Journal: Eur Heart J Cardiovasc Pharmacother

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Abstract

Outcomes of digoxin vs. beta-blocker in AF: report from ESC-EHRA EORP-AF Long-Term General Registry.

Ding WY, Boriani G, Marin F, Blomström-Lundqvist C, ... Fauchier L, Lip GYH
Background
The safety of digoxin therapy in atrial fibrillation (AF) remains ill-defined. We aimed to evaluate the effects of digoxin over beta-blocker therapy in AF.
Methods
Patients with AF who were treated with either digoxin or beta-blocker from the ESC-EHRA EORP-AF General Long-Term Registry were included. Outcomes of interest were all-cause mortality, cardiovascular (CV) mortality, non-CV mortality, quality of life and number of patients with unplanned hospitalisations.
Results
Of 6377 patients, 549(8.6%) were treated with digoxin. Over 24 months, there were 550(8.6%) all-cause mortality events and 1304(23.6%) patients with unplanned emergency hospitalisations. Compared to beta-blocker, digoxin therapy was associated with increased all-cause mortality (HR 1.90 [95%CI,1.48-2.44], CV mortality (HR 2.18 [95%CI,1.47-3.21] and non-CV mortality (HR 1.68 [95%CI,1.02-2.75] with reduced quality of life (Health Utility Score 0.555[±0.406] vs. 0.705[±0.346], P<0.001) but no differences in emergency hospitalisations (HR 1.00 [95%CI,0.56-1.80]) or AF-related hospitalisations (HR 0.95 [95%CI,0.60-1.52]).On multivariable analysis, there were no differences in any of the outcomes between both groups, after accounting for potential confounders. Similar results were obtained in the subgroups of patients with permanent AF and coexisting heart failure. There was no differences in outcomes between AF patients receiving digoxin with and without chronic kidney disease.
Conclusion
Poor outcomes related to the use of digoxin over beta-blocker therapy in terms of excess mortality and reduced quality of life are associated with the presence of other risk factors rather than digoxin per se. The choice of digoxin or beta-blocker therapy had no influence on the incidence of unplanned hospitalisations.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 18 Oct 2021; epub ahead of print
Ding WY, Boriani G, Marin F, Blomström-Lundqvist C, ... Fauchier L, Lip GYH
Eur Heart J Cardiovasc Pharmacother: 18 Oct 2021; epub ahead of print | PMID: 34665249
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Abstract

Interleukin-1 blockade with Anakinra and heart failure following ST-segment elevation myocardial infarction: results from a pooled analysis of the VCUART clinical trials.

Abbate A, Wohlford GF, Del Buono MG, Chiabrando JG, ... Lipinski MJ, Van Tassell BW
Aims
ST segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of death and heart failure (HF). In this study we sought to evaluate the effect of anakinra, a recombinant interleukin-1 receptor antagonist, on the incidence of HF.
Methods and results
We performed a pooled analysis of three early phase randomized clinical trials. The endpoints included the composite of all-cause death and new-onset HF, and the composite of all-cause death and hospitalization for HF at 1 year follow-up. Safety events, including injection site reaction and serious infections, were also recorded. We analyzed 139 patients with STEMI from three separate trials: VCUART (N = 10), VCUART2 (N = 30), and VCUART3 (N = 99). Of these, 84 (60%) patients were randomized to anakinra and 55 (40%) to placebo. Treatment with anakinra significantly reduced the incidence of all-cause death or new-onset HF (7 [8.2%] vs 16 [29.1%], log-rank P = 0.002) and of all-cause death or HF hospitalization (0 [0] vs 5 [9.1%], log-rank P = 0.007). Patients treated with anakinra had significantly higher injection site reactions (19 [22.6%] vs 3 [5.5%], P = 0.016) without a significant difference in the incidence of serious infections (11 [13.1%] vs 7 [12.7%], P = 0.435). Treatment with anakinra significantly reduced the area under the curve for high-sensitivity C-Reactive-Protein between baseline and 14 days (75.48 [41.7-147.47] vs 222.82 [222.82 [117.22-399.28] mg•day/L, P < 0.001).
Conclusions
IL-1 blockade with anakinra for 14 days in patients with STEMI reduces the incidence of new onset HF or hospitalization for HF at 1 year following STEMI.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 06 Oct 2021; epub ahead of print
Abbate A, Wohlford GF, Del Buono MG, Chiabrando JG, ... Lipinski MJ, Van Tassell BW
Eur Heart J Cardiovasc Pharmacother: 06 Oct 2021; epub ahead of print | PMID: 34617567
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Abstract

Comparison of dronedarone vs. flecainide in the maintenance of sinus rhythm, following electrocardioversion in adults with persistent atrial fibrillation: a systematic review and meta-analysis.

