Jun Xiao, Naiqi Zhang, Ziting Gao, Yajing Wei, Hongye Wei, Ziyi Qiu, Kristina Sundquist, Jan Sundquist, Jianguang Ji, Wuqing Huang
Background: Accumulating studies reported that several phosphodiesterases (PDEs) inhibitors might have cardiovascular benefits.
Objectives: This study aimed to explore the relationship between genetically-predicted PDEs and ischemia heart disease via drug target Mendelian randomization (MR) approach, and then examine the effect of inhibitors of identified target on the outcomes by using real-world data.
Methods: In the two-sample MR study, the expression of genes encoding PDEs was used to proxy the level of PDEs and available expression quantitative trait loci (eQTLs) for each target gene were identified as the genetic instruments. The outcomes included coronary heart disease (CHD) and myocardial infarction (MI). In the real-world study, a retrospective cohort was conducted to compare the incidence of outcomes between PDE5 inhibitors and alprostadil use by linking Swedish nationwide registers.
Results: MR analyses identified two types of PDEs, PDE5 and PDE8, genetically-predicted expression in blood of the encoded genes was significantly associated with the risk of CHD (ORPDE5A = 1.22,95% CI = 1.06-1.40; ORPDE8A = 1.26,95% CI = 1.07-1.49) and MI (ORPDE5A = 1.27,95% CI = 1.09-1.48; ORPDE8A = 1.24,95% CI = 1.04-1.48). Notably, the highest expression of PDE5A was observed in artery aorta, which was also positively related to CHD (OR = 1.17,95% CI = 1.05-1.32) and MI (OR = 1.15,95% CI = 1.02-1.30). Real-world study provided supportive evidence that as compared to alprostadil use, PDE5 inhibitors use significantly reduced the incidence of CHD (adjusted HR = 0.70,95% CI = 0.66-0.73) and MI (adjusted HR = 0.79,95% CI = 0.73-0.84).
Conclusion: This study provided observational and genetic evidence about the protective role of PDE5 inhibition against ischemic heart disease, indicating the potential of these drugs to be repurposed for ischemia heart disease prevention and treatment.
背景:越来越多的研究表明,几种磷酸二酯酶(PDEs)抑制剂可能对心血管有益:本研究旨在通过药物靶点孟德尔随机化(MR)方法探讨基因预测的磷酸二酯酶与缺血性心脏病之间的关系,然后利用真实世界的数据研究确定靶点的抑制剂对结果的影响:在双样本 MR 研究中,使用编码 PDEs 的基因的表达来替代 PDEs 的水平,并为每个靶基因确定可用的表达定量性状位点(eQTLs)作为遗传工具。研究结果包括冠心病(CHD)和心肌梗死(MI)。在真实世界研究中,通过链接瑞典全国范围内的登记册,进行了一项回顾性队列研究,以比较 PDE5 抑制剂和阿普斯地尔使用之间的结果发生率:MR分析确定了两种类型的PDE,即PDE5和PDE8,编码基因在血液中的遗传预测表达与冠心病(ORPDE5A = 1.22,95% CI = 1.06-1.40;ORPDE8A = 1.26,95% CI = 1.07-1.49)和心肌梗死(ORPDE5A = 1.27,95% CI = 1.09-1.48;ORPDE8A = 1.24,95% CI = 1.04-1.48)的风险显著相关。值得注意的是,PDE5A 在动脉主动脉中的表达量最高,这也与冠心病(OR = 1.17,95% CI = 1.05-1.32)和心肌梗死(OR = 1.15,95% CI = 1.02-1.30)呈正相关。真实世界研究提供的支持性证据表明,与使用阿普斯地尔相比,使用PDE5抑制剂可显著降低冠心病(调整后HR = 0.70,95% CI = 0.66-0.73)和心肌梗死(调整后HR = 0.79,95% CI = 0.73-0.84)的发病率:这项研究为PDE5抑制剂对缺血性心脏病的保护作用提供了观察和遗传学证据,表明这些药物有可能被重新用于缺血性心脏病的预防和治疗。
{"title":"Phosphodiesterase 5 and its inhibitors with ischemic heart disease: a Mendelian randomization analysis and a real-world study.","authors":"Jun Xiao, Naiqi Zhang, Ziting Gao, Yajing Wei, Hongye Wei, Ziyi Qiu, Kristina Sundquist, Jan Sundquist, Jianguang Ji, Wuqing Huang","doi":"10.1093/ehjcvp/pvae081","DOIUrl":"https://doi.org/10.1093/ehjcvp/pvae081","url":null,"abstract":"<p><strong>Background: </strong>Accumulating studies reported that several phosphodiesterases (PDEs) inhibitors might have cardiovascular benefits.</p><p><strong>Objectives: </strong>This study aimed to explore the relationship between genetically-predicted PDEs and ischemia heart disease via drug target Mendelian randomization (MR) approach, and then examine the effect of inhibitors of identified target on the outcomes by using real-world data.