Journal: Eur Heart J Cardiovasc Pharmacother

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Abstract

RNA-targeted therapeutics in cardiovascular disease: the time is now.

Krychtiuk KA, Rader DJ, Granger CB
RNA-targeted therapeutics, including antisense oligonucleotide technologies as well as small interfering RNAs, represent a new class of medications that may overcome several of the disadvantages of small molecule drugs or monoclonal antibodies. Specifically, upstream targeting at the mRNA level renders any disease-related protein a potential target, even those pathways previously deemed \'undruggable\'. Additional advantages include the comparably simple and cost-effective way of manufacturing and the long dosing intervals. A few agents are already approved and a wide array of cardiovascular drugs are in development, aimed at hypercholesterolemia, hypertension, myocardial storage diseases and the coagulation system. Here, we provide an update on the current status of RNA-targeted therapeutics in the cardiovascular arena.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 22 Sep 2022; epub ahead of print
Krychtiuk KA, Rader DJ, Granger CB
Eur Heart J Cardiovasc Pharmacother: 22 Sep 2022; epub ahead of print | PMID: 36138490
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Abstract

A systematic review and meta-analyses on the effects of atorvastatin on blood pressure and heart rate.

Costa GS, Julião-Silva LS, Belo VS, de Oliveira HCF, Chaves VE
Aims
Considering the inconsistencies in the literature on the atorvastatin effect on blood pressure (BP), we performed these meta-analyses.
Methods and results
Through a search of the EMBASE, PubMed and Web of Science databases, 1412 articles were identified, from which 33 randomized clinical trials (RCT) and 44 pre-clinical were selected. Populations from RCT were stratified according to baseline BP and lipid levels. We performed meta-analyses of the effect of atorvastatin on systolic (SBP), diastolic and mean BP; heart rate (HR); HR variability and baroreflex. Atorvastatin reduced SBP in the overall population (P = 0.05 vs. placebo; P = 0.03 vs. baseline), in normotensive and hyperlipidaemic (P = 0.04 vs. placebo; P = 0.0001 vs. baseline) and in hypertensive and hyperlipidaemic (P = 0.02 vs. placebo; P = 0.008 vs. baseline) individuals in parallel RCT, but it did not affect SBP in normotensive and normolipidemic individuals (P = 0.51 vs. placebo; P = 0.46 vs. baseline). Although an effect of atorvastatin was detected in hyperlipidaemic individuals, the meta-regression coefficient for the association of LDL-cholesterol reduction with SBP reduction in the overall population demonstrated that SBP reduction is not dependent on the changes in LDL-cholesterol. A meta-analysis of preclinical reports demonstrated that SBP was reduced in atorvastatin-treated hypertensive and normolipidemic rats [spontaneously hypertensive rats: P<0.00001], but not in normotensive and normolipidemic rats (control rats: P = 0.97). Atorvastatin also reduced the HR in spontaneously hypertensive rat.
Conclusion
Atorvastatin lowers blood pressure independent of LDL-cholesterol levels. Additional studies are needed to estimate the involvement of the autonomic nervous system in the blood-pressure-lowering effect of atorvastatin.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 22 Sep 2022; epub ahead of print
Costa GS, Julião-Silva LS, Belo VS, de Oliveira HCF, Chaves VE
Eur Heart J Cardiovasc Pharmacother: 22 Sep 2022; epub ahead of print | PMID: 36138492
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Abstract

Safety and efficacy of very low LDL-cholesterol intensive lowering: a meta-analysis and meta-regression of randomized trials.

Patti G, Spinoni EG, Grisafi L, Mehran R, Mennuni M
Objectives
We performed a study-level meta-analysis to provide more robust evidence on safety of very low LDL-cholesterol (LDL-C) levels.
Background
Concerns on the safety of LDL-C values achieved with potent lipid-lowering therapies have been raised.
Methods
We searched randomized trials reporting clinical outcomes with intensive lipid-lowering treatments leading to very low (<40 mg/dL) LDL-C levels vs a control group with higher LDL-C levels. Only studies with follow-up duration ≥ 3 months were considered. Primary endpoint was the incidence of various safety measures.
Results
A total of 10 randomized trials were overall included, with 38 427 patients being in the very low LDL-C group vs 70 668 in the control group. Median follow-up duration was 28.8 months. The incidence of all safety outcomes was similar in the two groups: cardiovascular death: OR 1.13, 95% CI 0.87-1.45; P = 0.36; any adverse events: OR 1.00, 0.90-1.11, P = 0.94; adverse events leading to drug discontinuation: OR 1.00, 0.87-1.15, P = 0.99; cancer: OR 1.02, 0.95-1.10, P = 0.57; haemorrhagic stroke OR 0.89, 0.66-1.20, P = 0.44; new-onset diabetes: OR 1.16, 0.91-1.47, P = 0.23; neurocognitive disorders: OR 0.97, 0.91-1.04, P = 0.41; haepatobiliary disorders: OR 0.99, 0.83-1.18, P = 0.93; muscle disorders: OR 0.94, 0.77-1.13, P = 0.49; cataract: OR 1.28, 0.78-2.10, P = 0.34. The rates of major adverse cardiovascular events were significantly lower in the very low LDL-C group: OR 0.82, 0.72-0.94, P = 0.005.
Conclusions
This meta-analysis indicates that very low LDL-C levels on intensive lipid-lowering treatments are not associated with any adverse event and maintain a persistent reduction of cardiovascular events.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 14 Sep 2022; epub ahead of print
Patti G, Spinoni EG, Grisafi L, Mehran R, Mennuni M
Eur Heart J Cardiovasc Pharmacother: 14 Sep 2022; epub ahead of print | PMID: 36102667
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Abstract

Cardiovascular risks associated with calcium supplementation in patients with osteoporosis: a nationwide cohort study.