Wilson H, Patton D, Moore Z, O\'Connor T, Nugent L
Aims
To compare flecainide and dronedarone for sinus rhythm (SR) maintenance following electrocardioversion of persistent atrial fibrillation (AF), in patients with minimal or no structural heart disease.
Methods and results
A systematic search of publications using EMBASE, CENTRAL, CINAHL, and MEDLINE (1989-2019), identified a total of 595 articles. No limitations were applied. Nine articles met the inclusion criteria [five randomized controlled trials (RCTs) and four cohort studies], encompassing 1349 persistent AF candidates. Two retrospective studies compared flecainide with dronedarone, indicating a 6% reduced risk of AF recurrence with flecainide; however, results were not statistically significant [risk ratio (RR) 0.94, 95% confidence interval (CI) 0.71-1.24; P = 0.66]. One RCT compared dronedarone to placebo, demonstrating a 28% reduced risk of AF recurrence at 6 months (RR 0.72, 95% CI 0.58-0.90; P = 0.004). Two RCTs compare flecainide to placebo, when a 16% decreased risk of AF recurrence at 6-12 months was indicated; however, these results were not statistically significant (RR 0.84, 95% CI 0.66-1.07; P = 0.16). Within a 6- to 12-month follow-up period, a combined recurrence rate of AF was examined, in which flecainide and dronedarone maintained SR in 50% and 42%, respectively. Four articles satisfied quality appraisal, one of which focused on flecainide data.
Conclusion
Dronedarone and flecainide displayed similar efficacy in maintaining SR in patients following electrocardioversion for persistent AF. The SR maintenance was numerically but not statistically significant in the flecainide group. Side effects uncovered similar pro-arrhythmic activity. However, in light of the deficiency of volume and quality of available evidence, the writer acknowledges the requirement for future research.

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

Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:363-372
Wilson H, Patton D, Moore Z, O'Connor T, Nugent L
Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:363-372 | PMID: 32163173
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Abstract

Haematuria and urinary tract cancers in patients with atrial fibrillation treated with oral anticoagulants.

Rasmussen PV, Dalgaard F, Gislason GH, Brandes A, ... Blanche P, Hansen ML
Aims
Patients with atrial fibrillation (AF) treated with oral anticoagulants (OACs) have an increased risk of bleeding including haematuria. In the general population, gross haematuria is associated with urinary tract cancer. Consequently, we aimed to investigate the potential association between gross haematuria and urinary tract cancer in anticoagulated patients with AF.
Methods and results 
Using Danish nationwide registers, we included Danish AF patients treated with OACs between 2001 and 2015. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risk of urinary tract cancer in patients with and without gross haematuria. We included 125 063 AF patients with a median age of 74 years (interquartile range 65-80) and a majority of males (57%). The absolute risk of gross haematuria 12 months after treatment initiation increased with age ranging from 0.37% [95% confidence interval (CI) 0.31-0.42] to 0.85% (95% CI 0.75-0.96) in the youngest and oldest age groups of ≤70 and >80 years of age, respectively. The 1-year risk of urinary tract cancer after haematuria ranged from 4.2% (95% CI 2.6-6.6) to 6.5% (95% CI 4.6-9.0) for patients in age group >80 and 71-80 years, respectively. Gross haematuria conferred large risk ratios of urinary tract cancer when comparing patients with and without haematuria across all age groups.
Conclusion 
Gross haematuria was associated with clinically relevant risks of urinary tract cancer in anticoagulated patients with AF. These findings underline the importance of meticulously examining anticoagulated patients with haematuria.

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

Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:373-379
Rasmussen PV, Dalgaard F, Gislason GH, Brandes A, ... Blanche P, Hansen ML
Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:373-379 | PMID: 32369580
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Abstract

Efficacy and safety of direct oral anticoagulants vs. low molecular weight heparin for cancer-related venous thromboembolism: a meta-analysis of randomized trials.

Elbadawi A, Shnoda M, Mahmoud K, Elgendy IY
Aims
To examine the efficacy and safety of direct oral anticoagulants (DOACs) vs. low molecular weight heparin (LMWH) in patients with cancer-related venous thromboembolism (VTE).
Methods and results
An electronic search of the MEDLINE, SCOPUS, and Cochrane databases without language restrictions was performed through April 2020 for randomized controlled trials that compared the outcomes with DOACs vs. LMWH among patients with cancer-related VTE. Summary estimates were reported using random effects model. The main efficacy outcome was VTE recurrence, while the main safety outcome was major bleeding . The final analysis included four randomized trials with a total of 2907 patients. The weighted mean follow-up was 6.1 months. Compared with LMWH, DOACs were associated with lower incidence of VTE recurrence [5.7% vs. 9.1%, risk ratio (RR) 0.62; 95% confidence interval (CI) 0.44-0.87; P = 0.01], driven by lower incidence of deep venous thrombosis (RR 0.60, 95% CI 0.39-0.93; P = 0.02). There was no difference in the incidence of major bleeding between DOACs and LMWH (4.8% vs. 3.6%, RR 1.33; 95% CI 0.84-2.11; P = 0.23). The incidence of all-cause mortality was similar (RR 0.99; 95% CI 0.84-1.16; P = 0.91). Subgroup analysis suggested no differences according to the type of DOAC regarding recurrent VTE or major bleeding (Pinteraction = 0.53 and Pinteraction = 0.11, respectively).
Conclusion
Among patients with cancer-related VTE, DOACs were associated with lower incidence of VTE recurrence and no difference in the incidence of major bleeding compared with LMWH. Future studies examining the subset of cancer patients who drive the most benefit are encouraged.