</p><p><strong>Methods: </strong>In the two-sample MR study, the expression of genes encoding PDEs was used to proxy the level of PDEs and available expression quantitative trait loci (eQTLs) for each target gene were identified as the genetic instruments. The outcomes included coronary heart disease (CHD) and myocardial infarction (MI). In the real-world study, a retrospective cohort was conducted to compare the incidence of outcomes between PDE5 inhibitors and alprostadil use by linking Swedish nationwide registers.</p><p><strong>Results: </strong>MR analyses identified two types of PDEs, PDE5 and PDE8, genetically-predicted expression in blood of the encoded genes was significantly associated with the risk of CHD (ORPDE5A = 1.22,95% CI = 1.06-1.40; ORPDE8A = 1.26,95% CI = 1.07-1.49) and MI (ORPDE5A = 1.27,95% CI = 1.09-1.48; ORPDE8A = 1.24,95% CI = 1.04-1.48). Notably, the highest expression of PDE5A was observed in artery aorta, which was also positively related to CHD (OR = 1.17,95% CI = 1.05-1.32) and MI (OR = 1.15,95% CI = 1.02-1.30). Real-world study provided supportive evidence that as compared to alprostadil use, PDE5 inhibitors use significantly reduced the incidence of CHD (adjusted HR = 0.70,95% CI = 0.66-0.73) and MI (adjusted HR = 0.79,95% CI = 0.73-0.84).</p><p><strong>Conclusion: </strong>This study provided observational and genetic evidence about the protective role of PDE5 inhibition against ischemic heart disease, indicating the potential of these drugs to be repurposed for ischemia heart disease prevention and treatment.</p>","PeriodicalId":11982,"journal":{"name":"European Heart Journal - Cardiovascular Pharmacotherapy","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marc P Bonaca, Andrei-Mircea Catarig, Yasemin Hansen, Kim Houlind, Chethana Kalmady Ramesh, Bernhard Ludvik, Joakim Nordanstig, Neda Rasouli, Harald Sourij, Subodh Verma
Background: People with lower extremity peripheral artery disease (PAD) suffer from a high burden of symptoms and significant functional impairment. There are few therapies that improve function and reduce symptoms in this population. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to improve glycemic control, reduce body weight and reduce the risk of major adverse cardiovascular events, in people with atherosclerotic cardiovascular disease and type 2 diabetes (T2D).
Methods: STRIDE (NCT04560998) is a randomized, placebo-controlled, double-blind phase 3b trial evaluating 1 mg once-weekly subcutaneous semaglutide (GLP-1 RA) vs. placebo, in people with symptomatic PAD (Fontaine IIa claudication) and T2D. Eligible participants were ≥ 18 years, had hemodynamically stable PAD, had no planned intervention, and were not receiving a GLP-1 RA. The primary endpoint is change in maximum walking distance on a constant-load treadmill (CLT). Secondary endpoints include quality of life and cardiometabolic assessments.
Results: A total of 792 participants were randomized in 20 countries. Participants' median age was 68 and they had T2D for a median of 12 years. Risk factors included 25.6% current smokers, 87.9% with hypertension, and 42.7% with coronary heart disease. The mean BMI was 29.6 kg/m2 and mean HbA1C was 7.3%. Participants exhibited baseline functional impairment with a median maximum walking distance of 186 meters on a CLT.
Conclusion: STRIDE has enrolled participants with symptomatic PAD and T2D, frequent risk factors and comorbidities, and functional impairment. The trial will provide evidence for the functional outcomes with semaglutide in people with PAD and T2D.