Kim KJ, Kim MS, Hong N, Bae JH, ... Lee J, Kim SG
Aims
This study aimed to evaluate the real effects of calcium supplementation on cardiovascular outcomes within a population-based cohort.
Methods and results
From a nationwide health screening database in South Korea, a total of 11 297 patients with osteoporosis who had taken calcium supplementation with or without vitamin D for at least 90 days [total calcium group; calcium supplementation only (CaO), n = 567; calcium supplementation in combination with vitamin D (CaD), n = 10 730] were matched at a 1:1 ratio to patients who had not taken calcium supplements (control group) by using propensity scores. The overall mean age was 59.9 ± 8.8 years and the percentage of women was 87.9% in our study population. Over a median follow-up of 54 months, the incidence rate of composite cardiovascular diseases (CVDs) per 1000 person-years was not different between the groups: 9.73 in the total calcium group and 8.97 in the control group [adjusted hazard ratio (HR): 1.12; 95% confidence interval (CI): 0.99-1.28; P = 0.08]. However, calcium supplementation without vitamin D was associated with an increased risk of composite CVD (HR: 1.54; 95% CI: 1.17-2.04; P < 0.01), especially non-fatal myocardial infarction (HR: 1.89; 95% CI: 1.23-2.91; P < 0.01), compared with no calcium supplementation.
Conclusion
Our population-based study supported that taking calcium supplementation combined with vitamin D did not appear to be harmful to cardiovascular health, but reminded that calcium supplementation without vitamin D should be used carefully even in populations with low dietary calcium intake.

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

Eur Heart J Cardiovasc Pharmacother: 03 Sep 2022; 8:568-577
Kim KJ, Kim MS, Hong N, Bae JH, ... Lee J, Kim SG
Eur Heart J Cardiovasc Pharmacother: 03 Sep 2022; 8:568-577 | PMID: 34244740
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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 LDL 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; for example, the predicted LDL-C lowering was 54% with atorvastatin 80 mg compared with 54% with atorvastatin 20 mg + bempedoic acid 180 mg, and 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: 03 Sep 2022; 8:578-586
Jadhav SB, Crass RL, Chapel S, Kerschnitzki M, ... Watts GF, Catapano AL
Eur Heart J Cardiovasc Pharmacother: 03 Sep 2022; 8:578-586 | PMID: 34448822
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Abstract

Cardiovascular outcomes with GLP-1 receptor agonists vs. SGLT-2 inhibitors in patients with type 2 diabetes.

Nørgaard CH, Starkopf L, Gerds TA, Vestergaard P, ... Torp-Pedersen C, Lee CJ
Aims
We examined cardiovascular outcomes associated with initiation of glucagon-like peptide-1 receptor agonist (GLP-1RA) vs. sodium-glucose co-transporter-2 inhibitor (SGLT-2i) treatment in a real-world setting among patients with type 2 diabetes.
Methods and results
This Danish nationwide registry-based cohort study included patients with type 2 diabetes with a first-ever prescription of either GLP-1RA or SGLT-2i from 2013 through 2015 with follow-up until end of 2018. All analyses were standardized with respect to age, sex, diabetes duration, comorbidity, and comedication. The main outcome was a composite of cardiovascular death, myocardial infarction, and stroke. Furthermore, the components of the composite outcome and hospitalization for heart failure were evaluated. Standardized average 3-year risks of outcomes and differences thereof were estimated using doubly robust estimation combining cause-specific Cox regression with propensity score regression. We identified 8913 new users of GLP-1RA and 5275 new users of SGLT-2i. The standardized 3-year risk associated with initiating GLP-1RA and SGLT-2i, respectively, was as follows: composite cardiovascular outcome, 5.6% [95% confidence interval (CI): 5.2-6.1] vs. 5.6% (95% CI: 4.8-6.3); cardiovascular mortality, 1.6% (95% CI: 1.3-1.9) vs. 1.5% (95% CI: 1.1-1.8); hospitalization for heart failure, 1.7% (95% CI: 1.5-2.0) vs. 1.8% (95% CI: 1.2-2.5); myocardial infarction, 2.1% (95% CI: 1.8-2.4) vs. 2.1% (95% CI: 1.5-2.6); and stroke, 2.5% (95% CI: 2.2-2.9) vs. 2.6% (95% CI: 2.2-3.1).
Conclusion
In this nationwide study of patients with type 2 diabetes, initiating GLP-1RA vs. SGLT-2i was not found to be associated with significant differences in cardiovascular risk.

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

Eur Heart J Cardiovasc Pharmacother: 03 Sep 2022; 8:549-556
Nørgaard CH, Starkopf L, Gerds TA, Vestergaard P, ... Torp-Pedersen C, Lee CJ
Eur Heart J Cardiovasc Pharmacother: 03 Sep 2022; 8:549-556 | PMID: 34215881
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Abstract

An international audit of the management of dyslipidaemia and hypertension in patients with rheumatoid arthritis: results from 19 countries.

