European Heart Journal - Cardiovascular Pharmacotherapy最新文献

Background: Carriers of cytochrome 2C19 (CYP2C19) loss-of-function (LoF) alleles treated with clopidogrel have impaired drug metabolism, resulting in reduced active metabolite levels, high platelet reactivity (HPR), and an increased risk of thrombotic events. Several alternative antiplatelet therapies have been proposed to overcome HPR in these patients, but their comparative effects remain poorly explored.

Methods: Randomized controlled trials (RCTs) comparing different oral antiplatelet therapies in carriers of CYP2C19 LoF alleles undergoing percutaneous coronary interventions (PCI) were included. A frequentist network meta-analysis was conducted to estimate mean difference (MD) or odds ratios and 95% confidence intervals (CI). The primary outcome was platelet reactivity assessed by VerifyNow and reported as P2Y12 reaction unit (PRU). The secondary outcome was the rate of HPR. Standard dose of clopidogrel (75 mg daily) was used as a reference treatment.

Results: A total of 12 RCTs testing 6 alternative strategies (i.e. clopidogrel 150 mg, prasugrel 3.75 mg, 5 mg, and 10 mg, ticagrelor 90 mg bid, and adjunctive cilostazol 100 mg bid) were included in the network. Compared with standard-dose clopidogrel, the greatest reduction in PRU was observed with prasugrel 10 mg (MD -127.91; 95% CI -141.04; -114.78) and ticagrelor 90 mg bid (MD -124.91; 95% CI -161.78; -88.04), followed by prasugrel 5 mg (MD -76.33; 95% CI -98.01; -54.65) and prasugrel 3.75 mg (MD -73.00; 95% CI -100.28; -45.72). Among other strategies, adjunctive cilostazol (MD -42.64; 95% CI -64.72; -20.57) and high-dose clopidogrel (MD -32.11; 95% CI -51.33; -12.90) were associated with a modest reduction in PRU compared with standard-dose clopidogrel.

Conclusion: Among carriers of CYP2C19 LoF alleles undergoing PCI, standard-dose prasugrel or ticagrelor are most effective in reducing platelet reactivity, while double-dose clopidogrel and additional cilostazol showed modest effects. Reduced-dose of prasugrel may represent a balanced strategy to overcome HPR without a significant increase in bleeding. The clinical implications of these pharmacodynamic findings warrant further investigation.

Aims: Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the accumulation of transthyretin (TTR) protein in the myocardium. The aim of this scoping review is to provide a descriptive summary of the clinical trials and observational studies that evaluated the clinical efficacy and safety of various agents used in ATTR-CM, with a goal of identifying the contemporary gaps in literature and to reveal future research opportunities.

Methods and results: The search was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search using several databases for observational and clinical trials investigating the treatment modalities for ATTR-CM was undertaken. We extracted data including study characteristics, primary endpoints, and adverse events from each study. A total of 19 studies were included in our scoping review. Out of which, 8 were clinical trials and 11 were observational analyses. The drugs evaluated included tafamadis, acoramidis, revusiran, doxycycline and tauroursodeoxycholic acid and doxycycline, diflusinil, inotersan, eplontersen, and patisiran. Tafamidis has shown to be efficacious in the management of ATTR-CM, particularly when initiated at earlier stages. RNA interference and antisense oligonucleotide drugs have shown promising impacts on quality of life. Additionally, this review identified gaps in the literature, particularly among long-term outcomes, comparative effectiveness, and the translation of research into economic contexts.

Conclusion: Multiple pharmacological options are potential disease-modifying therapies for ATTR-CM. However, many gaps exist in the understanding of these various drug therapies, warranting further research. The future directions for management of ATTR-CM are promising in regard to improving prognostic implications.

Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are effective in reducing cardiovascular events, but their impact on all-cause mortality and medical utilization compared to statins is unclear. This study investigated PCSK9 inhibitor use and its impact on mortality and medical utilization vs. statins, using TriNetX database data with up to 9 years of follow-up.

Methods and results: This retrospective cohort study analysed TriNetX data spanning 1 July 2015, to 31 December 2023, including 79 194 PCSK9 inhibitor users (alirocumab, evolocumab, inclisiran) and 5 437 513 statin users with hyperlipidaemia. The primary outcomes were all-cause mortality and medical utilization, including hospital inpatient services, emergency department visits, critical care, and mechanical ventilation. Propensity score matching showed that PCSK9 inhibitor use was associated with a 28.3% lower risk of all-cause mortality [adjusted hazard ratio (aHR) 0.717, 95% confidence interval (CI): 0.673-0.763] and significant reductions in medical utilization (hospital inpatient services usage: aHR 0.692, 95% CI: 0.664-0.721; emergency department services: aHR 0.756, 95% CI: 0.726-0.788; critical care services: aHR 0.619, 95% CI: 0.578-0.664; and mechanical ventilation: aHR 0.537, 95% CI: 0.484-0.596) compared to statins. These findings were consistent across various demographics and clinical subgroups. The sensitivity analyses supported the robustness of the findings.

Conclusion: PCSK9 inhibitors significantly reduced all-cause mortality and medical utilization compared to statins, suggesting their important role in dyslipidaemia management, particularly for statin-naïve or intolerant patients. Further research, including randomized controlled trials, is needed to confirm these findings and explore the underlying mechanisms.

Aims: Icosapent ethyl lowers triglycerides and significantly reduces major adverse cardiovascular events (MACE), though treatment effects may vary between individuals. This study aimed to determine the relative and absolute effects of icosapent ethyl on MACE according to baseline cardiovascular disease (CVD) risk in patients with atherosclerotic cardiovascular disease (ASCVD).