{"title":"Design and Baseline Characteristics of the STRIDE Trial: evaluating Semaglutide in People with Symptomatic Peripheral Artery Disease and Type 2 Diabetes.","authors":"Marc P Bonaca, Andrei-Mircea Catarig, Yasemin Hansen, Kim Houlind, Chethana Kalmady Ramesh, Bernhard Ludvik, Joakim Nordanstig, Neda Rasouli, Harald Sourij, Subodh Verma","doi":"10.1093/ehjcvp/pvae071","DOIUrl":"https://doi.org/10.1093/ehjcvp/pvae071","url":null,"abstract":"<p><strong>Background: </strong>People with lower extremity peripheral artery disease (PAD) suffer from a high burden of symptoms and significant functional impairment. There are few therapies that improve function and reduce symptoms in this population. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to improve glycemic control, reduce body weight and reduce the risk of major adverse cardiovascular events, in people with atherosclerotic cardiovascular disease and type 2 diabetes (T2D).</p><p><strong>Methods: </strong>STRIDE (NCT04560998) is a randomized, placebo-controlled, double-blind phase 3b trial evaluating 1 mg once-weekly subcutaneous semaglutide (GLP-1 RA) vs. placebo, in people with symptomatic PAD (Fontaine IIa claudication) and T2D. Eligible participants were ≥ 18 years, had hemodynamically stable PAD, had no planned intervention, and were not receiving a GLP-1 RA. The primary endpoint is change in maximum walking distance on a constant-load treadmill (CLT). Secondary endpoints include quality of life and cardiometabolic assessments.</p><p><strong>Results: </strong>A total of 792 participants were randomized in 20 countries. Participants' median age was 68 and they had T2D for a median of 12 years. Risk factors included 25.6% current smokers, 87.9% with hypertension, and 42.7% with coronary heart disease. The mean BMI was 29.6 kg/m2 and mean HbA1C was 7.3%. Participants exhibited baseline functional impairment with a median maximum walking distance of 186 meters on a CLT.</p><p><strong>Conclusion: </strong>STRIDE has enrolled participants with symptomatic PAD and T2D, frequent risk factors and comorbidities, and functional impairment. The trial will provide evidence for the functional outcomes with semaglutide in people with PAD and T2D.</p>","PeriodicalId":11982,"journal":{"name":"European Heart Journal - Cardiovascular Pharmacotherapy","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Usman Baber, Davide Cao, Timothy Collier, Samantha Sartori, George Dangas, Dominick J Angiolillo, Birgit Vogel, Vijay Kunadian, Carlo Briguori, David J Cohen, Dariusz Dudek, C Michael Gibson, Robert Gil, Kurt Huber, Upendra Kaul, Ran Kornowski, Mitchell W Krucoff, Shamir Mehta, David J Moliterno, E Magnus Ohman, Javier Escaned, Gennaro Sardella, Samin K Sharma, Richard Shlofmitz, Giora Weisz, Bernhard Witzenbichler, P Gabriel Steg, Stuart Pocock, Roxana Mehran
Aims: In standard time-to-first event analysis, early aspirin discontinuation followed by ticagrelor monotherapy has been shown to reduce bleeding without increasing ischemic complications compared with ticagrelor plus aspirin after percutaneous coronary intervention (PCI). We evaluated whether these treatment effects are preserved when recurrent events are considered.
Methods and results: In this TWILIGHT trial post hoc analysis, we assessed the effects of ticagrelor monotherapy on the total number of events that occurred over the 12-month follow-up among 7 119 high-risk patients randomized to aspirin or placebo in addition to ticagrelor at 3 months post-PCI if event-free and adherent to treatment. There were 391 patients with at least one Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding (primary endpoint). Of those, 28 (7.2%) had a recurrent event. The total number of BARC 2, 3, or 5 bleeding events were 148 in the ticagrelor monotherapy arm compared with 278 with ticagrelor plus aspirin arm (p < 0.001). Among 272 patients with at least one key secondary ischemic endpoint (all-cause death, myocardial infarction, or stroke), 37 (13.6%) sustained a recurrent event. Total ischemic events were similar (155 vs 159) in the two groups.
Conclusions: Among selected high-risk patients who underwent PCI and completed 3 months of dual antiplatelet therapy followed by ticagrelor with or without aspirin, recurrent bleeding was less common than recurrent ischemic events over 12 months. Analysis of total events indicates that ticagrelor monotherapy continues to be more effective than ticagrelor plus aspirin in reducing bleeding without a signal of ischemic harm.