Rollefstad S, Ikdahl E, Wibetoe G, Sexton J, ... Medková H, Semb AG
Aims
To assess differences in estimated cardiovascular disease (CVD) risk among rheumatoid arthritis (RA) patients from different world regions and to evaluate the management and goal attainment of lipids and blood pressure (BP).
Methods and results
The survey of CVD risk factors in patients with RA was conducted in 14 503 patients from 19 countries during 2014-19. The treatment goal for BP was <140/90 mmHg. CVD risk prediction and lipid goals were according to the 2016 European guidelines. Overall, 21% had a very high estimated risk of CVD, ranging from 5% in Mexico, 15% in Asia, 19% in Northern Europe, to 31% in Central and Eastern Europe and 30% in North America. Of the 52% with indication for lipid-lowering treatment (LLT), 44% were using LLT. The lipid goal attainment was 45% and 18% in the high and very high risk groups, respectively. Use of statins in monotherapy was 24%, while 1% used statins in combination with other LLT. Sixty-two per cent had hypertension and approximately half of these patients were at BP goal. The majority of the patients used antihypertensive treatment in monotherapy (24%), while 10% and 5% as a two- or three-drug combination.
Conclusion
We revealed considerable geographical differences in estimated CVD risk and preventive treatment. Low goal attainment for LLT was observed, and only half the patients obtained BP goal. Despite a high focus on the increased CVD risk in RA patients over the last decade, there is still substantial potential for improvement in CVD preventive measures.

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

Eur Heart J Cardiovasc Pharmacother: 03 Sep 2022; 8:539-548
Rollefstad S, Ikdahl E, Wibetoe G, Sexton J, ... Medková H, Semb AG
Eur Heart J Cardiovasc Pharmacother: 03 Sep 2022; 8:539-548 | PMID: 34232315
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Abstract

Immunomodulatory effect of different statin regimens on regulatory T-cells in patients with acute coronary syndrome: a systematic review and network meta-analysis of randomized clinical trials.

Greca E, Kacimi SEO, Poudel S, Wireko AA, ... Marzban S, Michel J
Aims
We conducted a network meta-analysis (NMA) to determine the effects of low-dose (20 mg/day or less) conventional statin therapy (CST) and high-dose (40 mg/day or more) intensive statin therapy (IST) on the frequency of Tregs and their associated cytokines (IFN-γ, IL-10, TGF-β) compared to placebo.
Methods and results
PubMed, Cochrane Library, and EMBASE databases were searched for randomized clinical trials (RCTs) to identify relevant articles published until June 2021. We pooled data extracted from the included studies using the standardized mean difference (SMD). A random-effects model was used to conduct this NMA. Heterogeneity was evaluated using Cochran\'s Q test and the I2 test. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to assess the quality of the study. Data analysis was conducted using R software.A total of 505 patients were enrolled in the 5 RCTs. NMA indicated a significant increase in Treg frequency in the CST group compared with the control group (SMD 1.77; 95% CI: 0.77-2.76; P = 0.0005) and a larger increase in the Treg frequency associated with the IST group compared with the control group (SMD 2.12; 95% CI: 1.15-3.10; P-value < 0.0001). However, there was significant heterogeneity and inconsistency among the included studies (τ2 = 0.6096; τ = 0.7808; I2 = 91.2% [80.5%; 96.0%]). When compared with placebo, both CST and IST increased the levels of secreted IL-10 (SMD 2.69; 95% CI: 2.07-3.31; P-value < 0.0001 and SMD 2.14; 95% CI: 1.76-2.52; P-value < 0.0001). Compared with the control group, CST was associated with increased levels of TGF-β (SMD 3.83; 95% CI: 0.63-7.0; P-value = 0.0189); this association was not seen in the IST group. IFN-γ levels decreased significantly in both the IST and CST groups (SMD -1.52; 95% CI: -1.94-1.10; P-value < 0.0001 and SMD -2.34; 95% CI: -2.73-1.95; P-value < 0.0001, respectively).
Conclusions
The findings of our study indicated that both high- and low-dose statin groups increased Treg frequency compared with the placebo group. IST demonstrated greater benefits than CST. Furthermore, statin therapy increased IL-10 and TGF-β levels and decreased IFN-γ levels. Overall, these results have significant implications for patients with ACS who would benefit from Treg-induced immunomodulatory balance.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 01 Sep 2022; epub ahead of print
Greca E, Kacimi SEO, Poudel S, Wireko AA, ... Marzban S, Michel J
Eur Heart J Cardiovasc Pharmacother: 01 Sep 2022; epub ahead of print | PMID: 36047962
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Abstract

Association between use of novel glucose-lowering drugs and COVID-19 hospitalization and death in patients with type 2 diabetes: a nationwide registry analysis.

