Cardiovascular disease and cardiovascular pharmacotherapy: the challenges and the research continue

As we end 2024 and enter the new year 2025, it is both interesting and gratifying to witness and review advances in the pharmacotherapy of cardiovascular disease. Antithrombotic drugs are the cornerstone of therapy in a wide range of cardiovascular diseases, but bleeding risk and the risk benefit-ratio remain a major challenge.1–3 Guidelines and risk scores guide clinicians.4,5 In this issue of the journal, a Swedish study by Jeppsson and colleagues examined the role of the Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score6 in the surgical arena. They found that PRECISE-DAPT criteria identify coronary artery bypass graft (CABG) patients with increased risk for major bleeding with moderate accuracy, comparable to what has been reported for patients after percutaneous coronary intervention (PCI). De-escalation of antithrombotic treatment is an emerging strategy in patients following an acute coronary syndrome and/or interventional procedure.7 Baber and colleagues report a post hoc analysis of the Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention (TWILIGHT) trial,8,9 which assessed the effect of ticagrelor monotherapy over a 12-month follow-up period as opposed to continuing aspirin-ticagrelor DAPT, randomizing to these arms at 3 months post-PCI. The post hoc study examined the total number of BARC 2, 3, or 5 bleeding events, as compared with first event only. The use of total events amplified the bleeding benefit of ticagrelor monotherapy, while total ischaemic events were similar in the two groups. The STOPDAPT-3 clinical study10,11 showed that an aspirin-free strategy using low-dose prasugrel monotherapy (3.75 mg/day) compared with a DAPT strategy failed to attain superiority for major bleeding within 1 month after PCI. The aspirin-free strategy was associated with a signal suggesting an excess of coronary events.10 In a pre-specified analysis of diabetic patients in the trial, patients who may be at risk for adverse outcomes, Yamamoto and colleagues found that the effects of prasugrel monotherapy relative to DAPT were not different in the diabetic and non-diabetic subsets. Should a de-escalation strategy be genotype-guided? Van den Broek et al. used a lifelong Markov model to compare lifetime costs, and quality-adjusted life years (QALYs) for a fictional cohort of 1000 patients, based on the perspective of the Dutch healthcare system. Probabilistic sensitivity analysis showed that the genotype-guided strategy was cost-saving in 93% and increased QALYs in 86% of simulations. Cardiogenic shock carries high mortality. Omerovic et al. investigated the effect of inotropes in shock patients using data from the SWEDEHEART registry (The Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies). A total of 16 214 patients were included. Inotropes were administered to 43.8% of patients. Patients treated with inotropes were, on average, 2 years younger and more likely to have an acute coronary syndrome, while those not treated had more previous episodes of myocardial infarction and were less likely to undergo PCI. Interestingly, the number of shock cases in the registry decreased by 12% per year, while inotrope use increased by 5% per year. Inotrope use was linked to higher mortality, particularly in patients younger than 70 years. The challenge of heart failure with fluid overload has prompted new strategies for decongestion. In this arena, subcutaneous furosemide is a novel therapeutic strategy.12 Campbell and colleagues present a systematic review of the current evidence for subcutaneous furosemide in patients with heart failure. Studies in the review used novel pH-neutral, subcutaneous preparations of furosemide, which achieved comparable diuresis, natriuresis, and bioavailability to intravenous furosemide, and were well tolerated. Hypokalaemia is associated with increased cardiovascular events and mortality. The non-steroidal mineralocorticoid receptor antagonist finerenone, a new key player in the management of chronic kidney disease,13 has a beneficial profile regarding potassium balance. In a prespecified pooled patient-dataset from the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trials, Pitt et al. found that hypokalaemia in the overall data set was considerable (serum potassium <4.0 and <3.5 mmol/L in 41.1 and 7.5%, respectively), but less so in patients treated with finerenone. There was a lesser hazard of cardiovascular and arrhythmia events with finerenone; interestingly, the benefit was observed irrespective of baseline serum potassium levels. The risk-benefit role of aspirin for primary prevention of cardiovascular disease continues to be debated.14–16 In an Australian study, Yu et al. performed genetic risk stratification of the Aspirin in Reducing Events in the Elderly randomized controlled trial.17 A total of 12 031 genotyped participants (5974 aspirin, 6057 placebo) were stratified by quintiles according to genotyped coronary artery disease (CAD) risk. In the overall population, aspirin resulted in a higher bleeding risk but no CAD reduction. However, among the highest quintile of polygenic risk, there was a 47% reduction in risk of CAD events with aspirin without increased bleeding, suggesting that genetic testing could be a useful factor to guide us in the aspirin prevention discussion. Two papers examine the cardiovascular effect of drugs used for other indications. Huang et al. studied phosphodiesterase (PDE) inhibitors. They showed that Mendelian randomization analyses identified two types of PDEs (PDE5 and PDE8) where genetically predicted expression in blood of the encoded genes was associated with the risk of coronary heart disease. Real-world data provided supportive evidence regarding PDE5 inhibitors and a lower incidence of heart disease, but the findings were not definitive since reverse causality may be at play. Regarding drugs used in Alzheimer's disease, Wessberg and colleagues investigated the possible beneficial effects of cholinesterase inhibitors (ChEi's) on the heart,18 using a propensity score matched cohort in Sweden. In 455 patients with and 455 without ChEi treatment, ChEi use was associated with lower mortality and hospitalization due to heart failure. The findings varied by drug: donepezil and galantamine but not rivastigmine were associated with lower risk of death compared to non-users. These observational data are relevant given the increase in ageing in many populations, with an increasing number of patients with both dementia and cardiovascular disease.