{"title":"Impact of ticagrelor with or without aspirin on total and recurrent bleeding and ischemic events after percutaneous coronary intervention: A sub-study of the TWILIGHT trial.","authors":"Usman Baber, Davide Cao, Timothy Collier, Samantha Sartori, George Dangas, Dominick J Angiolillo, Birgit Vogel, Vijay Kunadian, Carlo Briguori, David J Cohen, Dariusz Dudek, C Michael Gibson, Robert Gil, Kurt Huber, Upendra Kaul, Ran Kornowski, Mitchell W Krucoff, Shamir Mehta, David J Moliterno, E Magnus Ohman, Javier Escaned, Gennaro Sardella, Samin K Sharma, Richard Shlofmitz, Giora Weisz, Bernhard Witzenbichler, P Gabriel Steg, Stuart Pocock, Roxana Mehran","doi":"10.1093/ehjcvp/pvae080","DOIUrl":"https://doi.org/10.1093/ehjcvp/pvae080","url":null,"abstract":"<p><strong>Aims: </strong>In standard time-to-first event analysis, early aspirin discontinuation followed by ticagrelor monotherapy has been shown to reduce bleeding without increasing ischemic complications compared with ticagrelor plus aspirin after percutaneous coronary intervention (PCI). We evaluated whether these treatment effects are preserved when recurrent events are considered.</p><p><strong>Methods and results: </strong>In this TWILIGHT trial post hoc analysis, we assessed the effects of ticagrelor monotherapy on the total number of events that occurred over the 12-month follow-up among 7 119 high-risk patients randomized to aspirin or placebo in addition to ticagrelor at 3 months post-PCI if event-free and adherent to treatment. There were 391 patients with at least one Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding (primary endpoint). Of those, 28 (7.2%) had a recurrent event. The total number of BARC 2, 3, or 5 bleeding events were 148 in the ticagrelor monotherapy arm compared with 278 with ticagrelor plus aspirin arm (p < 0.001). Among 272 patients with at least one key secondary ischemic endpoint (all-cause death, myocardial infarction, or stroke), 37 (13.6%) sustained a recurrent event. Total ischemic events were similar (155 vs 159) in the two groups.</p><p><strong>Conclusions: </strong>Among selected high-risk patients who underwent PCI and completed 3 months of dual antiplatelet therapy followed by ticagrelor with or without aspirin, recurrent bleeding was less common than recurrent ischemic events over 12 months. Analysis of total events indicates that ticagrelor monotherapy continues to be more effective than ticagrelor plus aspirin in reducing bleeding without a signal of ischemic harm.</p>","PeriodicalId":11982,"journal":{"name":"European Heart Journal - Cardiovascular Pharmacotherapy","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Petur Petursson, Thorsteinn Gudmundsson, Truls Råmunddal, Oskar Angerås, Araz Rawshani, Moman A Mohammad, Jonas Persson, Joakim Alfredsson, Robin Hofmann, Tomas Jernberg, Ole Fröbert, David Erlinge, Björn Redfors, Elmir Omerovic
Background: The use of inotropic agents in treating cardiogenic shock (CS) remains controversial. This study investigates the effect of inotropes on 30-day mortality in CS 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).
Methods: Data were sourced from the national SWEDEHEART registry for all CS patients in Sweden from 2000 to 2022. The primary endpoint was 30-day all-cause mortality. We employed multilevel Cox proportional-hazards regression with instrumental variable and inverse probability weighting propensity score to adjust for confounders. The treatment-preference instrument was the quintile of preference for inotrope use at the treating hospital.
Results: A total of 16 214 patients (60.5% men, 39.5% women) were included; 23.5% had diabetes, 10.2% had a previous myocardial infarction (MI), and 13.8% had previous heart failure (HF). The median age was 70 years (IQR; 19), with 66.4% over 70. Acute coronary syndrome (ACS) caused CS in 82.9%. Inotropes were administered to 43.8% of patients, while 56.2% did not receive them. There were 7 875 (48.1%) deaths. Patients treated with inotropes were, on average, two years younger and more likely to have ACS, while those not treated had more previous MI and were less likely to undergo PCI. The number of CS cases decreased by 12% per year (Ptrend < 0.001), and inotrope use increased by 5% per year (Ptrend < 0.001). Unadjusted mortality in CS rose by 2% per calendar year (Ptrend < 0.001). Inotropes were associated with higher mortality (adjusted HR 1.72; 95% CI 1.26-2.35; P = 0.001), with significant interactions between inotrope treatment, age, and diagnosis (Pinteraction < 0.001 and Pinteraction = 0.018).
Conclusions: In this observational study, inotropes were linked to higher mortality in CS patients, particularly those younger than 70. While CS cases decreased, inotrope use and mortality increased in Sweden.