Ferrannini G, Lund LH, Benson L, Rizzo M, ... Savarese G, Cosentino F
Aims
Type 2 diabetes (T2DM) in patients with coronavirus disease-19 (COVID-19) is associated with worse prognosis. We separately investigated the associations between the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i), and the risk of COVID-19 hospitalization and death.
Methods and results
Patients with T2DM registered in the Swedish National Patient Registry and alive on 1st February 2020 were included. \"Incident severe COVID-19\" was defined as the first hospitalization and/or death from COVID-19. A modified Poisson regression approach was applied to a 1:1 propensity score-matched population receiving vs. not receiving SGLT2i, GLP-1 RA and DPP-4i to analyze the associations between their use and I) incident severe COVID-19, II) risk of 30-day mortality in patients hospitalized for COVID-19.Among 344,413 patients, 39,172 (11%) were treated with SGLT2i, 34,290 (10%) with GLP-1 RA and 53,044 (15%) with DPP-4i; 9,538 (2.8%) had incident severe COVID-19 by 15th May 2021. SGLT2i and DPP-4i were associated with a 10% and 11% higher risk of incident severe COVID-19, respectively, whereas there was no association for GLP-1 RA. DPP-4i were also associated with a 10% higher 30-day mortality in patients hospitalized for COVID-19, whereas there was no association for SGLT2i and GLP-1 RA.
Conclusion
SGLT2i and DPP-4i use was associated with higher risk of incident severe COVID-19. DPP-4i use was associated with higher 30-day mortality in patients with COVID-19, whereas SGLT2i use was not. No increased risk for any outcome was observed with GLP-1 RA.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 13 Aug 2022; epub ahead of print
Ferrannini G, Lund LH, Benson L, Rizzo M, ... Savarese G, Cosentino F
Eur Heart J Cardiovasc Pharmacother: 13 Aug 2022; epub ahead of print | PMID: 35963647
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Abstract

Outcomes after delayed primary percutaneous coronary intervention vs. pharmaco-invasive strategy in ST-segment elevation myocardial infarction in Norway.

Jortveit J, Pripp AH, Halvorsen S
Aims
Primary percutaneous coronary intervention (pPCI) is the preferred reperfusion strategy in patients with ST-segment elevation myocardial infarction (STEMI) provided it can be performed within 120 min from diagnosis. However, it is unclear whether pPCI or a pharmaco-invasive (P-I) strategy is the best choice in patients who cannot receive timely pPCI. The aim of the present study was to compare outcomes after delayed and late pPCI vs. a P-I strategy in STEMI patients who did not receive timely pPCI.
Methods and results
All patients with STEMI registered in the Norwegian Myocardial Infarction Registry (NORMI) between 2013 and 2019, with ≤12 h from symptom onset to first medical contact and available timelines were included in the study. The primary outcome was all-cause mortality, and follow-up was through 2019. A total of 21 121 (27% of 78 368) STEMI patients were registered in the NORMI. Among patients who met the inclusion criteria, 7238 (54%) patients underwent timely pPCI, 1537 (11%) delayed pPCI (121-180 min), 1012 (7%) late pPCI (>180 min), and 2338 (17%) patients were treated with a P-I strategy. After a median follow-up time of 2.5 years, mortality was higher in the delayed pPCI [adjusted hazard ratio (HR) 1.3, 95% confidence interval (CI) 1.0-1.5] and in the late pPCI group (adjusted HR 1.4, 95% CI 1.1-1.7) compared to the P-I strategy group, but bleeding complications were more frequent after P-I strategy.
Conclusions
In STEMI patients who did not receive timely percutaneous coronary intervention, a P-I strategy seemed to be associated with better long-term survival compared to delayed/late pPCI.

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

Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:442-451
Jortveit J, Pripp AH, Halvorsen S
Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:442-451 | PMID: 34038535
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Abstract

Statin but not aspirin treatment is associated with reduced cardiovascular risk in patients with diabetes without obstructive coronary artery disease: a cohort study from the Western Denmark Heart Registry.

Olesen KKW, Heide-Jørgensen U, Thim T, Thomsen RW, ... Sørensen HT, Maeng M
Aims
Patients with diabetes and no obstructive coronary artery disease (CAD) as assessed by coronary angiography (CAG) are frequently treated with aspirin and statins. We examined the effectiveness of aspirin and statin treatment on cardiovascular and bleeding incidence in patients with diabetes and absent obstructive CAD.
Methods and results
The study included patients with diabetes and absent obstructive CAD as assessed by CAG from 2003 to 2016 in Western Denmark. We stratified patients by aspirin and statin treatment within 6 months after CAG in two separate analyses. Outcomes were MACE (major adverse cardiovascular events, a composite of myocardial infarction, ischaemic stroke, and death) and bleeding (aspirin only). To account for confounding, we used propensity score-based weights to estimate the inverse probability of treatment-weighted hazard ratios (HRIPTW). We included 4124 patients with diabetes but without CAD as assessed by CAG, among whom 2474 (60%) received aspirin and 2916 (71%) received statin treatment within 6 months following CAG. Median follow-up was 4.9 years. Aspirin did not reduce 10-year MACE [21.3% vs. 21.8%, HRIPTW 1.01, 95% confidence interval (CI) 0.82-1.25], all-cause death (HRIPTW 0.96, 95% CI 0.74-1.23), or bleeding (HRIPTW 0.95, 95% CI 0.73-1.23), compared to those not receiving aspirin treatment. Statin treatment reduced MACE (25% vs. 37%, HRIPTW 0.58, 95% CI 0.48-0.70) compared to those not receiving statin treatment.
Conclusion
Among patients with diabetes and no obstructive CAD, aspirin neither reduced MACE nor increased bleeding. In contrast, statin treatment was associated with a major reduction in risk of MACE.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:434-441
Olesen KKW, Heide-Jørgensen U, Thim T, Thomsen RW, ... Sørensen HT, Maeng M
Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:434-441 | PMID: 33989394
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Abstract

Potential Effects of Icosapent Ethyl on Cardiovascular Outcomes in Cigarette Smokers: REDUCE-IT Smoking.