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

Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:380-388
Elbadawi A, Shnoda M, Mahmoud K, Elgendy IY
Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:380-388 | PMID: 32556105
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Abstract

Risk of fracture in patients with non-valvular atrial fibrillation initiating direct oral anticoagulants vs. vitamin K antagonists.

He N, Dell\'Aniello S, Zhai S, Suissa S, Renoux C
Aims
To determine the risk of fracture associated with direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF), accounting for cumulative duration of use.
Methods and results
Using Quebec administrative healthcare databases, we formed a cohort of all patients aged 40 years or older newly diagnosed with NVAF, who filled a first prescription for DOACs or VKAs between 2011 and 2014. Exposure was modelled as a time-varying variable whereby patients were considered unexposed up to 180 days of cumulative duration of use (to account for a biologically meaningful exposure) and exposed thereafter. The final cohort included 10 306 new users of DOACs and 15 357 new users of VKAs. After propensity score-based fine stratification and weighting, use of DOACs for 180 days or greater was associated with a 35% decreased risk of fracture [crude incidence rates 7.5 vs. 15.3 per 1000 person-years; adjusted hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.46-0.91] compared to VKA duration ≥180 days. Direct oral anticoagulants use was also associated with a lower risk of hip fracture (HR 0.51, 95% CI 0.31-0.86) compared with VKAs. There was no difference in the rate of fracture for shorter duration of use (HR 1.10; 95% CI 0.79-1.53). The risk was not modified by age, sex, chronic kidney disease, osteoporosis, history of fracture or falls.
Conclusion
Prolonged use of DOACs is associated with a lower risk of fracture compared with VKAs. These findings support the first-line recommendation for DOACs in patients with NVAF.

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

Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:389-397
He N, Dell'Aniello S, Zhai S, Suissa S, Renoux C
Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:389-397 | PMID: 32722764
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Abstract

The use of novel oral anticoagulants compared to vitamin K antagonists (warfarin) in patients with left ventricular thrombus after acute myocardial infarction.

Jones DA, Wright P, Alizadeh MA, Fhadil S, ... Mathur A, Antoniou S
Aim
Current guidelines recommend the use of vitamin K antagonist (VKA) for up to 3-6 months for treatment of left ventricular (LV) thrombus post-acute myocardial infarction (AMI). However, based on evidence supporting non-inferiority of novel oral anticoagulants (NOAC) compared to VKA for other indications such as deep vein thrombosis, pulmonary embolism (PE), and thromboembolic prevention in atrial fibrillation, NOACs are being increasingly used off licence for the treatment of LV thrombus post-AMI. In this study, we investigated the safety and effect of NOACs compared to VKA on LV thrombus resolution in patients presenting with AMI.
Methods and results
This was an observational study of 2328 consecutive patients undergoing coronary angiography ± percutaneous coronary intervention (PCI) for AMI between May 2015 and December 2018, at a UK cardiac centre. Patients\' details were collected from the hospital electronic database. The primary endpoint was rate of LV thrombus resolution with bleeding rates a secondary outcome. Left ventricular thrombus was diagnosed in 101 (4.3%) patients. Sixty patients (59.4%) were started on VKA and 41 patients (40.6%) on NOAC therapy (rivaroxaban: 58.5%, apixaban: 36.5%, and edoxaban: 5.0%). Both groups were well matched in terms of baseline characteristics including age, previous cardiac history (previous myocardial infarction, PCI, coronary artery bypass grafting), and cardiovascular risk factors (hypertension, diabetes, hypercholesterolaemia). Over the follow-up period (median 2.2 years), overall rates of LV thrombus resolution were 86.1%. There was greater and earlier LV thrombus resolution in the NOAC group compared to patients treated with warfarin (82% vs. 64.4%, P = 0.0018, at 1 year), which persisted after adjusting for baseline variables (odds ratio 1.8, 95% confidence interval 1.2-2.9). Major bleeding events during the follow-up period were lower in the NOAC group, compared with VKA group (0% vs. 6.7%, P = 0.030) with no difference in rates of systemic thromboembolism (5% vs. 2.4%, P = 0.388).
Conclusion
These data suggest improved thrombus resolution in post-acute coronary syndrome (ACS) LV thrombosis in patients treated with NOACs compared to VKAs. This improvement in thrombus resolution was accompanied with a better safety profile for NOAC patients vs. VKA-treated patients. Thus, provides data to support a randomized trial to answer this question.