{"title":"Inotropes and mortality in patients with cardiogenic shock: an instrumental variable analysis from the SWEDEHEART registry.","authors":"Petur Petursson, Thorsteinn Gudmundsson, Truls Råmunddal, Oskar Angerås, Araz Rawshani, Moman A Mohammad, Jonas Persson, Joakim Alfredsson, Robin Hofmann, Tomas Jernberg, Ole Fröbert, David Erlinge, Björn Redfors, Elmir Omerovic","doi":"10.1093/ehjcvp/pvae078","DOIUrl":"https://doi.org/10.1093/ehjcvp/pvae078","url":null,"abstract":"<p><strong>Background: </strong>The use of inotropic agents in treating cardiogenic shock (CS) remains controversial. This study investigates the effect of inotropes on 30-day mortality in CS 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).</p><p><strong>Methods: </strong>Data were sourced from the national SWEDEHEART registry for all CS patients in Sweden from 2000 to 2022. The primary endpoint was 30-day all-cause mortality. We employed multilevel Cox proportional-hazards regression with instrumental variable and inverse probability weighting propensity score to adjust for confounders. The treatment-preference instrument was the quintile of preference for inotrope use at the treating hospital.</p><p><strong>Results: </strong>A total of 16 214 patients (60.5% men, 39.5% women) were included; 23.5% had diabetes, 10.2% had a previous myocardial infarction (MI), and 13.8% had previous heart failure (HF). The median age was 70 years (IQR; 19), with 66.4% over 70. Acute coronary syndrome (ACS) caused CS in 82.9%. Inotropes were administered to 43.8% of patients, while 56.2% did not receive them. There were 7 875 (48.1%) deaths. Patients treated with inotropes were, on average, two years younger and more likely to have ACS, while those not treated had more previous MI and were less likely to undergo PCI. The number of CS cases decreased by 12% per year (Ptrend < 0.001), and inotrope use increased by 5% per year (Ptrend < 0.001). Unadjusted mortality in CS rose by 2% per calendar year (Ptrend < 0.001). Inotropes were associated with higher mortality (adjusted HR 1.72; 95% CI 1.26-2.35; P = 0.001), with significant interactions between inotrope treatment, age, and diagnosis (Pinteraction < 0.001 and Pinteraction = 0.018).</p><p><strong>Conclusions: </strong>In this observational study, inotropes were linked to higher mortality in CS patients, particularly those younger than 70. While CS cases decreased, inotrope use and mortality increased in Sweden.</p>","PeriodicalId":11982,"journal":{"name":"European Heart Journal - Cardiovascular Pharmacotherapy","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marco Zuin, Alberto Corsini, Chiara Dalla Valle, Catia De Rosa, Alessandro Maloberti, Marco Mojoli, Massimiliano Rizzo, Francesco Ciccirillo, Alfredo Madrid, Carmine Riccio, Massimo Grimaldi, Furio Colivicchi, Fabrizio Oliva, Pier Luigi Temporelli
Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have recently emerged as promising therapeutic agents for lowering low-density lipoprotein cholesterol and reducing the risk of cardiovascular events. Moreover, preliminary evidence from randomized controlled trials (RCTs) suggests that PCSK9i may also offer beneficial effects for patients following venous thromboembolism (VTE), with the most significant reductions in risk appearing over time, particularly beyond the first year of treatment. However, there is a lack of randomized controlled data supporting their efficacy and safety in conjunction with standard anticoagulation therapy. This article aims to critically evaluate the existing evidence for the use of PCSK9i as a complementary therapy for VTE risk reduction, while also identifying unmet clinical and research needs and proposing potential strategies to address these knowledge gaps.
{"title":"Role of PCSK9 Inhibitors in Venous Thromboembolism: Current Evidence and Unmet Clinical Needs.","authors":"Marco Zuin, Alberto Corsini, Chiara Dalla Valle, Catia De Rosa, Alessandro Maloberti, Marco Mojoli, Massimiliano Rizzo, Francesco Ciccirillo, Alfredo Madrid, Carmine Riccio, Massimo Grimaldi, Furio Colivicchi, Fabrizio Oliva, Pier Luigi Temporelli","doi":"10.1093/ehjcvp/pvae076","DOIUrl":"10.1093/ehjcvp/pvae076","url":null,"abstract":"<p><p>Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have recently emerged as promising therapeutic agents for lowering low-density lipoprotein cholesterol and reducing the risk of cardiovascular events. Moreover, preliminary evidence from randomized controlled trials (RCTs) suggests that PCSK9i may also offer beneficial effects for patients following venous thromboembolism (VTE), with the most significant reductions in risk appearing over time, particularly beyond the first year of treatment. However, there is a lack of randomized controlled data supporting their efficacy and safety in conjunction with standard anticoagulation therapy. This article aims to critically evaluate the existing evidence for the use of PCSK9i as a complementary therapy for VTE risk reduction, while also identifying unmet clinical and research needs and proposing potential strategies to address these knowledge gaps.</p>","PeriodicalId":11982,"journal":{"name":"European Heart Journal - Cardiovascular Pharmacotherapy","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bertram Pitt, Rajiv Agarwal, Stefan D Anker, Peter Rossing, Luis Ruilope, Charles A Herzog, Barry Greenberg, Roberto Pecoits-Filho, Marc Lambelet, Robert Lawatscheck, Andrea Scalise, Gerasimos Filippatos
Aims: Hypokalaemia is associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). This exploratory FIDELITY analysis, a prespecified pooled patient-dataset from FIDELIO-DKD and FIGARO-DKD, investigated the incidence and effect of hypokalaemia in patients with CKD and type 2 diabetes (T2D) treated with finerenone vs. placebo.
