivaroxaban group [absolute risk difference: 0.16% (95% CI -0.59% to 0.81%)].
Conclusion
In a nationwide cohort of 8187 patients with VTE treated with rivaroxaban or apixaban, there were no significant differences in the risks of all-cause mortality, recurrent VTE, or hospitalized bleeding.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:220-227
Sindet-Pedersen C, Staerk L, Pallisgaard JL, Gerds TA, ... Gislason GH, Olesen JB
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:220-227 | PMID: 29945162
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Impact:
Abstract

Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.

Rosano GMC, Tamargo J, Kjeldsen KP, Lainscak M, ... Walther T, Lewis BS

Renin angiotensin aldosterone system inhibitors/antagonists/blockers (RAASi) are a cornerstone in treatment of patients with cardiovascular diseases especially in those with heart failure (HF) due to their proven effect on surrogate and hard endpoints. Renin angiotensin aldosterone system inhibitors are also the basis in treatment of arterial hypertension, and they are furthermore indicated to reduce events and target organ damage in patients with diabetes and chronic kidney disease, where they have specific indication because of the evidence of benefit. Renin angiotensin aldosterone system inhibitor therapy, however, is associated with an increased risk of hyperkalaemia. Patients with chronic kidney disease and HF are at increased risk of hyperkalaemia and ∼50% of these patients experience two or more yearly recurrences. A substantial proportion of patients receiving RAASi therapy have their therapy down-titrated or more often discontinued even after a single episode of elevated potassium (K+) level. Since RAASi therapy reduces mortality and morbidity in patients with cardiovascular disease steps should, when hyperkalaemia develops, be considered to lower K+ level and enable patients to continue their RAASi therapy. The use of such measures are especially important in those patients with the most to gain from RAASi therapy.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:180-188
Rosano GMC, Tamargo J, Kjeldsen KP, Lainscak M, ... Walther T, Lewis BS
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:180-188 | PMID: 29726985
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Impact:
Abstract

Pre-admission use of platelet inhibitors and short-term stroke mortality: a population-based cohort study.

Würtz M, Schmidt M, Grove EL, Horváth-Puhó E, ... Christiansen CF, Sørensen HT
Aims
The impact of pre-admission antiplatelet treatment on prognosis after stroke is poorly understood. We, therefore, investigated whether pre-admission use of aspirin and clopidogrel was associated with mortality in patients hospitalized with ischaemic stroke, intracerebral haemorrhage (ICH), or subarachnoid haemorrhage (SAH).
Methods and results
We used nationwide population-based registries to identify all first-time hospitalizations for stroke and subsequent mortality in patients treated with aspirin and clopidogrel in Denmark during 2004-2012. Based on redeemed prescriptions, we computed absolute 30-day mortality rates and mortality rate ratios (MRRs) for current platelet inhibitor users and non-users. We used Cox regression to control for potentially confounding factors. Among platelet inhibitor non-users, 30-day stroke mortality was 12.0% (8.8% for ischaemic stroke, 29.6% for ICH, and 21.2% for SAH). Compared with non-users, the adjusted 30-day MRR (aMRR) was increased among ICH patients using aspirin [1.19, 95% confidence interval (CI) 1.09-1.31]. Although wider CIs, similar increased point estimates were observed in users of both aspirin and clopidogrel (aMRR = 1.26, 95% CI 0.84-1.91). In contrast, current use of both aspirin and clopidogrel was associated with reduced mortality from ischaemic stroke (aMRR = 0.67, 95% CI 0.48-0.94), while use of aspirin alone was not.
Conclusion
Among patients hospitalized for first-time ICH, pre-admission platelet inhibitor use was associated with increased 30-day mortality compared with non-use. In patients hospitalized for ischaemic stroke, 30-day mortality was reduced in users of both aspirin and clopidogrel, but not in users of aspirin alone.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:158-165
Würtz M, Schmidt M, Grove EL, Horváth-Puhó E, ... Christiansen CF, Sørensen HT
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:158-165 | PMID: 29528386
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Impact:
Abstract

New strategies for the development of lipid-lowering therapies to reduce cardiovascular risk.

