Polypill Strategy in Secondary Cardiovascular Prevention.

BACKGROUND: A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction. METHODS: In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke. RESULTS: A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups. CONCLUSIONS: Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.).

What can heart failure trialists learn from oncology trialists?

Globally, there has been little change in mortality rates from cardiovascular (CV) diseases or cancers over the past two decades (1997-2018). This is especially true for heart failure (HF) where 5-year mortality rates remain as high as 45-55%. In the same timeframe, the proportion of drug revenue, and regulatory drug approvals for cancer drugs, far out paces those for CV drugs. In 2018, while cancer drugs made 27% of Food and Drug Administration drug approvals, only 1% of drug approvals was for a CV drug, and over this entire 20 year span, only four drugs were approved for HF in the USA. Cardiovascular trialists need to reassess the design, execution, and purpose of CV clinical trials. In the area of oncology research, trials are much smaller, follow-up is shorter, and targeted therapies are common. Cardiovascular diseases and cancer are the two most common causes of death globally, and although they differ substantially, this review evaluates whether some elements of oncology research may be applicable in the CV arena. As one of the most underserved CV diseases, the review focuses on aspects of cancer research that may be applicable to HF research with the aim of streamlining the clinical trial process and decreasing the time and cost required to bring safe, effective, treatments to patients who need them. The paper is based on discussions among clinical trialists, industry representatives, regulatory authorities, and patients, which took place at the Cardiovascular Clinical Trialists Workshop in Washington, DC, on 8 December 2019 (https://www.globalcvctforum.com/2019 (14 September 2020)).

International differences in treatment effect: do they really exist and why?

With the increasing globalization of clinical trials, the opportunity exists to explore potential geographic differences in treatment effect within any major trial. Such geographic differences may arise because of international differences in patient selection, medical practice, or evaluation of outcomes, and such international variations need better documentation in trial reports. Appropriate pre-defined statistical analyses, including statistical tests of interaction regarding geographic heterogeneity in treatment effect, are important. Geographic variations are a particularly tricky form of subgroup analysis: they lack statistical power, are at best hypothesis-generating and can generate more confusion than insight. Referring to key examples, e.g. the PLATO and MERIT-HF, we emphasize the need for caution in interpreting evidence of potential geographic inconsistencies in treatment effect. Although it is appropriate to explore any biological or practical reasons for apparent geographic anomalies in treatment effect, the play of chance is often the most plausible and wise interpretation.

Diabetes clinical trials: helped or hindered by the current shift in regulatory requirements?

Glycaemic control is an inadequate surrogate marker of cardiovascular event reduction in patients with type 2 diabetes. Clinical trials to date have been unsuccessful in identifying a therapeutic approach that addresses the underlying problem in diabetes (glycaemic control) and reduces cardiovascular risk. The potential for some agents to increase the risk of cardiovascular events has led to substantial changes in regulatory requirements for new anti-diabetic therapies. These requirements, while key to ensuring the cardiovascular safety of new agents, fail to emphasize the need to show clinical benefits, such as less visual impairment, less need for dialysis, or fewer cardiovascular events and deaths. Changes in test results such as glycaemic control, serum creatinine, micro-albuminuria, or retinopathy are inadequate surrogates. Regulators should consider the potential advantages of offering extended patent protection in order to encourage companies to conduct long-term trials in diabetes and many other chronic medical conditions. Cooperative efforts among physicians, clinical trialists, regulators, and sponsors are needed to address unresolved issues including re-defining therapeutic targets that are meaningful to patients with diabetes, determining the appropriate length of follow-up for future trials, and considering the ethical and operational challenges of non-inferiority designs.

Implications of geographical variation on clinical outcomes of cardiovascular trials.

Cardiovascular clinical trials are increasingly conducted globally as a means to reduce costs, expedite timelines, provide broad applicability, and satisfy regulatory authorities. Potential problems with trial globalization include regional differences in patient characteristics, medical practice patterns, and health policies which may influence outcomes and limit generalizability. Moreover, concerns have been raised about ethical misconduct and unsatisfactory quality oversight in regions with less trial experience and infrastructure. This article reviews geographical differences in cardiovascular trials in heart failure, acute coronary syndromes, hypertension and atrial fibrillation. It also explores potential explanations for these differences and methods to standardize the presentation of trial results. This review is based on discussions between basic scientists and clinical trialists at the 8th Global Cardio Vascular Clinical Trialists Forum 2011 in Paris, France, from December 2 to 3.

Long-term antithrombotic management patterns in Asian patients with acute coronary syndrome: 2-year observations from the EPICOR Asia study.

