Themed Issue on Advances in Cardiovascular Pharmacotherapy
Cardiovascular disease (CVD) is the leading health burden in the United States, contributing significantly to morbidity and mortality.1 Traditional CVD risk factors, including hypertension, diabetes, and dyslipidemia, are major contributors to the development of atherosclerosis, and control of these risk factors is a mainstay of both primary prevention and secondary prevention.2, 3 Research on pharmacotherapy in CVD is advancing rapidly, with new insights occurring frequently, presenting challenges to clinicians in keeping up with the literature, particularly in new areas of rapid development, such as, cardiac amyloidosis, and lipid-lowering therapies.
In this themed issue of Pharmacotherapy, 11 articles provide insights into recent advances in diverse areas of pharmacotherapy research in patients with or at risk of CVD. This issue also provides contemporary reviews of novel and emerging areas in cardiovascular pharmacotherapy. The articles chosen for inclusion, written by experts in the field, have a broad scope, ranging from cardiovascular risk factors and atherosclerotic CVD to heart failure and advanced CVD, representing a diversity of topics in a wide array of cardiovascular subspecialties.
Starting with cardiovascular risk factors, 2 articles in this issue focus on the evolving management of dyslipidemia, focusing on newer therapies being developed and studied that impact clinical practice. In a systematic review and meta-analysis of 8 randomized controlled trials of pharmacologic agents targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), namely, PSCK9 inhibitors (evolucumab, alirocumab) and small interfering RNA-based agents targeting PCSK9 (inclisiran), Talasaz et al. synthesized the literature on low-density lipoprotein (LDL) reduction and clinical outcomes.4 This study found consistent reductions in LDL and composite major adverse cardiovascular events (MACE), but failed to identify significant individual reductions in components of the composite, such as death, myocardial infarction, and stroke. The other emerging area in dyslipidemia therapy is omega-3 fatty acids with the recent trials REDUCE-IT and STRENGTH providing inconsistent findings related to clinical outcomes benefit. Barry and Dixon's comprehensive and practical review on omega-3 fatty acids explores this conflicting evidence and also updates readers about the recent signals of increased risk of atrial fibrillation with prescription strength omega-3 fatty acids.5 In an additional article related to cardiovascular risk factors, An et al. conducted a retrospective cohort study of nearly 7,000 patients with diabetic kidney disease to examine whether combination therapy with a mineralocorticoid receptor antagonist added to angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) was associated with superior MACE and renal outcomes compared with ACE inhibitor/ARB monotherapy.6 While this study did not find a difference between groups in MACE during a short follow-up, patients with combination therapy had a greater reduction in urine albumin-to-creatinine ratio signally a renal benefit. However, hyperkalemia was nearly twofold higher in those taking combination therapy, reminding us of the importance of monitoring for drug safety outcomes in practice.
Moving on to coronary artery disease (CAD), in a retrospective cohort study of over 160,000 older persons with CAD, Sud et al. examined the association between the use of ACEi/ARB and MACE acute kidney injury events.7 In those with primary myocardial infarction, receipt of ACEi/ARB as used in clinical practice was associated with not only reduced MACE but also a lower risk of acute kidney injury. Given the underuse of ACEi/ARB for secondary prevention in CAD, this study will assist clinicians by prioritizing which patients have the best risk-benefit balance and would gain from our efforts to implement secondary prevention therapy with ACEi/ARB. An additional study in patients with existing CAD that may assist us in choosing pharmacotherapy options is a single-center, retrospective cohort, pharmacogenomics study by Wood et al.8 In nearly 1500 patients who underwent percutaneous coronary intervention and who also underwent CYP2C19 genotype testing, MACE was higher in carriers of a no function allele compared with those without a no function allele in both older and younger patients who were treated with clopidogrel while no difference was detected in prasugrel or ticagrelor users, suggesting clinical benefits of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention.
Heart failure is an area of cardiology that has seen tremendous growth and focus in recent years, including expansion of mortality-reducing drugs, progress toward treatments for heart failure with preserved ejection fraction, and updated clinical practice guidelines. Four articles in this issue address expanding areas of heart failure research and practice. Veeder et al. provide a detailed review of chemotherapy-associated cardiomyopathy including proposed mechanisms and a discussion of potentially cardioprotective therapies.9 Most of the reviewed research focuses on strategies to prevent chemotherapy-associated cardiomyopathy with anthracycline and HER-2-targeted therapies, with little consensus and few high-quality trials available to provide strong recommendations. Another under-diagnosed and undertreated cause of heart failure is transthyretin cardiac amyloidosis (ATTR-CA). Warner provides an updated review of all aspects of ATTR-CA, including diagnosis, traditional and emerging targeted therapies, and cost considerations.10 Moving on to the world of heart failure and preserved ejection fraction, Demeny et al. provide a pharmacogenomic analysis of the Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) population.11 They identified a subpopulation with a particular polymorphism (NR3C2 rs5522) in the gene responsible for encoding the mineralocorticoid receptor that associates with worsening of diastolic function and who may especially benefit from spironolactone therapy. Lastly, Jennings et al. evaluated a cohort of adults who had undergone heart transplant from January 2000 to August 2018, stratified by pre-transplant amiodarone use.12 Compared with nonusers, amiodarone use was associated with higher 1-year but not 5- or 10-year mortality after heart transplant. These studies each aid clinicians in identifying individuals who are more likely to benefit from certain treatments or who may be at risk for worse outcomes based on prior medication use.