Graham I, Shear C, De Graeff P, Boulton C, ... Zouridakis E,

The very high occurrence of cardiovascular events presents a major public health issue, because treatment remains suboptimal. Lowering LDL cholesterol (LDL-C) with statins or ezetimibe in combination with a statin reduces major adverse cardiovascular events. The cardiovascular risk reduction in relation to the absolute LDL-C reduction is linear for most interventions without evidence of attenuation or increase in risk at low LDL-C levels. Opportunities for innovation in dyslipidaemia treatment should address the substantial risk of lipid-associated cardiovascular events among patients optimally treated per guidelines but who cannot achieve LDL-C goals and who could benefit from additional LDL-C-lowering therapy or experience side effects of statins. Fresh approaches are needed to identify promising drug targets early and develop them efficiently. The Cardiovascular Round Table of the European Society of Cardiology (ESC) convened a workshop to discuss new lipid-lowering strategies for cardiovascular risk reduction. Opportunities to improve treatment approaches and the efficient study of new therapies were explored. Circulating biomarkers may not be fully reliable proxy indicators of the relationship between treatment effect and clinical outcome. Mendelian randomization studies may better inform development strategies and refine treatment targets before Phase 3. Trials should match the drug to appropriate lipid and patient profile, and guidelines may move towards a precision-based approach to individual patient management. Stakeholder collaboration is needed to ensure continued innovation and better international coordination of both regulatory aspects and guidelines. It should be noted that risk may also be addressed through increased attention to other risk factors such as smoking, hypertension, overweight, and inactivity.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:119-127
Graham I, Shear C, De Graeff P, Boulton C, ... Zouridakis E,
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:119-127 | PMID: 29194462
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Impact:
Abstract

Loop diuretics for chronic heart failure: a foe in disguise of a friend?

Kapelios CJ, Malliaras K, Kaldara E, Vakrou S, Nanas JN

Loop diuretics are recommended for relieving symptoms and signs of congestion in patients with chronic heart failure and are administered to more than 80% of them. However, several of their effects have not systematically been studied. Numerous cohort and four interventional studies have addressed the effect of diuretics on renal function; apart from one prospective study, which showed that diuretics withdrawal is accompanied by increase in some markers of early-detected renal injury, all others converge to the conclusion that diuretics receipt, especially in high doses is associated with increased rates of renal dysfunction. Although a long standing perception has attributed a beneficial effect to diuretics in the setting of chronic heart failure, many cohort studies support that their use, especially in high doses is associated with adverse outcome. Several studies have used propensity scores in order to match diuretic and non-diuretic receiving patients; their results reinforce the notion that diuretics use and high diuretics dose are true risk factors and not disease severity markers, as some have suggested. One small, randomized study has demonstrated that diuretics decrease is feasible and safe and accompanied by a better prognosis. In conclusion, until elegantly designed, randomized trials, powered for clinical endpoints answer the unsettled issues in the field, the use of diuretics in chronic heart failure will remain subject to physicians\' preferences and biases and not evidence based.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:54-63
Kapelios CJ, Malliaras K, Kaldara E, Vakrou S, Nanas JN
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:54-63 | PMID: 28633477
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Impact:
Abstract

Changes in oral anticoagulation for elective cardioversion: results from a European cardioversion registry.

Papp J, Zima E, Bover R, Karaliute R, ... Camm AJ, Atar D
Aims
In patients with atrial fibrillation (AF) pharmacological or electrical cardioversion may be performed to restore sinus rhythm. The procedure is associated with an increased risk of thromboembolic events, which can be significantly reduced by adequate anticoagulation (OAC). Our aim was to create a partly prospective, partly retrospective cardioversion registry, particularly focusing on OAC strategies in different European countries, and on emerging choice of OAC over time.
Methods
From September 2014 to October 2015, cardioversions due to AF performed in six European city hospitals in five European countries (Hungary: Budapest-1 and -2; Italy: Bari and Pisa; France: Amiens; Spain: Madrid; and Lithuania: Kaunas) were recorded in the registry.
Results
A total of 1101 patients (retrospective/prospective: 679/422, male/female: 742/359, mean age: 67.3 years ± 11.2) were registered. Most of the cardioversions were electrical (97%). Oral anticoagulants were administered in 87% of the patient, the usage of non-VKA oral anticoagulants (NOACs) vs Vitamin K antagonists (VKA) was 31.5% vs 68.5%, respectively. Seventy seven percent of the patients were given oral anticoagulants more than 3 weeks prior to the procedure, and 86% more than 4 weeks after the procedure. When using VKA, international normalized ratio (INR) at cardioversion was above 2.0 in 76% of the cases. A decline in VKA usage (P = 0.033) in elective cardioversion over approximately 1 year was observed. During the observation period, there was an increase in apixaban (P < 0.001), a slight increase in rivaroxaban (P = 0.028) and no changes in dabigatran (P = 0.34) usage for elective cardioversion. There were differences in use of OAC between the countries: Spain used most VKA (89%), while France used least VKA (39%, P < 0.001).
Conclusion
According to current AF guidelines, NOACs are adequate alternatives to VKA for thromboembolic prevention in AF patients undergoing elective cardioversion. Our results indicate that NOAC use is increasing and there is a significant decrease in VKA use.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:147-150
Papp J, Zima E, Bover R, Karaliute R, ... Camm AJ, Atar D
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:147-150 | PMID: 28329309
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Impact:
Abstract