Methods: Outcomes include the incidence of treatment-emergent hypokalaemia (serum potassium < 4.0 or < 3.5 mmol/L) and the effect of finerenone on cardiovascular composite outcome (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and arrhythmia composite outcome (new diagnosis of atrial fibrillation/atrial flutter, hospitalization due to arrhythmia, or sudden cardiac death) by baseline serum potassium subgroups.
Results: In the FIDELITY population, treatment-emergent hypokalaemia with serum potassium < 4.0 and < 3.5 mmol/L occurred in 41.1% and 7.5%, respectively. Hazards of cardiovascular and arrhythmia composite outcomes were higher in patients with baseline serum potassium < 4.0 vs. 4.0-4.5 mmol/L (hazard ratio [HR] 1.16; 95% confidence interval [CI] 1.02-1.32, P = 0.022 and HR 1.20; 95% CI 1.00-1.44, P = 0.055, respectively). Finerenone reduced the incidence of hypokalaemia with serum potassium < 4.0 mmol/L (HR 0.63; 95% CI 0.60-0.66) and < 3.5 mmol/L (HR 0.46; 95% CI 0.40-0.53) vs. placebo. Finerenone lessened the hazard of cardiovascular and arrhythmia events vs. placebo, irrespective of baseline serum potassium.
Conclusion: A substantial proportion of patients with CKD and T2D experienced hypokalaemia, which was associated with an increased hazard of adverse cardiovascular outcomes. Finerenone reduced the incidence of hypokalaemia. Finerenone reduced the hazard of cardiovascular and arrhythmia outcomes irrespective of serum potassium subgroups. Clinical trials registration: FIDELIO-DKD and FIGARO-DKD are registered with ClinicalTrials.gov, numbers NCT02540993 and NCT02545049, respectively (funded by Bayer AG).
{"title":"Hypokalaemia in patients with type 2 diabetes and chronic kidney disease: the effect of finerenone - a FIDELITY analysis.","authors":"Bertram Pitt, Rajiv Agarwal, Stefan D Anker, Peter Rossing, Luis Ruilope, Charles A Herzog, Barry Greenberg, Roberto Pecoits-Filho, Marc Lambelet, Robert Lawatscheck, Andrea Scalise, Gerasimos Filippatos","doi":"10.1093/ehjcvp/pvae074","DOIUrl":"https://doi.org/10.1093/ehjcvp/pvae074","url":null,"abstract":"<p><strong>Aims: </strong>Hypokalaemia is associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). This exploratory FIDELITY analysis, a prespecified pooled patient-dataset from FIDELIO-DKD and FIGARO-DKD, investigated the incidence and effect of hypokalaemia in patients with CKD and type 2 diabetes (T2D) treated with finerenone vs. placebo.</p><p><strong>Methods: </strong>Outcomes include the incidence of treatment-emergent hypokalaemia (serum potassium < 4.0 or < 3.5 mmol/L) and the effect of finerenone on cardiovascular composite outcome (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and arrhythmia composite outcome (new diagnosis of atrial fibrillation/atrial flutter, hospitalization due to arrhythmia, or sudden cardiac death) by baseline serum potassium subgroups.</p><p><strong>Results: </strong>In the FIDELITY population, treatment-emergent hypokalaemia with serum potassium < 4.0 and < 3.5 mmol/L occurred in 41.1% and 7.5%, respectively. Hazards of cardiovascular and arrhythmia composite outcomes were higher in patients with baseline serum potassium < 4.0 vs. 4.0-4.5 mmol/L (hazard ratio [HR] 1.16; 95% confidence interval [CI] 1.02-1.32, P = 0.022 and HR 1.20; 95% CI 1.00-1.44, P = 0.055, respectively). Finerenone reduced the incidence of hypokalaemia with serum potassium < 4.0 mmol/L (HR 0.63; 95% CI 0.60-0.66) and < 3.5 mmol/L (HR 0.46; 95% CI 0.40-0.53) vs. placebo. Finerenone lessened the hazard of cardiovascular and arrhythmia events vs. placebo, irrespective of baseline serum potassium.</p><p><strong>Conclusion: </strong>A substantial proportion of patients with CKD and T2D experienced hypokalaemia, which was associated with an increased hazard of adverse cardiovascular outcomes. Finerenone reduced the incidence of hypokalaemia. Finerenone reduced the hazard of cardiovascular and arrhythmia outcomes irrespective of serum potassium subgroups. Clinical trials registration: FIDELIO-DKD and FIGARO-DKD are registered with ClinicalTrials.gov, numbers NCT02540993 and NCT02545049, respectively (funded by Bayer AG).</p>","PeriodicalId":11982,"journal":{"name":"European Heart Journal - Cardiovascular Pharmacotherapy","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Felix Götzinger, Michael Kunz, Lucas Lauder, Michael Böhm, Felix Mahfoud