Miller M, Bhatt DL, Steg PG, Brinton EA, ... Mason RP, REDUCE-IT Investigators
Aims
Cigarette smoking is among the most well-established risk factors for adverse cardiovascular outcomes. We sought to determine whether icosapent ethyl (IPE), a highly purified form of eicosapentaenoic acid with anti-atherothrombotic properties, may reduce the excessive risk of cardiovascular disease (CVD) attributable to smoking.
Methods and results
REDUCE-IT was a multinational, double-blind trial that randomized 8179 statin-treated patients with elevated triglycerides and CV risk to IPE or placebo, with a median follow-up period of 4.9 years. IPE reduced the primary composite endpoint (CV death, nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, or hospitalization for unstable angina) by 25% (P<0.0001). In the current analyses, the effect of IPE was evaluated in REDUCE-IT using post hoc analyses based upon smoking history. Groups were classified as current smokers (n = 1241), former smokers (n = 3672) and never smokers (n = 3264). Compared with placebo, IPE use in combined current and former smokers (n = 4913) was associated with significant reductions in time to the primary composite endpoint (hazard ratio, 0.77 [95% CI, 0.68-0.87]; P<0.0001) and in total events (rate ratio, 0.71 [95% CI, 0.61-0.82]; P<0.0001). These benefits remained significant when subdivided into current and former smokers (P = 0.04, P = 0.005), with reductions in the key secondary composite endpoint (P<0.0001) and in the individual components of CV death or nonfatal MI (P = 0.04, P = 0.01) and fatal or nonfatal MI (P = 0.009, P = 0.01), respectively. Benefits were consistent and significant in nonsmokers as well. Overall, there were similar estimated rates of first occurrences of primary CVD endpoints in current smokers (23.8%) and former smokers (23.0%) assigned to IPE compared with never smokers on placebo (25.7%).
Conclusion
In REDUCE-IT, IPE treatment was associated with reduced risk of CV events in current and former smokers to levels observed in never smokers. While smoking cessation should always be recommended, these data raise the possibility that IPE treatment may attenuate CV hazards attributable to smoking.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; epub ahead of print
Miller M, Bhatt DL, Steg PG, Brinton EA, ... Mason RP, REDUCE-IT Investigators
Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; epub ahead of print | PMID: 35953437
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Abstract

Efficacy and safety of dual-pathway inhibition in patients with cardiovascular disease: a meta-analysis of 49 802 patients from 7 randomized trials.

Galli M, Capodanno D, Benenati S, D\'Amario D, ... Andreotti F, Angiolillo DJ
Aims
Low-dose (LD) direct oral anticoagulants (DOACs) in adjunct to antiplatelet therapy, known as dual-pathway inhibition (DPI), have been tested to prevent ischaemic events in patients with cardiovascular disease (CVD). We conducted a systematic review and meta-analysis to determine the overall safety and efficacy of LD DOACs vs placebo on a background of antiplatelet therapy.
Methods and results
All randomized controlled trials (RCTs) comparing LD DOAC (defined as a dosage below the lowest approved for stroke prevention) vs placebo among patients with CVD receiving single or dual antiplatelet therapy (DAPT) in at least 50% of the population and followed for at least 6 months, were included. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were used to overcome different follow-up durations across trials. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint major bleeding. A pre-specified subgroup analysis was performed for different DOAC-dose regimens. A total of 49 802 patients from 7 RCTs were included. Low-dose DOACs vs placebo were associated with significant reductions in MACE (IRR 0.85, 95% CI 0.78-0.91, number needed to treat, NNT, 86) and myocardial infarction (IRR 0.86, 95% CI 0.78-0.95, NNT 355) and significant increases of major (IRR 2.05, 95% CI 1.50-2.80, number needed to harm, NNH, 89) or all bleeding (IRR 1.82, 95% CI 1.49-2.22, NNH 23). Cardiovascular death (IRR 0.90, 95% CI 0.79-1.03, NNT 784), intracranial (IRR 1.18, 95% CI 0.71-1.96, NNH 1810), and fatal bleeding (IRR 1.13, 95% CI 0.76-1.69, NNH 3170) did not differ significantly between strategies. Non-significant reductions of all-cause death (IRR 0.90, 95% CI 0.80-1.01, NNT 821) and stroke (IRR 0.73, 95% CI 0.53-1.01, NNT 315) favoured LD DOACs. Meta-regression analyses showed a significant interaction between percentage of DAPT use and increased risk of major bleeding (P = 0.04), intracranial haemorrhage (P = 0.035), and stroke (P = 0.0003). Subgroup analysis of very LD DOAC, defined as ≤1/3 of the lowest approved dose for stroke prevention (i.e. rivaroxaban 2.5 mg twice daily) seemed to mitigate the risk of bleeding without any trade-off in efficacy compared to other LD DOAC regimens.
Conclusions
In patients with CVD, LD DOAC vs placebo on a background of antiplatelet therapy, reduced ischaemic events at the expense of increased major and all bleeding, but without significantly increasing intracranial or fatal bleeds, while the reduction of cardiovascular or total mortality and stroke was not statistically significant. A DPI with very LD DOAC (i.e. rivaroxaban 2.5 mg twice daily) appeared particularly advantageous, especially when combined with a single antiplatelet agent and used among patients at high ischaemic and low bleeding risk.
Study registration
This study is registered in PROSPERO (CRD42021232744).