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

Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:398-404
Jones DA, Wright P, Alizadeh MA, Fhadil S, ... Mathur A, Antoniou S
Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:398-404 | PMID: 32730627
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Impact:
Abstract

Effectiveness and safety of oral anticoagulants among non-valvular atrial fibrillation patients with polypharmacy.

Lip GYH, Keshishian A, Kang A, Dhamane AD, ... Yuce H, Deitelzweig S
Aims
Polypharmacy is prevalent among non-valvular atrial fibrillation (NVAF) patients and presents a potential issue for the effective management of NVAF. This study compared the risk of stroke/systemic embolism (SE) and major bleeding (MB) among NVAF patients with polypharmacy newly prescribed oral anticoagulants (OACs).
Methods and results
A retrospective study of NVAF patients with polypharmacy who initiated OACs from 01 January 2013 to 30 September 2015 was conducted using US CMS Medicare and four commercial databases. Polypharmacy was defined as ≥6 concomitant medications on the index date. Propensity score matching was conducted to compare non-vitamin K antagonists OACs (NOACs) to warfarin as well as between NOACs. Cox proportional hazard models were used to evaluate the risk of stroke/SE and MB. A total of 188 893 patients with polypharmacy were included, with an average of 8 concomitant medications (interquartile range 6-9). Compared to warfarin, apixaban [hazard ratio (HR): 0.59, 95% confidence interval (CI): 0.52-0.68], and rivaroxaban (HR: 0.75, 95% CI: 0.69-0.83) were associated with a lower risk of stroke/SE. Apixaban (HR: 0.57, 95% CI: 0.54-0.61) and dabigatran (HR: 0.76, 95% CI: 0.66-0.88) were associated with a decreased risk of MB compared with warfarin. Compared with dabigatran and rivaroxaban, apixaban was associated with a lower risk of stroke/SE and MB. Dabigatran was associated with lower risk of MB compared with rivaroxaban.
Conclusions
In this observational study of anticoagulated NVAF patients with polypharmacy, effectiveness and safety profiles are more favourable for NOACs vs. warfarin. Our observations are hypothesis generating and may help inform future clinical trials regarding appropriate OAC treatment selection in polypharmacy patients.

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

Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:405-414
Lip GYH, Keshishian A, Kang A, Dhamane AD, ... Yuce H, Deitelzweig S
Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:405-414 | PMID: 33010157
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Abstract

The burden of cholesterol accumulation through the lifespan: why pharmacological intervention should start earlier to go further?

Zambon A, Mello E Silva A, Farnier M
Among the cardiovascular risk factors, cholesterol-rich atherogenic lipoproteins play a central role in the pathogenesis of atherosclerosis. In middle-aged adults, the size of the total atherosclerotic plaque burden is influenced by both the concentration of circulating atherogenic lipoproteins and the total duration of exposure to these lipoproteins. This review describes the evidence supporting a causal link between lifelong elevations in atherogenic lipoproteins and future risk of atherosclerosis; evidence strengthened by recent epidemiological, genetic, and clinical data. By consequence, adolescence and early adulthood are a crucial time for determining later cardiovascular disease risk. Arguments showing that early optimal lipid control leads to improved outcomes will be presented and suggestions put forward for how those most at risk should be identified and managed.

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

Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:435-441
Zambon A, Mello E Silva A, Farnier M
Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:435-441 | PMID: 33119073
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Impact:
Abstract

The age of randomized clinical trials: three important aspects of randomized clinical trials in cardiovascular pharmacotherapy with examples from lipid, diabetes, and antithrombotic trials.

Drexel H, Lewis BS, Rosano GMC, Saely CH, ... Agewall S, Pocock SJ
This review article aims to explain the important issues that data safety monitoring boards (DSMB) face when considering early termination of a trial and is specifically addressed to the needs of clinical and research cardiologists. We give an insight into the overall background and then focus on the three principal reasons for stopping trials, i.e. efficacy, futility, and harm. The statistical essentials are also addressed to familiarize clinicians with the key principles. The topic is further highlighted by numerous examples from lipid trials and antithrombotic trials. This is followed by an overview of regulatory aspects, including an insight into industry-investigator interactions. To conclude, we summarize the key elements that are the basis for a decision to stop a randomized clinical trial (RCT).