BACKGROUND: Despite guideline recommendations, dual antiplatelet therapy (DAPT) is frequently used for longer than 1 year after an acute coronary syndrome (ACS) event. In Asia, information on antithrombotic management patterns (AMPs), including DAPT post discharge, is sparse. This analysis evaluated real-world AMPs up to 2 years post discharge for ACS. HYPOTHESIS: There is wide variability in AMP use for ACS management in Asia. METHODS: EPICOR Asia (NCT01361386) is a prospective observational study of patients discharged after hospitalization for an ACS in eight countries/regions in Asia, followed up for 2 years. Here, we describe AMPs used and present an exploratory analysis of characteristics and outcomes in patients who received DAPT for ≤12 months post discharge compared with >12 months. RESULTS: Data were available for 12 922 patients; of 11 639 patients discharged on DAPT, 2364 (20.3%) received DAPT for ≤12 months and 9275 (79.7%) for >12 months, with approximately 60% still on DAPT at 2 years. Patients who received DAPT for >12 months were more likely to be younger, obese, lower Killip class, resident in India (vs China), and to have received invasive reperfusion. Clinical event rates during year 2 of follow-up were lower in patients with DAPT >12 vs ≤12 months, but no causal association can be implied in this non-randomized study. CONCLUSIONS: Most ACS patients remained on DAPT up to 1 year, in accordance with current guidelines, and over half remained on DAPT at 2 years post discharge. Patients not on DAPT at 12 months are a higher risk group requiring careful monitoring.

Two-year outcomes post-discharge in Asian patients with acute coronary syndrome: Findings from the EPICOR Asia study.

AIMS: Approximately half of cases of cardiovascular disease (CVD) worldwide occur in Asia, with acute coronary syndrome (ACS) a leading cause of mortality. Long-term ACS-related outcomes data in Asia are limited. This analysis examined 2-year ACS-related outcomes in patients enrolled in the EPICOR Asia study, and the association between patient characteristics and management on outcomes. METHODS: EPICOR Asia is a multinational, prospective, primary data collection study of real-world management of Asian patients with ACS. Overall, 12,922 eligible adults (hospitalized for ACS within 48 h of symptom onset and who survived to discharge) were enrolled from 219 centers in eight Asian countries. Patients were followed up post-discharge for 2 years and clinical outcomes recorded. RESULTS: Patients were of mean age 60 years and 76% were male. Diagnoses were STEMI (51.2%), NSTEMI (19.9%), and UA (28.9%). During follow-up, 5.2% of patients died; NSTEMI patients had the highest risk profile. Mortality rate (adjusted HR [95% CI]) was similar in NSTEMI (0.97 [0.81-1.17]) and lower in UA (0.52 [0.33-0.82]) vs STEMI. Similar trends (adjusted) were seen for the composite endpoint of death, myocardial infarction, or ischemic stroke, and bleeding rates did not differ significantly. For all three diagnoses, patients who were medically managed had a markedly elevated risk of both death and the composite endpoint. CONCLUSIONS: During 2-year follow-up, adjusted risks of mortality, the composite endpoint, and bleeding rates were similar in NSTEMI and STEMI patients. Outcomes risk was better for invasive management. Long-term management strategies in Asia need to be optimized.

Rationale, Design, and Baseline Characteristics of the EPICOR Asia Study (Long-tErm follow-uP of antithrombotic management patterns In Acute CORonary Syndrome patients in Asia).

BACKGROUND: In-hospital and postdischarge mortality for acute coronary syndromes (ACS) vary across Asia and remain generally poorer than globally. The relationship between real-life antithrombotic management patterns (AMPs) and ACS-related outcomes in Asia is unclear. METHODS: EPICOR Asia (Long-tErm follow-uP of antithrombotic management patterns In acute CORonary syndrome patients in Asia) (NCT01361386) is a prospective, multinational, observational study of patients discharged after hospitalization for an ACS, with 2-year follow-up. The aim is to describe short- and long-term (up to 2 years post-index event) AMPs in patients hospitalized for ACS and to record clinical outcomes, healthcare resource use, and self-reported health status. Pre- and in-hospital management, AMPs, and associated outcomes, with particular focus on ischemic and bleeding events, will be recorded during the 2-year follow up. RESULTS: Between June 2011 and May 2012, 13 005 patients were enrolled. From these, 12 922 patients surviving an ACS (6616 with STEMI, 2570 with NSTEMI, and 3736 with UA) were eligible for inclusion from 219 hospitals across 8 countries and regions in Asia: China (n = 8214), Hong Kong (n = 177), India (n = 2468), Malaysia (n = 100), Singapore (n = 93), South Korea (n = 705), Thailand (n = 957), and Vietnam (n = 208). CONCLUSIONS: EPICOR Asia will provide information regarding clinical management and AMPs for ACS patients in Asia. Impact of AMPs on clinical outcomes, healthcare resource use, and self-reported health status both during hospitalization and up to 2 years after discharge will also be described.

[Multiple coronary embolisms in a woman with risk factors for thromboembolic disease]. / Embolismo coronario múltiple en una mujer con factores de riesgo pra enfermedad tromboembólica.