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:519-528
Galli M, Capodanno D, Benenati S, D'Amario D, ... Andreotti F, Angiolillo DJ
Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:519-528 | PMID: 34146091
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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: 11 Aug 2022; 8:483-491
Sarajlic P, Simonsson M, Jernberg T, Bäck M, Hofmann R
Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:483-491 | PMID: 34423350
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Abstract

Impact of chronic kidney disease on the pharmacodynamic and pharmacokinetic effects of ticagrelor in patients with diabetes mellitus and coronary artery disease.

Franchi F, Rollini F, Been L, Maaliki N, ... Bass TA, Angiolillo DJ
Aims
Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) are at increased risk of atherothrombotic events. Ticagrelor reduces ischaemic events compared to clopidogrel, with the greatest risk reduction in patients with both DM and CKD. How CKD status affects the pharmacodynamic (PD) and pharmacokinetic (PK) profiles of different ticagrelor maintenance dose regimens in patients with DM is unknown.
Methods and results
In this randomized, crossover study, patients with DM on treatment with dual antiplatelet therapy (aspirin and clopidogrel) were stratified according to CKD status and randomized to ticagrelor 90 or 60 mg bid. PK/PD assessments were performed at baseline, after 7-10 days of ticagrelor (peak and trough), and after 7-10 days of alternative ticagrelor regimen (peak and trough). PK assessments included plasma concentrations of ticagrelor and its major metabolite. PD assessments included vasodilator-stimulated phosphoprotein (VASP)-platelet reactivity index (PRI), VerifyNow P2Y12, and light transmittance aggregometry (LTA). A total of 92 patients with DM (CKD, n = 44; non-CKD, n = 48) were randomized. Levels of platelet reactivity were lower with the 90 mg compared with the 60 mg ticagrelor dose, which was statistically significant in non-CKD but not in CKD patients for most PD measures. There were no significant differences in the primary endpoint (trough levels of VASP-PRI following ticagrelor 90 mg dosing) between cohorts (31 ± 20 vs. 25 ± 14; P = 0.105). VerifyNow and LTA provided similar findings. PK assessments tracked PD profiles showing increased plasma concentrations of ticagrelor and its major metabolite in CKD compared to non-CKD patients.
Conclusion
In patients with DM, although ticagrelor maintenance dose regimens (60 and 90 mg) yield potent P2Y12 inhibition, levels of platelet reactivity tended to be higher and subject to broader variability in non-CKD compared with CKD patients.
Clinical trial registration
http://www.clinicaltrials.gov Unique Identifier: NCT02539160.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:452-461
Franchi F, Rollini F, Been L, Maaliki N, ... Bass TA, Angiolillo DJ
Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:452-461 | PMID: 34114623
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Abstract

Guided and unguided de-escalation from potent P2Y12 inhibitors among patients with acute coronary syndrome: 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 and results
PubMed, Google Scholar, and Cochrane Central Register of Controlled Trials were searched for eligible randomized controlled trials. Aspirin monotherapy trials were excluded. Five randomized trials (n = 10 779 patients) that assigned DAPT de-escalation (genetically guided to clopidogrel n = 1242; platelet function guided to clopidogrel n = 1304; unguided to clopidogrel n = 1672; unguided to lower dose n = 1170) vs. standard DAPT (control group n = 5391) 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 (PFT), 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: 11 Aug 2022; 8:492-502
Tavenier AH, Mehran R, Chiarito M, Cao D, ... Sharma SK, Dangas G
Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:492-502 | PMID: 34459481
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Abstract

Low-dose rivaroxaban plus aspirin in patients with polypharmacy and multimorbidity: an analysis from the COMPASS trial.

Vanassche T, Verhamme P, Anand SS, Shestakovska O, ... Eikelboom JW, Bosch J
Aims
To analyse whether the benefits and risks of rivaroxaban plus aspirin vary in patients with comorbidities and receiving multiple drugs. In patients with coronary or peripheral artery disease, adding low-dose rivaroxaban to aspirin reduces cardiovascular events and mortality. Polypharmacy and multimorbidity are frequent in such patients.
Methods and results
We describe ischaemic events (cardiovascular death, stroke, or myocardial infarction) and major bleeding in participants from the randomized, double-blind COMPASS study by number of cardiovascular medications and concomitant medical conditions. We compared event rates and hazard ratios (HRs) for rivaroxaban plus aspirin vs. aspirin alone by the number of medications and concomitant conditions, and tested for interaction between polypharmacy or multimorbidity and the antithrombotic regimen. The risk of ischaemic events was higher in patients with more concomitant drugs (HR 1.7, 95% confidence interval 1.5-2.1 for >4 vs. 0-2) and with more comorbidities (HR 2.3, 1.8-2.1 for >3 vs. 0-1). Multimorbidity, but not polypharmacy, was associated with a higher risk of major bleeding. The relative efficacy, safety, and net clinical benefit of rivaroxaban were not affected by the number of drugs or comorbidities. Patients taking more concomitant medications derived the largest absolute reduction in the net clinical outcome with added rivaroxaban (1.1% vs. 0.4% reduction with >4 vs. 0-2 cardiovascular drugs, number needed to treat 91 vs. 250).
Conclusion
Adding low-dose rivaroxaban to aspirin resulted in benefits irrespective of the number of concomitant drugs or comorbidities. Multiple comorbidities and/or polypharmacy should not dissuade the addition of rivaroxaban to aspirin in otherwise eligible patients.

