scholarly journals Report of the European Society of Cardiology Cardiovascular Round Table regulatory workshop update of the evaluation of new agents for the treatment of acute coronary syndrome: Executive summary

2016 ◽  
Vol 8 (8) ◽  
pp. 745-754
Author(s):  
Héctor Bueno ◽  
Pieter de Graeff ◽  
Isabelle Richard-Lordereau ◽  
Joseph Emmerich ◽  
Keith AA Fox ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Randomized Controlled Trials ◽  
European Society ◽  
Round Table ◽  
Controlled Trials ◽  
New Agents ◽  
Coronary Syndrome ◽  
Randomized Controlled ◽  
Guidance Documents ◽  
European Society Of Cardiology

Regulatory authorities interpret the results of randomized controlled trials according to published principles. The European Medicines Agency (EMA) is planning a revision of the 2000 and 2003 guidance documents on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (ACS) to achieve consistency with current knowledge in the field. This manuscript summarizes the key output from a collaborative workshop, organized by the Cardiovascular Round Table and the European Affairs Committee of the European Society of Cardiology, involving clinicians, academic researchers, trialists, European and US regulators, and pharmaceutical industry researchers. Specific questions in four key areas were selected as priorities for changes in regulatory guidance: patient selection, endpoints, methodologic issues and issues related to the research for novel agents. Patients with ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) should be studied separately for therapies aimed at the specific pathophysiology of either condition, particularly for treatment of the acute phase, but can be studied together for other treatments, especially long-term therapy. Unstable angina patients should be excluded from acute phase ACS trials. In general, cardiovascular death and reinfarction are recommended for primary efficacy endpoints; other endpoints may be considered if specifically relevant for the therapy under study. New agents or interventions should be tested against a background of evidence-based therapy with expanded follow-up for safety assessment. In conclusion, new guidance documents for randomized controlled trials in ACS should consider changes regarding patient and endpoint selection and definitions, and trial designs. Specific requirements for the evaluation of novel pharmacological therapies need further clarification.

scholarly journals Antithrombotic Therapy Recommendations in the European Society of Cardiology Guidelines: How Robust Are the Randomized Controlled Trials Underpinning Them?

TH Open ◽  
2021 ◽  
Vol 05 (02) ◽  
pp. e125-e133
Author(s):  
Catarina M. dos Santos ◽  
Luísa Prada ◽  
Cláudio David ◽  
João Costa ◽  
Joaquim J. Ferreira ◽  
...  
Keyword(s):  
Randomized Controlled Trials ◽  
European Society ◽  
Antithrombotic Therapy ◽  
Statistical Significance ◽  
Controlled Trials ◽  
Coronary Syndrome ◽  
Randomized Controlled ◽  
Number Of Patients ◽  
Esc Guidelines ◽  
European Society Of Cardiology

Abstract Introduction Criticisms have been raised against the sole use of p-value in interpreting results from randomized controlled trials (RCTs). Additional tools have been suggested, like the fragility index (FI), a measure of a trial's robustness/fragility, and derivative measures. The FI is the minimum number of patients who would have to be converted from nonevents to events, in the group with the least events, for a result to lose statistical significance. Objective This study aimed to evaluate RCT supporting European Society of Cardiology (ESC) guidelines regarding antithrombotics, using the FI and FI-related measures. Methods FI, fragility quotient (FQ), and FI minus LTF lost to follow-up (FI − LTF) were calculated for the RCT underpinning recommendations regarding antithrombotic therapy from the updated ESC guidelines. LTF was compared with FI. Results were calculated for the total group of studies, as per guideline and as per recommendation type. Results Overall, 61 studies were included. The median FI was 24.5 (interquartile range [IQR]: 9.0–60.0) and median FQ was 0.0035 (IQR: 0.0019–0.0056). Median FI − LTF was 2.0 (IQR: 0.0–38.0). Twenty (32.8%) of the studies had one primary or main safety outcome with LTF exceeding FI. Peripheral arterial disease guideline and chronic coronary syndrome guideline had the lowest (2.5; IQR: 1.8–3.3) and the highest (48.5; IQR: 23.8–73.0) FI, respectively. Conclusion The median FI suggests robustness of clinical trials evaluating antithrombotic drugs cited in the guidelines, but about one-third of them had LTF larger than FI. This emphasizes the need for assessing trials' robustness when constructing guidelines.