Methods and results: Participants from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) with ASCVD were included (n = 5785). The primary outcome was 3-point MACE, i.e. non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. Baseline 5-year risk of MACE was estimated using the European Society of Cardiology (ESC) guideline-recommended SMART2 risk score. Modification of the relative treatment effects of icosapent ethyl by baseline risk was assessed using Cox proportional hazards models, including a treatment-by-risk interaction. Next, treatment effects were assessed stratified by quartiles of baseline risk. During a median follow-up of 4.8 years (interquartile range 3.2-5.3), MACE occurred in 361 vs. 489 patients in the icosapent ethyl vs. placebo group [95% confidence interval (CI)]; hazard ratio (HR) 0.72 (0.63-0.82), absolute risk reduction (ARR) 4.4% (2.6-6.2%), number needed to treat (NNT) 23 (16-38), and 5-year Kaplan-Meier estimated cumulative incidence reduction (CIR) 5.7% (3.5-7.9%). Icosapent ethyl significantly reduced MACE in all risk quartiles, with an HR (95% CI) of 0.62 (0.43-0.88), 0.66 (0.48-0.92), 0.69 (0.53-0.90), and 0.78 (0.63-0.96), respectively (P for treatment-by-risk interaction = 0.106). The ARR (95% CI) increased across risk quartiles, i.e. was 3.9% (1.0-6.8%), 4.3% (1.2-7.3%), 5.1% (1.4-8.7%), and 5.6% (1.3-10.0%), respectively. This translates to NNTs (95% CI) of 26 (15-98), 24 (14-84), 20 (11-70), and 18 (10-77). The 5-year CIR (95% CI) was 4.8% (1.3-8.2%), 5.0% (1.3-8.7%), 6.1% (1.7-10.5%), and 7.7% (2.3-13.2%), respectively. Consistent results were obtained for 5-point MACE, additionally including coronary revascularization and unstable angina.

Conclusion: Among patients with ASCVD and elevated triglyceride levels, icosapent ethyl significantly reduces the risk of MACE irrespective of baseline CVD risk, though absolute benefits are largest for patients at the highest risk.

Background: Antihypertensive drugs are known to lower cardiovascular mortality, but the role of different types of antihypertensive drugs in lifespan has not been clarified. Moreover, the underlying mechanisms remain unclear.

Methods and results: To minimize confounding, we used Mendelian randomization to assess the role of different antihypertensive drug classes in longevity and examined the pathways via proteins. Genetic variants associated with systolic blood pressure (SBP) corresponding to drug-target genes were used as genetic instruments. The genetic associations with lifespan were obtained from a large genome-wide association study including 1 million European participants from UK Biobank and LifeGen. For significant antihypertensive drug classes, we performed sex-specific analysis, drug-target analysis, and colocalization. To examine the mediation pathways, we assessed the associations of 2291 plasma proteins with lifespan, and examined the associations of drug classes with the proteins affecting lifespan. After correcting for multiple testing, genetically proxied beta-blockers (BBs), calcium channel blockers (CCBs), and vasodilators were related to longer life years (BBs: 2.03, 95% CI 0.78-3.28 per 5 mmHg reduction in SBP, CCBs: 3.40, 95% CI 1.47-5.33, and vasodilators: 2.92, 95% CI 1.08-4.77). The beneficial effects of BBs and CCBs were more obvious in men. ADRB1, CACNA2D2, CACNB3, CPT1A, CPT2, and EDNRA genes were related to extended lifespan, with CPT2 further supported by colocalization evidence. Eighty-six proteins were related to lifespan, of which four proteins were affected by CCBs. CDH1 may mediate the association between CCBs and lifespan.

Conclusions: Beta-blockers, CCBs, and vasodilators may prolong lifespan, with potential sex differences for BBs and CCBs. The role of CCBs in lifespan is partly mediated by CDH1. Prioritizing the potential protein targets can provide new insights into healthy aging.

Aims: Examine whether the low-density lipoprotein cholesterol (LDL -C) determination method influences the rate of statin initiation for primary prevention of cardiovascular disease.

Methods and results: We conducted a register-based retrospective study in the Region of Southern Denmark. Two hospital-based laboratories in the region directly measure LDL -C whereas four laboratories calculate LDL -C using Friedewald's formula. Physicians do not choose which method is used. We included all statin-naïve patients ≥40 years with no history of cardiovascular disease, diabetes, or chronic kidney disease, who had their LDL -C determined during 2018-2019. There were 202 807 people who had LDL -C determined during the study period (median age 59 years, 44% women) of which 37% had a direct LDL -C measurement. The median reported LDL -C was 3.40 mmol/L [interquartile range (IQR) 2.90-4.00] for those with a direct measurement vs. 3.00 mmol/L (IQR 2.40-3.50) for those with calculated LDL -C. For those with direct measurement, re-calculated LDL -C (using Friedewald's formula) was 0.35 mmol/L lower than the reported direct LDL -C measurement. Among those with directly measured LDL -C, 3.6% initiated statins compared with 2.7% of those with a calculated LDL -C. Direct LDL -C measurement led to higher odds of having a statin initiated compared with calculated LDL -C (adjusted odds ratio 1.23, 95% CI 1.17-1.30); for those with triglycerides >1.7 mmol/L the adjusted odds ratio was 1.41 (95% CI 1.30-1.52).

Conclusion: Differences in the reporting of LDL -C from laboratories using different methods have a substantial influence on physician's decisions to prescribe statins.