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

Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:462-473
Vanassche T, Verhamme P, Anand SS, Shestakovska O, ... Eikelboom JW, Bosch J
Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:462-473 | PMID: 34191011
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Abstract

Concerns about the use of digoxin in acute coronary syndromes.

Bugiardini R, Cenko E, Yoon J, van der Schaar M, ... Badimon L, Manfrini O
Aims
The use of digitalis has been plagued by controversy since its initial use. We aimed to determine the relationship between digoxin use and outcomes in hospitalized patients with acute coronary syndromes (ACSs) complicated by heart failure (HF) accounting for sex difference and prior heart diseases.
Methods and results
Of the 25 187 patients presenting with acute HF (Killip class ≥2) in the International Survey of Acute Coronary Syndromes Archives (NCT04008173) registry, 4722 (18.7%) received digoxin on hospital admission. The main outcome measure was all-cause 30-day mortality. Estimates were evaluated by inverse probability of treatment weighting models. Women who received digoxin had a higher rate of death than women who did not receive it [33.8% vs. 29.2%; relative risk (RR) ratio: 1.24; 95% confidence interval (CI): 1.12-1.37]. Similar odds for mortality with digoxin were observed in men (28.5% vs. 24.9%; RR ratio: 1.20; 95% CI: 1.10-1.32). Comparable results were obtained in patients with no prior coronary heart disease (RR ratio: 1.26; 95% CI: 1.10-1.45 in women and RR ratio: 1.21; 95% CI: 1.06-1.39 in men) and those in sinus rhythm at admission (RR ratio: 1.34; 95% CI: 1.15-1.54 in women and RR ratio: 1.26; 95% CI: 1.10-1.45 in men).
Conclusion
Digoxin therapy is associated with an increased risk of early death among women and men with ACS complicated by HF. This finding highlights the need for re-examination of digoxin use in the clinical setting of ACS.

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

Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:474-482
Bugiardini R, Cenko E, Yoon J, van der Schaar M, ... Badimon L, Manfrini O
Eur Heart J Cardiovasc Pharmacother: 11 Aug 2022; 8:474-482 | PMID: 34251454
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Abstract

Use of sodium-glucose cotransporter-2 inhibitors and the risk for sudden cardiac arrest and for all-cause death in patients with type 2 diabetes mellitus.

Eroglu TE, Coronel R, Zuurbier CJ, Blom M, de Boer A, Souverein PC
Aims
Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic agents that can have direct cardiac effects by impacting on cardiac ion transport mechanisms that control cardiac electrophysiology. We studied the association between SGLT-2i use and all-cause mortality and the risk of sudden cardiac arrest (SCA) in patients with type 2 diabetes.
Methods
Using data from the UK Clinical Practice Research Datalink, a cohort study among patients initiating a new antidiabetic drug class on or after January 2013 through September 2020 was conducted. Cox regression with time-dependent covariates was performed to estimate the hazard ratios (HRs) of SCA and all-cause mortality comparing SGLT-2is with other second- to third-line antidiabetic drugs. Stratified analyses were performed according to sex, diabetes duration (<5 or ≥ 5 years), and the presence of cardiovascular disease.
Results
A total of 152 591 patients were included. Use of SGLT-2i was associated with reduced HR of SCA when compared to other second- to third-line antidiabetic drugs after adjustment for common SCA risk factors, although this association marginally failed to reach statistical significance (HR:0.62 [95%-CI:0.38-1.01]). The HR of all-cause mortality associated with SGLT-2i use when comparing to other second-to third-line antidiabetics was 0.43 (95%-CI:0.39-0.48) and did not vary by sex, diabetes duration or the presence of cardiovascular disease. SGLT-2i use remained associated with lower all-cause mortality in patients without concomitant insulin use (HR:0.56 [95%-CI:0.50-0.63]).
Conclusion
SGLT-2i use was associated with reduced all-cause mortality in patients with type 2 diabetes. The association between use of SGLT-2i and reduced risk of SCA was not statistically significant.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 27 Jul 2022; epub ahead of print
Eroglu TE, Coronel R, Zuurbier CJ, Blom M, de Boer A, Souverein PC
Eur Heart J Cardiovasc Pharmacother: 27 Jul 2022; epub ahead of print | PMID: 35894858
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Abstract

Edoxaban for stroke prevention in atrial fibrillation and age-adjusted predictors of clinical outcomes in routine clinical care.

