European Heart Journal - Cardiovascular Pharmacotherapy最新文献

Aims: A genotype-guided P2Y12-inhibitor de-escalation strategy, switching acute coronary syndrome (ACS) patients without a CYP2C19 loss-of-function allele from ticagrelor or prasugrel to clopidogrel, has shown to reduce bleeding risk without affecting effectivity of therapy by increasing ischemic risk. We estimated the cost-effectiveness of this personalized approach compared to standard dual antiplatelet therapy (DAPT; aspirin plus ticagrelor/prasugrel) in the Netherlands.

Methods and results: We developed a one-year decision tree based on results of the FORCE-ACS registry, comparing a cohort of ACS patients who underwent genotyping with a cohort of ACS patients treated with standard DAPT. This was followed by a lifelong Markov model to compare lifetime costs, and quality-adjusted life years (QALYs) for a fictional cohort of 1000 patients. The cost-effectiveness analysis was performed from the perspective of the Dutch healthcare system. A genotype-guided de-escalation strategy led to anincrease of 55.30 QALYs and saved €698,286 compared to standard DAPT based on a lifetime horizon. Probabilistic sensitivity analysis showed that the genotype-guided strategy was cost-saving in 93% and increased QALYs in 86% of simulations. The intervention remained cost-effective in the scenario where prices for all P2Y12-inhibitors were equalized. The genotype-guided strategy remained dominant in various other scenario and sensitivity analyses.

Conclusion: A genotype-guided de-escalation strategy in patients with ACS was both cost-saving and yielded higher QALYs compared to standard DAPT, highlighting its potential for implementation in clinical practice. Trial registration: ClinicalTrials.gov identifier: NCT03823547.

Background and aim: Intravenous loop diuretics are the primary treatment for congestion in patients with decompensated heart failure (HF). Furosemide is the most commonly used loop diuretic and is licensed for administration either orally, intramuscularly or intravenously but not subcutaneously. Recently developed, pH-neutral, concentrated, 'skin-friendly' preparations of furosemide have been developed which allow subcutaneous administration. In this systematic review, we summarize and critically appraise the current evidence for subcutaneous furosemide in patients with HF.

Methods and results: The electronic databases MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov registry were searched up to 31 December 2023. Of the 17 studies identified, 5 were randomised controlled trials (RCTs), 2 were non-randomised controlled studies, 3 were prospective observational cohort studies, and 7 were retrospective observational studies.All RCTs utilised novel pH-neutral, subcutaneous preparations of furosemide. Bioavailability of novel subcutaneous preparations were similar to intravenous furosemide 10 mg/ml: 99.7% for an 8 mg/ml preparation and 112% for a 30 mg/ml preparation. Natriuresis and diuresis were also similar with novel subcutaneous and conventional intravenous furosemide. Adverse events of novel preparations included infusion site pain or discomfort, localised skin erythema and minimal swelling. All studies of conventional subcutaneous furosemide were non-randomised with very limited data re bioavailability or diuretic and natriuretic effect. Conventional subcutaneous furosemide was associated with substantial skin irritation (affecting 3-23% of patients), and skin infections requiring treatment with antibiotics (3-17%).

Conclusions: Novel, pH-neutral preparations of subcutaneous furosemide achieved similar diuresis, natriuresis, and bioavailability to intravenous furosemide, and were well tolerated. Novel preparations may be a treatment option for patients with HF.

Aims: Although dual antiplatelet therapy with aspirin and a potent P2Y12 receptor inhibitor is currently recommended in patients with acute coronary syndrome (ACS), its use in elderly patients remains challenging. The aim of this trial is to evaluate the pharmacodynamic and pharmacokinetic profile of ticagrelor 60 vs. 90 mg twice daily among elderly patients (≥75 years) with ACS undergoing percutaneous coronary intervention (PCI).