Steroidal mineralocorticoid receptor antagonists (MRAs) bind to the mineralocorticoid receptor and antagonize the effects of aldosterone, which contributes to the development and progression of cardio- and renovascular diseases. Guidelines recommend steroidal MRAs in patients with heart failure with reduced or mildly reduced ejection fraction, as they reduce morbidity and mortality. In heart failure with preserved ejection fraction, MRAs have not convincingly shown to improve prognosis. Steroidal MRAs delay the progression of chronic kidney disease, reduce proteinuria and lower blood pressure in resistant hypertension but can induce hyperkalaemia. Due to their limited selectivity to the mineralocorticoid receptor, steroidal MRAs can cause significant adverse effects, i.e. libido loss, erectile dysfunction, gynaecomastia, and amenorrhoea, leading to low rates of persistance. Against this background, new avenues for developing non-steroidal, selective (ns)MRAs and aldosterone-synthase inhibitors have been taken. Finerenone has been shown to delay the progression of diabetic nephropathy and lower the incidence of heart failure hospitalizations in patients with chronic kidney disease and diabetes compared with placebo. Finerenone has therefore been recommended by the 2023 European Society of Cardiology Guidelines for the management of diabetes in patients with type 2 diabetes and chronic kidney disease. Further randomized controlled trials assessing the safety and effectiveness of finerenone in patients with heart failure are currently ongoing. Esaxerenone provides antihypertensive effects and has been approved for the treatment of hypertension in Japan. Baxdrostat and lorundostat, novel selective aldosterone-synthase inhibitors, are currently under investigation. In phase II trials, baxdrostat and lorundostat were safe and effective in lowering blood pressure in resistant hypertension. In this review, we summarize and critically discuss the evidence for new drugs mitigating aldosterone in heart failure, hypertension, and chronic kidney disease.
{"title":"New ways of mitigating aldosterone in cardiorenal disease.","authors":"Felix Götzinger, Michael Kunz, Lucas Lauder, Michael Böhm, Felix Mahfoud","doi":"10.1093/ehjcvp/pvae049","DOIUrl":"10.1093/ehjcvp/pvae049","url":null,"abstract":"<p><p>Steroidal mineralocorticoid receptor antagonists (MRAs) bind to the mineralocorticoid receptor and antagonize the effects of aldosterone, which contributes to the development and progression of cardio- and renovascular diseases. Guidelines recommend steroidal MRAs in patients with heart failure with reduced or mildly reduced ejection fraction, as they reduce morbidity and mortality. In heart failure with preserved ejection fraction, MRAs have not convincingly shown to improve prognosis. Steroidal MRAs delay the progression of chronic kidney disease, reduce proteinuria and lower blood pressure in resistant hypertension but can induce hyperkalaemia. Due to their limited selectivity to the mineralocorticoid receptor, steroidal MRAs can cause significant adverse effects, i.e. libido loss, erectile dysfunction, gynaecomastia, and amenorrhoea, leading to low rates of persistance. Against this background, new avenues for developing non-steroidal, selective (ns)MRAs and aldosterone-synthase inhibitors have been taken. Finerenone has been shown to delay the progression of diabetic nephropathy and lower the incidence of heart failure hospitalizations in patients with chronic kidney disease and diabetes compared with placebo. Finerenone has therefore been recommended by the 2023 European Society of Cardiology Guidelines for the management of diabetes in patients with type 2 diabetes and chronic kidney disease. Further randomized controlled trials assessing the safety and effectiveness of finerenone in patients with heart failure are currently ongoing. Esaxerenone provides antihypertensive effects and has been approved for the treatment of hypertension in Japan. Baxdrostat and lorundostat, novel selective aldosterone-synthase inhibitors, are currently under investigation. In phase II trials, baxdrostat and lorundostat were safe and effective in lowering blood pressure in resistant hypertension. In this review, we summarize and critically discuss the evidence for new drugs mitigating aldosterone in heart failure, hypertension, and chronic kidney disease.</p>","PeriodicalId":11982,"journal":{"name":"European Heart Journal - Cardiovascular Pharmacotherapy","volume":" ","pages":"557-565"},"PeriodicalIF":5.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The impact of sodium-glucose cotransporter 2 inhibitors in post-myocardial infarction management: insights from EMPACT-MI and DAPA-MI trials.","authors":"Eri Toda Kato, Koji Hasegawa, Koh Ono","doi":"10.1093/ehjcvp/pvae053","DOIUrl":"10.1093/ehjcvp/pvae053","url":null,"abstract":"","PeriodicalId":11982,"journal":{"name":"European Heart Journal - Cardiovascular Pharmacotherapy","volume":" ","pages":"486-487"},"PeriodicalIF":5.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Katrine Enge, Arnljot Tveit, Steve Enger, Sophia Onarheim, Are Hugo Pripp, Peter Selmer Rønningen, Magnar Gangås Solberg, Rune Byrkjeland, Kristoffer Andresen, Anders Halsen, Hanne Aaserud Aulie, Trude Steinsvik, Christian Hall, Sara Reinvik Ulimoen
Aims: Short-term treatment with calcium channel blockers lowers levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) and reduces rhythm-related symptoms compared to treatment with beta-blockers. The aim of this study was to compare the effects of metoprolol and diltiazem for rate control in patients with permanent atrial fibrillation (AF) after 6 months.