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

Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:453-459
Drexel H, Lewis BS, Rosano GMC, Saely CH, ... Agewall S, Pocock SJ
Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:453-459 | PMID: 33135079
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Impact:
Abstract

Off-label underdosed apixaban use in Asian patients with non-valvular atrial fibrillation.

Lee SR, Choi EK, Park SH, Jung JH, ... Oh S, Lip GYH
Aims
To compare the effectiveness and safety of off-label underdosed apixaban with on-label standard dose apixaban in Asian patients with atrial fibrillation (AF).
Methods and results
Using the Korean nationwide claims database, we identified patients who were prescribed apixaban and did not fulfil the dose reduction criteria for apixaban between January 2015 and December 2017. A multivariable Cox hazard regression model was performed, and hazard ratios (HRs) for ischaemic stroke, major bleeding (MB), all-cause death, and composite outcome were analysed. Compared to patients prescribed on-label standard dose apixaban (n = 4194), patients prescribed off-label underdosed apixaban (n = 2890) showed a higher risk of ischaemic stroke [adjusted HR (aHR) 1.38, 95% confidence interval (CI) 1.06-1.81], all-cause death (aHR 1.19, 95% CI 1.01-1.39), and the composite outcome (aHR 1.17, 95% CI 1.03-1.34), but with no significant differences in MB between the two groups. Among the patients who did not meet any dose reduction criteria, off-label underdosed apixaban use was associated with a significantly higher risk of ischaemic stroke than on-label standard dose apixaban use (aHR 1.85, 95% CI 1.25-2.73). Among the patients who met a single dose reduction criterion, off-label underdosed apixaban use was associated with a higher risk of all-cause death than on-label standard dose apixaban (aHR 1.32, 95% CI 1.07-1.64).
Conclusion
The off-label underdosed apixaban group showed higher risks of ischaemic stroke, all-cause death, and composite clinical outcomes than the on-label standard dose apixaban group, but both showed comparable risks of MB. Label adherence to apixaban dosing should be emphasized to achieve the best clinical outcomes for Asian patients with AF.

Published on behalf of the European Society of Cardiology. © The Author(s) 2021.

Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:415-423
Lee SR, Choi EK, Park SH, Jung JH, ... Oh S, Lip GYH
Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:415-423 | PMID: 33471125
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Abstract

Renal protection in chronic heart failure: focus on sacubitril/valsartan.

Pontremoli R, Borghi C, Perrone Filardi P
Chronic kidney disease (CKD) is highly prevalent in patients with chronic heart failure (CHF) and increases the risk of overall and cardiovascular (CV) mortality. Despite evidence supporting the effectiveness of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers, and mineralocorticoid receptor antagonists in decreasing mortality in patients with CHF, CKD hampers the optimization of standard pharmacologic therapy for heart failure. Therefore, other treatment options are needed to optimize treatment outcomes in CHF patients with CKD. The first-in-class angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan, has a complementary activity that counteracts the potential unwanted long-term effects of over-activation of the renin-angiotensin-aldosterone system. Sacubitril/valsartan reduced the risk of CV mortality compared to standard therapy with an ACE-I in patients with heart failure with reduced ejection fraction (HFrEF) in the PARADIGM-HF trial and has been shown to be safe and effective in a broad range of HFrEF patients. However, data on the efficacy and tolerability of sacubitril/valsartan in patients with more advanced CKD are limited. This review discusses the evidence for the role of sacubitril/valsartan in providing additional renal benefit in patients with HFrEF. Data from clinical trials and real-world experience in patients with HFrEF and advanced CKD support the benefits of dual angiotensin/neprilysin inhibition across the breadth of kidney disease stages, including patients with significant renal impairment that was not reported in the pivotal PARADIGM-HF trial, and suggests a central role for the cardiac benefits of sacubitril/valsartan in nephroprotection.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:445-452
Pontremoli R, Borghi C, Perrone Filardi P
Eur Heart J Cardiovasc Pharmacother: 20 Sep 2021; 7:445-452 | PMID: 33822031
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Abstract

Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and non-critically ill patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.