Comparison of dabigatran, rivaroxaban and apixaban for effectiveness and safety in atrial fibrillation; a nationwide cohort study.

Rutherford OC, Jonasson C, Ghanima W, Söderdahl F, Halvorsen S
Aim
The aim of this study was to compare the risk of stroke or systemic embolism (SE) and major bleeding in patients with atrial fibrillation (AF) using dabigatran, rivaroxaban and apixaban in routine clinical practice.
Methods and results
Using nationwide registries in Norway from January 2013 through December 2017, we established a cohort of 52 476 new users of non-vitamin K antagonist oral anticoagulants (NOACs) with AF. Users of individual NOACs were matched 1:1 on the propensity score to create three pair-wise matched cohorts: dabigatran vs rivaroxaban (20 504 patients), dabigatran vs apixaban (20 826 patients), and rivaroxaban vs apixaban (27 398 patients). Hazard ratios (HRs) for the risk of stroke or SE and major bleeding were estimated.In the propensity matched comparisons of the risk of stroke or SE, the HRs were 0.88 (95% CI, 0.76-1.02) for dabigatran vs rivaroxaban, 0.88 (95% CI, 0.75-1.02) for dabigatran vs apixaban and 1.00 (95% CI 0.89-1.14) for apixaban vs rivaroxaban. For the risk of major bleeding, the HRs were 0.75 (95% CI, 0.64-0.88) for dabigatran vs rivaroxaban, 1.03 (95% CI, 0.85-1.24) for dabigatran vs apixaban and 0.79 (95% CI, 0.68-0.91) for apixaban vs rivaroxaban.
Conclusion
In this nationwide study of patients with AF in Norway, we found no statistically significant differences in risk of stroke or SE in propensity matched comparisons between dabigatran, rivaroxaban and apixaban. However, dabigatran and apixaban were both associated with significantly lower risk of major bleeding compared to rivaroxaban.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 13 Jan 2020; epub ahead of print
Rutherford OC, Jonasson C, Ghanima W, Söderdahl F, Halvorsen S
Eur Heart J Cardiovasc Pharmacother: 13 Jan 2020; epub ahead of print | PMID: 31942972
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Impact:
Abstract

Advocating cardiovascular precision medicine with P2Y12 receptor inhibitors.

Winter MP, Grove EL, De Caterina R, Gorog DA, ... Navarese EP, Siller-Matula JM

Antiplatelet therapy with P2Y12-receptor inhibitors has become the cornerstone of medical treatment in patients with acute coronary syndrome treated with percutaneous coronary intervention (PCI). With over 100 million prescriptions filled since its approval, clopidogrel is the most widely used P2Y12-receptor inhibitor. Dual antiplatelet therapy with clopidogrel plus aspirin has been associated with a lower rate of major cardiovascular events in patients after PCI than aspirin monotherapy. However, an alarmingly high number of clopidogrel-treated patients experience adverse thrombotic events. Insufficient P2Y12-inhibition or high on-treatment platelet reactivity to adenosine diphosphate has stimulated the increased use of more potent P2Y12 inhibitors: prasugrel (a third generation thienopyridine) and ticagrelor (a cyclopentyl-triazolo-pyrimidine). However, more potent platelet inhibition and low on-treatment platelet reactivity has resulted in increased major bleeding and higher costs. These limitations have suggested the need for an individualized antiplatelet approach in order to decrease thrombotic events and minimize bleeding. This model of personalized medicine integrates a patient\'s demographic and biological data (pharmacodynamic, genomic, epigenomic, transcriptomic, and metabolic information) to target therapy in order to maximize efficacy while minimizing bleeding and costs. This review discusses the role of diagnostic tools such as platelet function and pharmacogenomic testing to personalize antiplatelet therapy.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:221-234
Winter MP, Grove EL, De Caterina R, Gorog DA, ... Navarese EP, Siller-Matula JM
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:221-234 | PMID: 28204303
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Impact:
Abstract

Hydroxychloroquine for the prevention of recurrent cardiovascular events in myocardial infarction patients: rationale and design of the OXI trial.