Methods and results: Men and women with permanent AF and preserved left ventricular systolic function were randomized to receive either diltiazem 360 mg or metoprolol 100 mg once daily. The primary endpoint was the level of NT-proBNP after a 6-month treatment period. Secondary endpoints included heart rate, rhythm-related symptoms and exercise capacity. A total of 93 patients (mean age 71 ± 7 years, 28 women) were randomized. After 6-months' treatment, mean levels of NT-proBNP decreased in the diltiazem group and increased in the metoprolol group, with a significant between-group difference (409.8 pg/mL, 95% CI: 230.6-589.1, P < 0.001). Treatment with diltiazem significantly reduced rhythm-related symptoms compared to baseline, but no change was observed in the metoprolol group. Diltiazem and metoprolol had similar effects on heart rate and exercise capacity.
Conclusion: Diltiazem reduced NT-proBNP levels and improved rhythm-related symptoms. Metoprolol increased peptide levels but had no impact on symptoms despite similar heart rate reduction. Non-dihydropyridine calcium channel blockers should be considered more often for rate control in permanent AF.
{"title":"Diltiazem reduces levels of NT-proBNP and improves symptoms compared with metoprolol in patients with permanent atrial fibrillation.","authors":"Katrine Enge, Arnljot Tveit, Steve Enger, Sophia Onarheim, Are Hugo Pripp, Peter Selmer Rønningen, Magnar Gangås Solberg, Rune Byrkjeland, Kristoffer Andresen, Anders Halsen, Hanne Aaserud Aulie, Trude Steinsvik, Christian Hall, Sara Reinvik Ulimoen","doi":"10.1093/ehjcvp/pvae032","DOIUrl":"10.1093/ehjcvp/pvae032","url":null,"abstract":"<p><strong>Aims: </strong>Short-term treatment with calcium channel blockers lowers levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) and reduces rhythm-related symptoms compared to treatment with beta-blockers. The aim of this study was to compare the effects of metoprolol and diltiazem for rate control in patients with permanent atrial fibrillation (AF) after 6 months.</p><p><strong>Methods and results: </strong>Men and women with permanent AF and preserved left ventricular systolic function were randomized to receive either diltiazem 360 mg or metoprolol 100 mg once daily. The primary endpoint was the level of NT-proBNP after a 6-month treatment period. Secondary endpoints included heart rate, rhythm-related symptoms and exercise capacity. A total of 93 patients (mean age 71 ± 7 years, 28 women) were randomized. After 6-months' treatment, mean levels of NT-proBNP decreased in the diltiazem group and increased in the metoprolol group, with a significant between-group difference (409.8 pg/mL, 95% CI: 230.6-589.1, P < 0.001). Treatment with diltiazem significantly reduced rhythm-related symptoms compared to baseline, but no change was observed in the metoprolol group. Diltiazem and metoprolol had similar effects on heart rate and exercise capacity.</p><p><strong>Conclusion: </strong>Diltiazem reduced NT-proBNP levels and improved rhythm-related symptoms. Metoprolol increased peptide levels but had no impact on symptoms despite similar heart rate reduction. Non-dihydropyridine calcium channel blockers should be considered more often for rate control in permanent AF.</p>","PeriodicalId":11982,"journal":{"name":"European Heart Journal - Cardiovascular Pharmacotherapy","volume":" ","pages":"515-525"},"PeriodicalIF":5.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140852303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}