This issue includes two other articles in additional areas that present challenge for clinicians caring for individuals with cardiovascular disease. In those undergoing cardiac surgery, heparin is commonly used for those utilizing cardiopulmonary bypass. As such, heparin-induced thrombocytopenia (HIT) can develop, complicating post-surgical care. Stewart et al. conducted a nested case-control study comparing the predictive ability of two risk scores for HIT in a population who had undergone cardiac surgery from 2008 to 2018.13 While the discriminatory ability of the two scores was similar, differences may exist, suggesting improvements to risk prediction of HIT in cardiac surgical populations remain. Pericarditis, an inflammation of the pericardium, has received attention in recent years following the resurgence of colchicine as a treatment option. Schwier et al. provide a detailed update of literature for options to manage pericarditis both in pediatric and adult populations.14 This includes anti-inflammatory drugs such as colchicine and nonsteroidal anti-inflammatory drugs, as well as immunotherapies and issues of adverse event mitigation and pharmacovigilance.
Cardiovascular pharmacotherapy is a rapidly evolving field, often with an abundance of therapeutic choices from which clinicians must select the most optimal therapy for a patient. The articles included in this cardiovascular theme issue provide the latest information in many cardiovascular fields, giving timely information that will assist clinicians with choosing therapies with the best risk-benefit balance to optimize outcomes for patients with heart disease.
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1 Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics—2021 update: a report from the American Heart Association. Circulation. 2021; 143: e254- e743. doi:10.1161/CIR.0000000000000950
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4 Talasaz AH, Ho A, Bhatty F, et al. Meta-analysis of clinical outcomes of PCSK9 Modulators in patients with established ASCVD. Pharmacotherapy. 2021; 12: 1009- 1023.
5 Barry A, Dixon D. Omega-3 fatty acids for the prevention of atherosclerotic cardiovascular disease. Pharmacotherapy. 2021; 12: 1056- 1065.
6 An J, Fang N, Sim J. Cardiovascular and kidney outcomes of spironolactone or eplerenone in combination with ACEI/ARBs in patients with diabetic kidney disease. Pharmacotherapy. 2021; 12: 998- 1008.
7 Sud M, Ko DT, Chong A, et al. Renin-angiotensin-aldosterone system inhibitors and major cardiovascular and acute kidney injury in patients with coronary artery disease. Pharmacotherapy. 2021; 12: 988- 997.
8 Wood B, Lee CR, Mulrenin IR, et al. Effects of aging on clinical outcomes in patients receiving genotype-guided P2Y12 inhibitor selection after percutaneous coronary intervention. Pharmacotherapy. 2021; 12: 970- 977.
9 Veeder J, Hothem LN, Cipriani AE, et al. Chemotherapy-associated cardiomyopathy: mechanisms of toxicity and cardioprotective strategies. Pharmacotherapy. 2021; 12: 1066- 1080.
10 Warner AL. Advances in the treatment of transthyretin cardiac amyloidosis: current and emerging therapies. Pharmacotherapy. 2021; 12: 1081- 1091.
11 Demeny L, Vardeny O, Edelmann F, et al. NR3C2 genotype is associated with response to spironolactone in diastolic heart failure patients from the Aldo-DHF trial. Pharmacotherapy. 2021; 12: 978- 987.
12 Jennings DL, Gadela NV, Jaiswal A, et al. Pre-transplant amiodarone use does not affect long-term heart transplant survival. Pharmacotherapy. 2021; 12: 1024- 1032.
13 Stewart JJ, Turgeon R, Parker A, et al. Comparison of risk-scoring systems for heparin-induced thrombocytopenia in cardiac surgery patients. Pharmacotherapy. 2021; 12: 1033- 1040.
14 Schwier NC, Tsui J, Perrine JA, et al. Current pharmacotherapy management of children and adults with pericarditis: prospectus for improved outcomes. Pharmacotherapy. 2021; 12: 1041- 1055.