Hartman O, Kovanen PT, Lehtonen J, Eklund KK, Sinisalo J
Background
Inflammation of the arterial wall plays a central role in the pathogenesis of atherosclerosis. Among patients with rheumatic diseases, anti-rheumatic medication reduces the incidence of cardiovascular (CV) diseases, but only few studies have addressed their cardioprotective effects on patients with no rheumatic diseases. Hydroxychloroquine (HCQ) is an anti-rheumatic drug commonly used in the treatment of rheumatoid arthritis and systemic lupus erythematosus. In addition to its anti-inflammatory properties, HCQ reduces cholesterol levels and the risk of type II diabetes, and has also anti-platelet effects.
Design
The OXI trial is an event-driven trial that will randomize 2500 patients hospitalized for myocardial infarction (MI). Participants will receive active HCQ or placebo for at least 12 months, and until 350 CV events are confirmed. The primary trial endpoint is the composite of death, MI, hospitalization for unstable angina, urgent percutaneous coronary intervention, and urgent coronary artery bypass grafting. Secondary trial endpoints are the primary end point plus stroke, the effect of HCQ treatment on lipids, on the incidence of Type 2 diabetes, on the level of haemoglobin A1c, and on inflammatory parameters. A 6 months placebo-controlled safety pilot trial with 200 patients is currently ongoing to assess the safety of HCQ in the setting of MI.
Summary
The OXI trial will determine whether treatment with HCQ, as compared with placebo, will reduce recurrent CV events among MI patients. If positive, then the OXI trial would provide an entirely novel multitarget approach for the secondary prevention of atherosclerotic cardiovascular diseases (ACVD).

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:92-97
Hartman O, Kovanen PT, Lehtonen J, Eklund KK, Sinisalo J
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:92-97 | PMID: 28025216
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Abstract

Influence of sibutramine in addition to diet and exercise on the relationship between weight loss and blood glucose changes.

Kamil S, Finer N, James WPT, Caterson ID, Andersson C, Torp-Pedersen C
Aims
Weight loss is expected to improve glycaemic control in patients with diabetes or at high risk hereof. Sibutramine causes weight loss and is associated with an increased risk of myocardial infarction and stroke in high-risk patients. We examined the impact of sibutramine-induced weight loss on glycaemic control.
Methods and results
In total, 8192 obese patients with diabetes were randomized to sibutramine or placebo plus diet and exercise after a preliminary 6 weeks in which all patients received sibutramine. Patients were classified into four groups of weight change. A total of 1582 patients had a weight loss >5.7 kg; 2047 patients lost 3.7-5.7 kg; 2432 patients lost <3.7 kg, and 1875 patients gained weight. Patients on sibutramine lost slightly more weight than those on placebo (-0.2 kg on average, P < 0.0001). Mean blood glucose changes in the placebo group were -0.6 mmol/L (±3.1, P = 0.0002), -0.2  mmol/L (±2.7, P = 0.04), and -0.1  mmol/L (±3.0, P = 0.01) in the moderate, modest, and mild weight loss groups, respectively; in the weight gain group blood glucose levels increased by +0.2 mmol/L (±3.1, P = 0.003). Corresponding mean blood glucose changes in the sibutramine-treated patients were -0.4 mmol/L (±3.2, P = 0.0002), +0.1 mmol/L (±3.0, P = 0.04), +0.4 mmol/L (±2.8, P = 0.01), and +0.2 mmol/L (±3.4, P = 0.003). Mean values of HbA1c followed the same pattern though the HbA1c changes were smaller with weight loss and greater with weight gain in the sibutramine group. All results were statistically significant (P < 0.0001).
Conclusion
Weight loss induced by sibutramine, diet, and exercise attenuates falls in blood glucose levels and HbA1c compared with similar weight loss with placebo, diet, and exercise.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:134-139
Kamil S, Finer N, James WPT, Caterson ID, Andersson C, Torp-Pedersen C
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2016; 3:134-139 | PMID: 27680881
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Abstract

Non-vitamin-K oral anticoagulants and laboratory testing: now and in the future: Views from a workshop at the European Medicines Agency (EMA).