Methods and results: PLINY The ELDER (NCT04739384) was a randomized, crossover trial testing the non-inferiority of a lower vs. standard dose of ticagrelor with respect to the primary endpoint of P2Y12 inhibition as determined by pre-dose P2Y12 reaction units (PRU) using the VerifyNow-P2Y12 (Accumetrics, San Diego, CA, USA). Other pharmacodynamic tests included light transmittance aggregometry, multiple electrode aggregometry, and response to aspirin. Plasma levels of ticagrelor and its active metabolite AR-C124910XX were also evaluated. A total of 50 patients (mean age 79.6 ± 4.0 years, females 44%) were included in the trial. Ticagrelor 60 mg was non-inferior to ticagrelor 90 mg according to VerifyNow-P2Y12 results (PRU 26.4 ± 32.1 vs. 30.4 ± 39.0; least squares mean difference: -4; 95% confidence interval: -16.27 to 8.06; P for non-inferiority = 0.002). Other pharmacodynamic parameters were similar between the two ticagrelor doses and there were no differences in response to aspirin. Plasma levels of ticagrelor (398.29 ± 312.36 ng/mL vs. 579.57 ± 351.73 ng/mL, P = 0.006) and its active metabolite were significantly lower during treatment with ticagrelor 60 mg.

Conclusion: Although plasma concentrations were lower, ticagrelor 60 mg twice daily provided a similar magnitude of platelet inhibition compared with ticagrelor 90 mg twice daily among elderly patients undergoing PCI.

Obesity and underweight are a growing health problem worldwide and a challenge for clinicians concerning antithrombotic therapy, due to the associated risks of thrombosis and/or bleeding. This clinical consensus statement updates a previous one published in 2018, by reviewing the most recent evidence on antithrombotic drugs based on body size categories according to the World Health Organization classification. The document focuses mostly on individuals at the extremes of body weight, i.e. underweight and moderate-to-morbid obesity, who require antithrombotic drugs, according to current guidelines, for the treatment or prevention of cardiovascular diseases or venous thromboembolism. Managing antithrombotic therapy or thromboprophylaxis in these individuals is challenging, due to profound changes in body composition, metabolism and organ function, and altered drug pharmacokinetics and pharmacodynamics, as well as weak or no evidence from clinical trials. The document also includes artificial intelligence simulations derived from in silico pharmacokinetic/pharmacodynamic models, which can mimic the pharmacokinetic changes and help identify optimal regimens of antithrombotic drugs for severely underweight or severely obese individuals. Further, bariatric surgery in morbidly obese subjects is frequently performed worldwide. Bariatric surgery causes specific and additional changes in metabolism and gastrointestinal anatomy, depending on the type of the procedure, which can also impact the pharmacokinetics of antithrombotic drugs and their management. Based on existing literature, the document provides consensus statements on optimizing antithrombotic drug management for underweight and all classes of obese patients, while highlighting the current gaps in knowledge in these complex clinical settings, which require personalized medicine and precision pharmacology.

Dyslipidaemia is a common chronic kidney disease (CKD) and contributes to excessively elevated cardiovascular mortality. The pathophysiology is complex and modified by comorbidities like the presence/absence of proteinuria, diabetes mellitus or drug treatment. This paper provides an overview of currently available treatment options. We focused on individuals with CKD and excluded those on renal replacement therapy (haemodialysis, peritoneal dialysis, or kidney transplantation). The use of statins is safe and recommended in most patients, but guidelines vary with respect to low-density lipoprotein (LDL) cholesterol goals. While no dedicated primary or secondary prevention studies are available for pro-protein convertase subtilisin/kexin type 9 inhibitors, secondary analyses of large outcome trials reveal no effect modification on endpoints by the presence of CKD. Similar data have been shown for bempedoic acid, but no definite conclusion can be drawn with respect to efficacy and safety. No outcome trials are available for inclisiran while the cholesterol lowering effects seem to be unaffected by CKD. Finally, the value of fibrates and icosapent ethyl in CKD is unclear. Lipid abnormalities contribute to the massive cardiovascular disease burden in CKD. Lowering of LDL cholesterol with statins (and most likely PCSK9 inhibitors) reduces the event rate and thus statin therapy should be initiated in almost all individuals. Other interventions (bempedoic acid, inclisiran, fibrates, or icosapent ethyl) currently need a case-by-case decision before prescription.