scholarly journals Duration of Dual Antiplatelet Therapy in Patients With Acute Coronary Syndrome Treated With New Generation Stents: A Meta-Analysis of Randomized Controlled Trials

2021 ◽  
Vol 8 ◽  
Author(s):  
Wen-Jiao Zhang ◽  
Xuan Qiao ◽  
Wen-Fen Guo ◽  
Xi-Ying Liang ◽  
Yan Li ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Randomized Controlled Trials ◽  
Major Bleeding ◽  
Meta Analysis ◽  
Cardiovascular Death ◽  
Controlled Trials ◽  
Target Vessel Revascularization ◽  
Coronary Syndrome ◽  
Randomized Controlled ◽  
New Generation

Background and Objective: The optimum duration of dual antiplatelet therapy (DAPT) remains uncertain in patients with acute coronary syndrome treated with new generation stents. This meta-analysis was performed to investigate ischemia and bleeding outcomes with different DAPT strategies.Methods: PubMed, Embase, Cochrane and Web of science from inception to May 27, 2020, were systematically searched. Randomized controlled trials were included to compare short-term (6 months or less) with standard (12 months) DAPT in patients with acute coronary syndrome treated with new generation stents. The primary endpoints were myocardial infarction, definite or probable stent thrombosis and major bleeding. The secondary endpoints included all-cause death, cardiovascular death, stroke, target vessel revascularization and net adverse clinical events. Random effect model and fixed effect model were used to calculate the odds ratio (OR) and 95% confidence interval (CI) of each endpoint.Results: Four randomized controlled trials and seven subgroup analyses of larger randomized controlled trials, including a total of 21,344 patients with acute coronary syndrome, met our inclusion criteria. The shorter DAPT was associated with significantly lower major bleeding compared with the standard DAPT (OR 0.71, 95% CI 0.56–0.90, P = 0.005, I2 = 25%), while without increasing the risk of myocardial infarction (OR 1.18, 0.88–1.58, P = 0.28, I2 = 20%), definite or probable stent thrombosis (OR 1.60, 0.98–2.59, P = 0.06, I2 = 0%). No significantly difference was observed in the risk of all-cause death (OR 0.96, 0.72–1.27, P = 0.76, I2 = 2%), cardiovascular death (OR 0.91, 0.62–1.33, P = 0.62, I2 = 0%), stroke (OR 0.84, 0.54–1.30, P = 0.43, I2 = 0%), target vessel revascularization (OR 1.14, 0.84–1.55, P = 0.41, I2 = 8%), and net adverse clinical events (OR 0.93, 0.80–1.07, P = 0.3, I2 = 18%) between the two groups.Conclusions: In patients with acute coronary syndrome treated with new generation stents, the shorter DAPT leads to a marked reduction in the risk of major bleeding compared with the standard DAPT. This benefit is achieved without increasing the risk of mortality or ischemic outcomes. The study protocol was registered in PROSPERO (CRD42020189871).

scholarly journals Early aspirin discontinuation following acute coronary syndrome or percutaneous coronary intervention: a systematic review and meta-analysis of randomized controlled trials

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P Guedeney ◽  
J Mesnier ◽  
S Sorrentino ◽  
F Abcha ◽  
M Zeitouni ◽  
...  
Keyword(s):  
Percutaneous Coronary Intervention ◽  
Acute Coronary Syndrome ◽  
Randomized Controlled Trials ◽  
Major Bleeding ◽  
Coronary Intervention ◽  
Controlled Trials ◽  
Coronary Syndrome ◽  
Randomized Controlled ◽  
Percutaneous Coronary ◽  
Significant Difference