Ortega-Paz L, Galli M, Capodanno D, Franchi F, ... Andreotti F, Angiolillo DJ
Background
The clinical impact of different prophylactic anticoagulation regimens among hospitalized patients with COVID-19 remains unclear. We pooled evidence from available randomized controlled trials (RCTs) to provide insights on this topic.
Methods and results
We searched for RCTs comparing treatment with an escalated-dose (intermediate-dose or therapeutic-dose) versus a standard-dose prophylactic anticoagulation regimen in critically and non-critically-ill COVID-19 patients requiring hospitalization and without a formal indication for anticoagulation. The primary efficacy endpoint was all-cause death, and the primary safety endpoint was major bleeding. Seven RCTs were identified, including 5,154 patients followed on average of 33 days. Compared to standard-dose prophylactic anticoagulation, escalated-dose prophylactic anticoagulation was not associated with a reduction of all-cause death (17.8% vs. 18.6%; Risk Ratio [RR] 0.96, 95% Confidence Interval [CI] 0.78-1.18) but was associated with an increase in major bleeding (2.4% vs. 1.4%; RR 1.73, 95%CI 1.15-2.60). Compared to prophylactic anticoagulation used at a standard-dose, an escalated-dose was associated with lower rates of venous thromboembolism (2.5% vs. 4.7%; RR 0.55, 95%CI 0.41-0.74) without a significant effect on myocardial infarction (RR 0.80, 95%CI 0.47-1.36), stroke (RR 0.94, 95%CI 0.43-2.09), or systemic arterial embolism (RR 1.20, 95%CI 0.29-4.95). There were no significant interactions in the subgroup analysis for critically and non-critically-ill patients.
Conclusions
Our findings provide comprehensive and high-quality evidence for the use of standard-dose prophylactic anticoagulation over an escalated-dose regimen as routine standard of care for hospitalized patients with COVID-19 who do not have an indication for therapeutic anticoagulation, irrespective of disease severity.
Study registration
This study is registered in PROSPERO (CRD42021257203).

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 13 Sep 2021; epub ahead of print
Ortega-Paz L, Galli M, Capodanno D, Franchi F, ... Andreotti F, Angiolillo DJ
Eur Heart J Cardiovasc Pharmacother: 13 Sep 2021; epub ahead of print | PMID: 34519777
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Abstract

Challenges in Cardiovascular Pharmacogenomics Implementation: A viewpoint from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.

Magavern EF, Kaski JC, Turner RM, Drexel H, ... Pirmohamed M, Caulfield MJ
Pharmacogenomics promises to advance cardiovascular therapy, but there remain pragmatic barriers to implementation. These are particularly important to explore within Europe, as there are differences in the populations, availability of resources and expertise, as well as in ethico-legal frameworks. Differences in healthcare delivery across Europe present a challenge, but also opportunities to collaborate on PGx implementation. Clinical work force upskilling is already in progress but will require substantial input. Digital infrastructure and clinical support tools are likely to prove crucial. It is important that widespread implementation serves to narrow rather than widen any existing gaps in health equality between populations. This viewpoint supplements the working group position paper on cardiovascular pharmacogenomics to address these important themes.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 30 Aug 2021; epub ahead of print
Magavern EF, Kaski JC, Turner RM, Drexel H, ... Pirmohamed M, Caulfield MJ
Eur Heart J Cardiovasc Pharmacother: 30 Aug 2021; epub ahead of print | PMID: 34463331
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Impact:
Abstract

Guided and unguided de-escalation from potent P2Y12 inhibitors among patients with ACS: a meta-analysis.

Tavenier AH, Mehran R, Chiarito M, Cao D, ... Sharma SK, Dangas G
Aim
Optimal dual antiplatelet therapy (DAPT) in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) intends to balance ischemic and bleeding risks. Various DAPT de-escalation strategies, defined as switching from a full-dose potent to a reduced dose or less potent P2Y12 inhibitor, have been evaluated in several ACS-PCI trials. We aimed to compare DAPT de-escalation to standard DAPT with full dose potent P2Y12 inhibitors in ACS patients who underwent PCI.
Methods & results
PubMed, Google Scholar and Cochrane Central Register of Controlled Trials were searched for eligible randomised controlled trials. Aspirin monotherapy trials were excluded. Five randomised trials (n = 10,779 patients) that assigned DAPT de-escalation (genetically guided to clopidogrel n = 1,242; platelet function guided to clopidogrel n = 1,304; unguided to clopidogrel n = 1,672; unguided to lower dose n = 1,170) versus standard DAPT (control group n = 5,391) were included in this analysis. DAPT de-escalation was associated with a significant reduction in Bleeding Academic Research Consortium ≥ 2 bleeding (HR 0.57, 95% CI 0.42-0.78; I2 = 77%) as well as major adverse cardiac events, represented in most trials by the composite of cardiovascular mortality, myocardial infarction, stent thrombosis and stroke (HR 0.77, 95% CI 0.62-0.96; I2 = 0%). Notwithstanding the limited power, consistency was noted across various de-escalation strategies.
Conclusion
De-escalation of DAPT after PCI for ACS, both unguided and guided by genetic or platelet function testing, was associated with lower rates of clinically relevant bleeding and ischemic events as compared to standard DAPT with potent P2Y12 inhibitors based on five open-label RCTs reviewed.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 29 Aug 2021; epub ahead of print
Tavenier AH, Mehran R, Chiarito M, Cao D, ... Sharma SK, Dangas G
Eur Heart J Cardiovasc Pharmacother: 29 Aug 2021; epub ahead of print | PMID: 34459481
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Abstract

Pharmacodynamic effect of bempedoic acid and statin combinations: predictions from a dose-response model.