Kirchhof P, Pecen L, Bakhai A, de Asmundis C, ... Souza J, De Caterina R
Introduction
Patients with atrial fibrillation (AF) treated with oral anticoagulation still suffer from cardiovascular complications including cardiovascular death, stroke and major bleeding. To identify risk factors for predicting stroke and bleeding outcomes in anticoagulated patients, we assessed two-year outcomes in patients with AF treated with edoxaban in routine care. We also report the age-adjusted risk predictors of clinical outcomes.
Methods and results
ETNA-AF-Europe (NCT02944019) is a prospective, multi-centre, post-authorisation, observational study with an overall four-year follow-up conducted in 825 centres enrolling edoxaban-treated patients in 10 European countries. Of the 13 133 patients with AF (mean age: 73.6 ± 9.5 years), 5682 (43.3%) were female. At the two-years follow-up, 9017/13 113 patients were still on edoxaban; 1830 discontinued treatment including 937 who died (annualised event rate of all-cause death was 3.87%). 518 (2.14%) patients died of cardiovascular causes; 234 (0.97%) experienced major bleeding and 168 (0.70%) experienced stroke or systemic embolic events (SEE). Intracranial haemorrhage was noted in 49 patients (0.20%).History of transient ischaemic attack (TIA) at baseline was the strongest predictor of ischaemic stroke or SEE (Wald Chi-square: 73.63; P < 0.0001). Low kidney function at baseline was the strongest predictor of major bleeding (Wald Chi-Square: 30.68; P < 0.0001). History of heart failure (HF) was the strongest predictor of all-cause (Wald Chi-Square: 146.99; P < 0.0001) and cardiovascular death (Wald Chi-Square: 100.38; P < 0.0001).
Conclusion
Patients treated with edoxaban in ETNA-AF-Europe reported low two-year event rates in unselected AF patients. Prior stroke, reduced kidney function, and HF identify patients at high risk of stroke, bleeding and all-cause/cardiovascular death, respectively.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 26 Jul 2022; epub ahead of print
Kirchhof P, Pecen L, Bakhai A, de Asmundis C, ... Souza J, De Caterina R
Eur Heart J Cardiovasc Pharmacother: 26 Jul 2022; epub ahead of print | PMID: 35881467
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Abstract

Non-steroidal anti-inflammatory drugs and risk of myocardial infarction adjusting for use of proton pump-inhibitors in patients with no major risk factors: a nested case-control study in the UK Clinical Practice Research Datalink.

Baak BN, Jick SS
Aims
Studies have found an increased risk of myocardial infarction (MI) in association with some non-steroidal anti-inflammatory drugs (NSAID). We evaluated this association in patients without major cardiovascular risk factors and assessed potential reverse causality bias.
Methods and results
In this nested case-control study of patients aged 40-79 in Clinical Practice Research Datalink GOLD who received at least one NSAID prescription between 2006 and 2019, we found 8639 MI cases and 34 556 matched controls. We calculated odds ratios (ORs) and 95% confidence intervals (CI) for MI comparing NSAID users to non-exposed according to number and timing of NSAID prescriptions and proton-pump inhibitor (PPI) use. Current diclofenac use was associated with a twofold increased risk of MI regardless of duration of use (adjusted OR, 2.08; 95% CI, 1.82-2.38). ORs ranged from 3 to 5 among current and recent diclofenac users newly exposed to PPIs. There was no spike in risk in new current diclofenac users not exposed to PPIs, but ORs rose with increasing prescriptions. Risk of MI in ibuprofen users was concentrated in new PPI users. There was no material increased risk in naproxen users, nor in past users of most NSAIDs in the absence of PPIs.
Conclusion
Risk of MI was elevated in current diclofenac users, particularly in new concomitant PPI users. ORs increased in new users of ibuprofen and PPIs but declined with extended use and were lower in non-PPI users. This suggests that some of the findings may be explained by reverse causality bias.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 25 Jul 2022; epub ahead of print
Baak BN, Jick SS
Eur Heart J Cardiovasc Pharmacother: 25 Jul 2022; epub ahead of print | PMID: 35876661
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Abstract

Racial and Ethnic Differences in Pharmacotherapy to Prevent Coronary Artery Disease and Thrombotic Events.

Tamargo J, Kaski JC, Kimura T, Barton JC, ... Agewall S, Hasegawa K
Awareness of racial/ethnic disparities represents a key challenge for healthcare systems that attempt to provide effective healthcare and to reduce existing inequalities in the use of and adherence to guideline-recommended cardiovascular drugs to improve clinical outcomes for cardiovascular disease (CVD). In this review, we describe important racial/ethnic differences between and within ethnic groups in the prevalence, risk factors, haemostatic factors, anti-inflammatory and endothelial markers, recurrence, and outcomes of CVD. We discuss important differences in the selection, doses, and response (efficacy and adverse drug reactions [ADRs]) in ethnically diverse patients treated with antithrombotics or lipid-lowering drugs. Differences in drug response are mainly related to racial/ethnic differences in the frequency of polymorphisms in genes encoding drug-metabolizing enzymes (DMEs) and drug transporters. These polymorphisms markedly influence the pharmacokinetics, dose requirements, and safety of warfarin, clopidogrel, and statins. This review aims to support a better understanding of the genetic differences between and among populations to identify patients who may experience an ADR or a lack of drug response, thus optimizing therapy and improving outcomes. The greater the understanding of the differences in the genetic variants of DMEs and transporters that determine the differences in the exposure, efficacy, and safety of cardiovascular drugs between races/ethnicities, the greater the probability that personalized medicine will become a reality.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 15 Jul 2022; epub ahead of print
Tamargo J, Kaski JC, Kimura T, Barton JC, ... Agewall S, Hasegawa K
Eur Heart J Cardiovasc Pharmacother: 15 Jul 2022; epub ahead of print | PMID: 35848895
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This program is still in alpha version.