Abstract Background The respective ischemic and bleeding risks of early aspirin discontinuation following an acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) remains uncertain. Objectives To evaluate the safety and efficacy of early aspirin discontinuation in ACS or PCI patients treated with P2Y12 inhibitors with or without anticoagulants. Methods We performed a review of randomized controlled trials (RCTs) comparing a P2Y12 inhibitor-based single antiplatelet strategy following early aspirin discontinuation to a strategy of sustained dual antiplatelet therapy (DAPT) in ACS or PCI patients requiring or not anticoagulation for another indication. The primary safety endpoint was major bleeding while non-major bleeding and all bleeding were secondary safety endpoints. The primary efficacy endpoint was all-cause mortality while secondary efficacy endpoints included major adverse cardiovascular and cerebrovascular events (MACCE), myocardial infarction (MI), definite stent thrombosis (ST) or any stroke. We estimated risk ratios (RR) and 95% confidence intervals (CI) using random effect models. The study is registered in PROSPERO (CRD42019139576). Results We included 9 RCTs comprising 40,621 patients.Compared to prolonged DAPT, major bleeding (2.2% vs. 2.8%; RR 0.68; 95% CI: 0.54 to 0.87; p=0.002; I2: 63%), non-major bleeding (5.0% vs. 6.1%; RR: 0.66; 95% CI: 0.47 to 0.94; p=0.02; I2:87%) and all bleeding (7.4% vs. 9.9%; RR: 0.65; 95% CI: 0.53 to 0.79; p<0.0001; I2: 88%) were significantly reduced with early aspirin discontinuation (Figure 1), without significant difference for all-cause death (p=0.60), MACCE (p=0.60), MI (p=0.77), definite ST (p=0.63), and any stroke (p=0.59). Results were consistent in patients with or without anticoagulation, without significant interaction for any outcomes but MI (p=0.04). Conclusions In patients on DAPT after an ACS or a PCI, early aspirin discontinuation prevents bleeding events with no effect on the ischemic risk or mortality. Figure 1. Central illustration Funding Acknowledgement Type of funding source: None

P653PCSK-9 inhibitors and acute coronary syndrome in hyperlipidemic patients: a systematic review and meta-analysis

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A A Asbeutah ◽  
A M Asbeutah ◽  
M A Abu-Assi ◽  
F K Welty
Keyword(s):  
Acute Coronary Syndrome ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Inhibitor Therapy ◽  
Controlled Trials ◽  
Number Needed To Treat ◽  
Significant Heterogeneity ◽  
Coronary Syndrome ◽  
Randomized Controlled ◽  
Coronary Events

Abstract Introduction Hyperlipidemia has been associated with several adverse cardiac and cerebrovascular events. Treatment with statins has proven to reduce the risk of cardiovascular events, however not all patients could reach adequate low-density lipoprotein targets or tolerate statin therapy. This has led to a recent increase in the use of PCSK-9 inhibitors for management of uncontrolled hyperlipidemia. Purpose Effect of PCSK-9 inhibitors on the reduction of acute coronary events in patients with hyperlipidemia. Methods A systematic search of electronic databases for published phase 2 or 3 randomized controlled trials involving hyperlipidemic adults on PCSK-9 inhibitors was conducted. Trials involving evolocumab or alirocumab were included in the analysis. The end points of myocardial infarction and unstable angina were computed together as the composite outcome of acute coronary events. Meta-analysis using a random effects model, with dichotomous outcomes expressed as odds ratios (OR) with 95% confidence intervals (CI), was performed. Results Thirty randomized controlled trials comprising 62,961 patients were included in the meta-analysis, including the recently published ODYSSEY OUTCOMES trial with 18,942 patients. Analysis was stratified according to PCSK-9 inhibitor, either evolocumab or alirocumab. In the stratified analysis, evolocumab was associated with a significantly lower rate of acute coronary events with an OR: 0.79 (95% CI, 0.72–0.87; P<0.001). In contrast, alirocumab was not associated with a significantly lower rate of acute coronary events with an OR: 0.71 (95% CI, 0.47–1.10; P=0.12). For the combined group, compared with no PCSK-9 inhibitor therapy, PCSK9 inhibitor therapy was associated with a significantly lower rate of acute coronary events (4.3% versus 5.8%; OR: 0.81 (95% CI, 0.75–0.87; P<0.001). The modest reduction of risk of acute coronary events of 1.5% translates into a number needed to treat of 67. Neither publication bias, nor significant heterogeneity was observed in the analysis. Acute coronary events Conclusions PCSK-9 inhibitor therapy significantly reduces the risk of acute coronary syndrome when compared to the usual standard of care in adults with uncontrolled hyperlipidemia.

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