Jadhav SB, Crass RL, Chapel S, Kerschnitzki M, ... Watts GF, Catapano AL
Aims
Many patients are unable to achieve guideline recommended low-density lipoprotein cholesterol (LDL-C) targets, despite taking maximally tolerated lipid-lowering therapy. Bempedoic acid, a competitive inhibitor of ATP-citrate lyase, significantly lowers LDL-C with or without background statin therapy in diverse populations. Because pharmacodynamic interaction between statins and bempedoic acid is complex, a dose-response model was developed to predict LDL-C pharmacodynamics following administration of statins combined with bempedoic acid.
Methods and results
Bempedoic acid and statin dosing and LDL-C data were pooled from 14 phase 1-3 clinical studies. Dose-response models were developed for bempedoic acid monotherapy and bempedoic acid-statin combinations using previously published statin parameters. Simulations were performed using these models to predict change in LDL-C levels following treatment with bempedoic acid combined with clinically relevant doses of atorvastatin, rosuvastatin, simvastatin, and pravastatin.Dose-response models predicted that combining bempedoic acid with the lowest statin dose of commonly used statins would achieve a similar degree of LDL-C lowering as quadrupling that statin dose; eg, the predicted LDL-C lowering was 54% with atorvastatin 80 mg compared with 54% with atorvastatin 20 mg + bempedoic acid 180 mg, and by 42% with simvastatin 40 mg compared with 46% with simvastatin 10 mg + bempedoic acid 180 mg.
Conclusion
These findings suggest bempedoic acid combined with lower statin doses, offers similar LDL-C lowering compared with statin monotherapy at higher doses, potentially sparing patients requiring additional lipid-lowering therapies from the adverse events associated with higher statin doses.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 26 Aug 2021; epub ahead of print
Jadhav SB, Crass RL, Chapel S, Kerschnitzki M, ... Watts GF, Catapano AL
Eur Heart J Cardiovasc Pharmacother: 26 Aug 2021; epub ahead of print | PMID: 34448822
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Abstract

Incidence, associated outcomes, and predictors of upper gastrointestinal bleeding following acute myocardial infarction: a SWEDEHEART-based nationwide cohort study.

Sarajlic P, Simonsson M, Jernberg T, Bäck M, Hofmann R
Aims
Of all spontaneous bleeding complications in patients with acute myocardial infarction (MI), upper gastrointestinal bleeding (UGIB) is common and of specific interest since it could be prevented by several prophylactic measures. We aimed to determine the incidence, associated outcomes, and predictors of UGIB following acute MI.
Methods and results
All patients with acute MI enrolled in the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) registry from January 2007 to June 2016 and discharged alive on any antithrombotic therapy (n = 149 477) were followed regarding UGIB for 1 year. Associated outcomes were determined by Cox proportional hazards regression with UGIB as a time-dependent covariate, adjusting for baseline characteristics, invasive treatment, and medical treatment at discharge. Predictors of UGIB were determined by logistic regression and machine learning models.At 1 year, UGIB had occurred in 2230 patients (cumulative incidence 1.5%) and was significantly associated with an increased risk of all-cause death [hazard ratio (HR) 2.86, 95% confidence interval (CI) 2.58-3.16] and stroke (HR 1.80, 95% CI 1.32-2.45) but not with recurrent MI (HR 1.17, 95% CI 0.97-1.42). The most important predictors of UGIB were haemoglobin, age, systolic blood pressure, blood glucose, smoking status, previous upper gastrointestinal bleeding, and antithrombotic and gastroprotective treatment.
Conclusion
After acute MI, readmission because of UGIB is common and significantly associated with poor prognosis. By using machine learning in addition to traditional logistic regression, new predictors of UGIB, such as blood glucose and smoking status, were identified.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 22 Aug 2021; epub ahead of print
Sarajlic P, Simonsson M, Jernberg T, Bäck M, Hofmann R
Eur Heart J Cardiovasc Pharmacother: 22 Aug 2021; epub ahead of print | PMID: 34423350
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Abstract

DOAC discontinuation among patients with atrial fibrillation according to gender and cohabitation status; A Nationwide Cohort Study.