Salmonson T, Dogné JM, Janssen H, Garcia Burgos J, Blake P

In contrast to vitamin K antagonists, no routine coagulation monitoring is required in patients taking non-vitamin-K oral anticoagulants (NOACs). However, dosing must take into account factors such as patient age, renal function, and accompanying haemorrhagic risk. There has been considerable debate about when laboratory measurement might be appropriate and which tests should be used. A workshop at the European Medicines Agency recently discussed the evidence about laboratory measurement from formal studies, clinical experience, and the multiple perspectives on NOAC treatment, and considered how our knowledge might be further enhanced.

© The Author 2017. Published on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 30 Dec 2016; 3:42-47
Salmonson T, Dogné JM, Janssen H, Garcia Burgos J, Blake P
Eur Heart J Cardiovasc Pharmacother: 30 Dec 2016; 3:42-47 | PMID: 28025213
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Abstract

Antithrombotic therapy use and clinical outcomes following thrombo-embolic events in patients with atrial fibrillation: insights from ARISTOTLE.

Goto S, Merrill P, Wallentin L, Wojdyla DM, ... Lopes RD, Alexander JH
Aims
We investigated baseline characteristics, antithrombotic use, and clinical outcomes of patients with atrial fibrillation (AF) and a thrombo-embolic event in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study to better inform the care of these high-risk patients.
Method and results
Thrombo-embolic events were defined as stroke (ischaemic or unknown cause) or systemic embolism (SE). Clinical outcomes were estimated using the Kaplan-Meier method. All-cause mortality and International Society on Thrombosis and Haemostasis (ISTH) major bleeding after events were analysed using a Cox proportional hazards model with time-dependent covariates. Of 18 201 patients in ARISTOTLE, 365 experienced a thrombo-embolic event [337 strokes (ischaemic or unknown cause), 28 SE]; 46 (12.6%) of which were fatal. In the 30 days before and after a thrombo-embolic event, 11% and 37% of patients, respectively, were not taking an oral anticoagulant. During follow-up (median 1.8 years), 22 patients (7.1%/year) had a recurrent stroke, 97 (30.1%/year) died, and 10 (6.7%/year) had major bleeding. Compared with patients without a thrombo-embolic event, the short- and long-term adjusted hazards of death in patients with a thrombo-embolic event were high [≤30 days: hazard ratio (HR) 54.3%, 95% confidence interval (95% CI) 41.4-71.3; >30 days: HR 3.5, 95% CI 2.5-4.8; both P < 0.001]. The adjusted hazards of major bleeding were also high short-term (HR 10.37, 95% CI 3.87-27.78; P < 0.001) but not long-term (HR 1.7, 95% CI: 0.77-3.88; P = 0.18).
Conclusions
Thrombo-embolic events were rare but associated with high short- and long-term morbidity and mortality. Substantial numbers of patients are not receiving oral anticoagulattherapy before and, despite this risk, after a first thrombo-embolic event.
Clinical trial registration
ClinicalTrials.gov (NCT00412984).



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:75-81
Goto S, Merrill P, Wallentin L, Wojdyla DM, ... Lopes RD, Alexander JH
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:75-81 | PMID: 29385429
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Abstract

Management and prognosis of atrial fibrillation in diabetic patients: an EORP-AF General Pilot Registry report.