We report the case of a 33-years-old woman, smoker and taking oral contraceptives, who presented to the emergency room with an anterior ST-elevation myocardial infarction. Thrombolytic treatment was initiated and a few minutes after, chest pain returned and an inferior ST-segment-elevation infarction was diagnosed at that moment. Catheterization revealed multiple embolic occlusion of coronary branches. We discuss tests performed and pathophysiology of myocardial infarction in this patient.

[Inflammation markers and risk stratification in patients with acute coronary syndromes: design of the SIESTA Study (Systemic Inflammation Evaluation in Patients with non-ST segment elevation Acute coronary syndromes)]. / Marcadores de inflamación y estratificación de riesgo en pacientes con síndorome coronario agudo: diseño del estudio SIESTA (Systemic Inflammation Evaluation in patients with non-ST segment elevaton Acute coronary syndromes).

BACKGROUND AND OBJECTIVE: Evidence is growing regarding the prognostic value of markers of inflammation in unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI). However, the independent value of these variables has not been systematically investigated in prospective studies. The main objective of the SIESTA study is to assess the relative prognostic roles of C-reactive protein, fibrinogen, neopterin, interleukins 6, 8, 10 and 18, tumor necrosis factor, e-selectin, endothelin 1, tissue factor, VCAM-1, ICAM-1, pregnancy-associated plasma protein-A, B-type natriuretic peptide, leukocytes, troponin I or T and serum creatine kinase-MB (CKMB) in UA/NSTEMI patients. PATIENTS AND METHOD: SIESTA is a prospective, multicenter trial involving patients with chest pain suggestive of acute coronary syndrome (ACS) within 48 hours of enrolment and at least one of the following: abnormal troponin levels, electrocardiographic signs of ischaemia or previously documented vascular disease. Clinical outcome data and serial biochemical determinations will be assessed during hospital admission and at 30, 180 and 365 days of follow-up. The TIMI (Thrombolysis In Myocardial Infarction) and PEPA (Proyecto de Estudio del Pronóstico de la Angina) risk scores will be also validated. Study variables will include death due to any cause, cardiac death, non-fatal myocardial infarction, unstable angina requiring re-admission, emergency revascularization and a composite of death, myocardial infarction and need for emergency hospitalization or myocardial revascularization. Each of these conditions will be treated as secondary end-points when assessed individually. This study will provide valuable prospective information about the prognostic value of inflammatory markers in real life ACS patients of Mediterranean origin.

Update in cardiology: Vascular risk and cardiac rehabilitation.

Atherosclerotic cardiovascular disease remains the major cause of premature death in developed and developing countries. Nevertheless, surveys show that most patients still do not achieve the lifestyles, risk factor levels, and therapeutic targets recommended in primary and secondary prevention. The present update reflects the most recent novelties in risk classification and estimation of risk and documents the latest changes in fields such as smoking, diet and nutrition, physical activity, lipids, hypertension, diabetes, and cardiovascular rehabilitation, based on experimental trials and population-based observational studies.

[Glycaemic management in type 1 and 2 diabetes patients undergoing interventional cardiology procedures. Heart and Diabetes Working Group. Sociedad Espan˜ola de Cardiologi´a. Sociedad Espan˜ola de Diabetes]. / Control glucémico de los pacientes con diabetes tipo 1 y 2 tratados mediante procedimientos de cardiología intervencionista.

Despite the growing number of therapeutic alternatives available as well as general reviews and treatment guidelines for the treatment of diabetes, physicians are often left without a clear pathway of therapy to follow in specific clinical contexts such as interventional cardiology. The present document proposes a consensus treatment algorithm, based both on a critical appraisal of evidence from recent clinical trials and on value judgements supported by the authors' collective clinical knowledge and experience, in an attempt to guide practitioners when choosing the most appropriate alternatives in the context of glycemic management in type 1 and 2 diabetic patients scheduled to undergo interventional cardiology procedures in a haemodynamic laboratory.

[Current topics (2005) in clinical cardiology: cardiovascular disease in women]. / Temas de actualidad en cardiología clínica y extrahospitalaria. Un nuevo proyecto: enfermedad cardiovascular en la mujer.

Ischemic heart disease has mistakenly been considered of little relevance to women because it occurs infrequently during the fertile years. This is despite the fact that a larger percentage of women than men die from cardiovascular disease. There are differences in cardiovascular risk factors and disease between females and males, including differences in clinical presentation, disease course, diagnostic criteria, prognosis, and treatment. There is a need for increased information and education, earlier and more aggressive control of risk factors, and a more appropriate approach to diagnosis and treatment. The American Heart Association has published guidelines on the prevention of cardiovascular disease in women and the European Society of Cardiology is planning to publish a scientific statement on the management of heart disease in women. Spanish cardiologists should also consider adopting a similar approach.