Binding C, Olesen JB, Lee CJ, Lip G, ... Gislason G, Bonde AN
Aims
The aim of this study was to evaluate the risk of discontinuing treatment with direct oral anticoagulants (DOACs) among patients with atrial fibrillation (AF) according to cohabitation status and gender.
Methods and results
Using the Danish national registers, we identified 32,364 patients with AF aged 40-90 years in treatment with DOAC. The study period was from 2013 to 2017, and patients were followed for two years, or until death, outcome, or emigration. The main outcome was discontinuation of DOAC-treatment for at least 30 days.The absolute two-year risk of DOAC discontinuation was highest among men living alone (35.7%, 95% Confidence interval (CI): 37.3% to 34.1%). Men living alone had a 4.6% (95% CI: 6.4% to 2.8%) higher absolute risk of discontinuation and a 12% (HR 1.12, 95% CI: 1.04 to 1.20) higher relative risk of discontinuation compared to men living with a partner. Female patients living alone likewise had a higher absolute risk of DOAC discontinuation (2.6%, 95% CI: 4.4% to 0.09%) compared to female patients living with a partner, yet no statistically significant difference in relative risk. In an analysis evaluating gender, we found male gender to be associated with a significantly higher relative risk of DOAC-discontinuation (HR: 1.33, 95% CI: 1.26 to 1.40) compared to female gender (p-value for interaction with cohabitant status, P = 0.5996).
Conclusion
In this nationwide population study, male gender and living alone was associated with a higher risk of DOAC discontinuation among patients with AF.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 19 Aug 2021; epub ahead of print
Binding C, Olesen JB, Lee CJ, Lip G, ... Gislason G, Bonde AN
Eur Heart J Cardiovasc Pharmacother: 19 Aug 2021; epub ahead of print | PMID: 34415024
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Abstract

Oral antithrombotic therapy for the prevention of recurrent cerebrovascular events.

Capodanno D, Angiolillo DJ
Stroke is frequently a disabling and even life-threatening condition that has an ischemic cause in most cases. Transient ischemic attack (TIA) is a lower-risk condition that still exposes to the risk of future major cardiovascular events. The causes of stroke can be classified as cardioembolic disease, large vessel disease, small vessel disease, undetermined, or others. Cardioembolic disease and atherothrombosis of large arteries are the most common underlying processes of ischemic stroke and TIA. Therefore, antithrombotic therapy is a central strategy in the pharmacological management of these patients. However, because antithrombotic therapy provides ischemic protection at the price of increased bleeding, defining the fine balance between efficacy and safety is a clinical challenge. Numerous trials have recently defined the current indications to the use of anticoagulant and antiplatelet therapy in patients with various subtypes of ischemic stroke or TIA. In this review, we provide an updated appraisal of the currently available evidence on the use of various oral antithrombotic agents for prevention of recurrent events after an ischemic stroke or TIA.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 09 Aug 2021; epub ahead of print
Capodanno D, Angiolillo DJ
Eur Heart J Cardiovasc Pharmacother: 09 Aug 2021; epub ahead of print | PMID: 34374741
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Abstract

Rationale and design of the pragmatic clinical trial tREatment with Beta-blockers after myOcardial infarction withOut reduced ejection fracTion (REBOOT).

Rossello X, Raposeiras-Roubin S, Latini R, Dominguez-Rodriguez A, ... Ibáñez B, REBOOT-CNIC investigators
Background
There is a lack of evidence regarding the benefits of β-blocker treatment after invasively managed acute myocardial infarction (MI) without reduced left ventricular ejection fraction (LVEF).
Methods and results
TREatment with Beta-blockers after myOcardial infarction withOut reduced ejection fraction (REBOOT) trial is a pragmatic, controlled, prospective, randomized, open-label blinded endpoint (PROBE design) clinical trial testing the benefits of β-blocker maintenance therapy in patients discharged after MI with or without ST-segment elevation. Patients eligible for participation are those managed invasively during index hospitalization (coronary angiography), with LVEF >40%, and no history of heart failure (HF). At discharge, patients will be randomized 1:1 to β-blocker therapy (agent and dose according to treating physician) or no β-blocker therapy. The primary endpoint is a composite of all-cause death, nonfatal reinfarction, or HF hospitalization over a median follow-up period of 2.75 years (minimum 2 years, maximum 3 years). Key secondary endpoints include the incidence of the individual components of the primary composite endpoint, the incidence of cardiac death, and incidence of malignant ventricular arrhythmias or resuscitated cardiac arrest. The primary endpoint will be analyzed according to the intention-to-treat principle.
Conclusion
The REBOOT trial will provide robust evidence to guide the prescription of β-blockers to patients discharged after MI without reduced LVEF.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 04 Aug 2021; epub ahead of print
Rossello X, Raposeiras-Roubin S, Latini R, Dominguez-Rodriguez A, ... Ibáñez B, REBOOT-CNIC investigators
Eur Heart J Cardiovasc Pharmacother: 04 Aug 2021; epub ahead of print | PMID: 34351426
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This program is still in alpha version.