Fumagalli S, Said SA, Laroche C, Gabbai D, ... Lip GYH,
Aims
Diabetes mellitus (DM) is one of the most important cardiovascular risk factors. The aim of this study was to evaluate clinical correlates of DM, including management and outcomes, in the EURObservational Research Programme (EORP)-Atrial Fibrillation (AF) General Pilot (EORP-AF) Registry of the European Society of Cardiology.
Methods and results
We studied consecutive patients (N = 3101) enrolled in 70 centres of nine European countries between February 2012 and March 2013, and compared diabetics with non-diabetics during a 1-year follow-up. In the overall cohort, the prevalence of DM was 20.6%. Diabetics were older (71 ± 9 vs. 68 ± 12 years, P < 0.0001) and had more comorbidities, higher CHA2DS2-VASc score (4.6 ± 1.6 vs. 2.9 ± 1.7, P < 0.0001) and higher prevalence of permanent AF (21.5 vs. 16.0%, P = 0.0022). Quality of life amongst DM patients was significantly worse [atrial fibrillation quality of life questionnaire (AF-QoL) score 45.2 ± 19.2 vs. 49.3 ± 20.1, P < 0.0001]. Amongst diabetics, the use of electrical cardioversion (16.2 vs. 24.6%, P < 0.0001) and catheter ablation (3.3 vs. 8.6%, P < 0.0001) was lower, whilst oral anticoagulants were more often prescribed (84.3 vs. 78.9%, P = 0.0027). After one year, diabetic patients had significantly higher all-cause (11.9 vs. 4.9%, P < 0.0001), cardiovascular (6.2 vs. 1.9%, P < 0.0001), and non-cardiovascular mortality (2.3 vs. 1.1%, P = 0.0356).
Conclusion
In AF patients, DM is associated with a higher prevalence of comorbidities and a worse quality of life. After one year, all-cause, cardiovascular, and non-cardiovascular mortality were significantly higher in diabetic subjects.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:172-179
Fumagalli S, Said SA, Laroche C, Gabbai D, ... Lip GYH,
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:172-179 | PMID: 29309557
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Abstract

Circadian variation of ticagrelor-induced platelet inhibition in healthy adulty.

Fournier S, Guenat F, Fournier A, Alberio L, ... Eeckhout E, Muller O
Aims
The circadian variation of platelet aggregation is well demonstrated. However, whether this has an impact on antiplatelet inhibition therapy is poorly documented. We aimed to observe whether ticagrelor-induced platelet inhibition follows a circadian rhythm.
Methods and results
The study included 25 healthy volunteers (11 female; 14 male). Blood samples were collected every 4 h. Ticagrelor was added in vitro at a concentration that provided 50% inhibition of the maximum response using the VerifyNow System Platelet Reactivity Test® thus avoiding any bias induced by circadian gastrointestinal absorption. Platelet aggregation testing was subsequently performed using the VerifyNow. Circadian changes in total platelet count, percentage of platelets inhibition, Von Willebrand activity, and volunteers\' physiological parameters were analysed by fitting individuals\' data to a sine curve with a 24-h period. Volunteers\' physiological parameters [heart rate (b.p.m.), systolic/diastolic blood pressure (mmHg), and body temperature (Celsius)] followed a significant mean circadian pattern of 6 b.p.m. (P < 0.001), 5 mmHg/7 mmHg (P < 0.002), and 0.3°C (P < 0.001), respectively. Ticagrelor-induced platelet inhibition was significantly lower at 13:00 (38.4%) than at any other time (45.2%) (P = 0.018). Percentage of inhibited platelets plotted against time followed a circadian rhythm (P < 0.001), with mean minimum/maximum values at 13:00/02:00, respectively. Von Willebrand activity also followed a circadian pattern (P < 0.001), with an amplitude of 12.24% and a maximum activity at 12:00.
Conclusion
Ticagrelor-induced platelet inhibition follows a circadian rhythm, with the lowest mean values achieved at 13:00. These results deserve further studies in patients with coronary artery disease.



Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:166-171
Fournier S, Guenat F, Fournier A, Alberio L, ... Eeckhout E, Muller O
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:166-171 | PMID: 29370383
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Abstract

Interleukin-1 blockade for the treatment of pericarditis.

Buckley LF, Viscusi MM, Van Tassell BW, Abbate A

Pericarditis is a debilitating condition that results from profound inflammation of the pericardial tissue. Between 10 and 15% of first episodes of acute pericarditis will be followed by several episodes refractory to conventional treatment. Current standard of care for pericarditis treatment includes high-dose non-steroidal anti-inflammatory drugs, colchicine, and systemic corticosteroids, each associated with potentially severe toxicities and nominal efficacy. Interleukin-1 (IL-1), an apical pro-inflammatory cytokine, plays an important role as an autocrine magnifier of systemic inflammation in pericarditis. Interruption of the IL-1 circuit has been shown to have a favourable risk profile in several disease states. In this review, we discuss the growing body of evidence which supports the use of IL-1 blockade in the treatment of recurrent pericarditis as well as provide practical considerations for the use of IL-1 blockade in clinical practice.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: [email protected]

Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:46-53
Buckley LF, Viscusi MM, Van Tassell BW, Abbate A
Eur Heart J Cardiovasc Pharmacother: 31 Dec 2017; 4:46-53 | PMID: 28633474
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Impact:

This program is still in alpha version.