The future of clinical trials in secondary prevention after acute coronary syndromes

Randomized clinical trials (RCTs) are the gold standard for building evidence. However, the strength of evidence in cardiovascular disease guidelines is not keeping pace with the number of emerging recommendations,1 perhaps reflecting the growing difficulties in developing adequately powered RCTs. In the context of secondary prevention after acute coronary syndromes (ACS), the increase in sample size needed to establish benefit, the rising costs, and the growing complexity of the regulatory environment and study logistics are challenging the development of new therapies. In response to these concerns, the European Society of Cardiology (ESC) convened an ad hoc meeting in May 2009. This paper summarizes the discussions and offers suggestions for improvement (Table 1), which may complement previous proposals.2 [Note: the ideas presented are those of the individual participants (listed in the Appendix) and do not reflect the ideas of the participating bodies]. Strategies to improve research on secondary prevention after acute coronary syndromes Foster better understanding of fundamental pathophysiological mechanisms involved in atherosclerosis progression, thrombus formation and their homeostatic mechanisms Improve the development of animal and non-live human disease models (biosimulation, in silico or virtual models) of vascular disease progression and atherothrombosis Explore new therapeutic targets for atherosclerosis stabilization and/or regression and thrombosis prevention ‘Enrichment’ through recruitment of higher risk patients (elderly, diabetic, chronic kidney disease) Improve external validity: Recruitment of patients from different regions, and reduction of regional variations in processes of care/background therapy Provide log of similar patients contemporaneously treated but not enrolled Identification/measurement of markers or predictors of individual response New creative designs: i.e. ‘intention-to-continue’ (Figure 2) New or improved endpoints: ○ Clinical scores, number of days without symptoms ○ Improve definition, and pre-specified weighing of composite outcomes ○ Establish reliable surrogates Focus on different outcomes: ○ Reducing side-effects ○ Quality of life/return to work ○ Economic evaluation (cost contention, cost-effectiveness) Collection of all data instead of first event Single trials spanning acute coronary syndromes and long-term prevention Strategies to replace old evidence-based treatments instead of incrementally adding new ones Use of registry information for post-marketing surveillance, comparative effectiveness, extending indications, new groups… Foster better understanding of fundamental pathophysiological mechanisms involved in atherosclerosis progression, thrombus formation and their homeostatic mechanisms Improve the development of animal and non-live human disease models (biosimulation, in silico or virtual models) of vascular disease progression and atherothrombosis Explore new therapeutic targets for atherosclerosis stabilization and/or regression and thrombosis prevention ‘Enrichment’ through recruitment of higher risk patients (elderly, diabetic, chronic kidney disease) Improve external validity: Recruitment of patients from different regions, and reduction of regional variations in processes of care/background therapy Provide log of similar patients contemporaneously treated but not enrolled Identification/measurement of markers or predictors of individual response New creative designs: i.e. ‘intention-to-continue’ (Figure 2) New or improved endpoints: ○ Clinical scores, number of days without symptoms ○ Improve definition, and pre-specified weighing of composite outcomes ○ Establish reliable surrogates Focus on different outcomes: ○ Reducing side-effects ○ Quality of life/return to work ○ Economic evaluation (cost contention, cost-effectiveness) Collection of all data instead of first event Single trials spanning acute coronary syndromes and long-term prevention Strategies to replace old evidence-based treatments instead of incrementally adding new ones Use of registry information for post-marketing surveillance, comparative effectiveness, extending indications, new groups… Strategies to improve research on secondary prevention after acute coronary syndromes Foster better understanding of fundamental pathophysiological mechanisms involved in atherosclerosis progression, thrombus formation and their homeostatic mechanisms Improve the development of animal and non-live human disease models (biosimulation, in silico or virtual models) of vascular disease progression and atherothrombosis Explore new therapeutic targets for atherosclerosis stabilization and/or regression and thrombosis prevention ‘Enrichment’ through recruitment of higher risk patients (elderly, diabetic, chronic kidney disease) Improve external validity: Recruitment of patients from different regions, and reduction of regional variations in processes of care/background therapy Provide log of similar patients contemporaneously treated but not enrolled Identification/measurement of markers or predictors of individual response New creative designs: i.e. ‘intention-to-continue’ (Figure 2) New or improved endpoints: ○ Clinical scores, number of days without symptoms ○ Improve definition, and pre-specified weighing of composite outcomes ○ Establish reliable surrogates Focus on different outcomes: ○ Reducing side-effects ○ Quality of life/return to work ○ Economic evaluation (cost contention, cost-effectiveness) Collection of all data instead of first event Single trials spanning acute coronary syndromes and long-term prevention Strategies to replace old evidence-based treatments instead of incrementally adding new ones Use of registry information for post-marketing surveillance, comparative effectiveness, extending indications, new groups… Foster better understanding of fundamental pathophysiological mechanisms involved in atherosclerosis progression, thrombus formation and their homeostatic mechanisms Improve the development of animal and non-live human disease models (biosimulation, in silico or virtual models) of vascular disease progression and atherothrombosis Explore new therapeutic targets for atherosclerosis stabilization and/or regression and thrombosis prevention ‘Enrichment’ through recruitment of higher risk patients (elderly, diabetic, chronic kidney disease) Improve external validity: Recruitment of patients from different regions, and reduction of regional variations in processes of care/background therapy Provide log of similar patients contemporaneously treated but not enrolled Identification/measurement of markers or predictors of individual response New creative designs: i.e. ‘intention-to-continue’ (Figure 2) New or improved endpoints: ○ Clinical scores, number of days without symptoms ○ Improve definition, and pre-specified weighing of composite outcomes ○ Establish reliable surrogates Focus on different outcomes: ○ Reducing side-effects ○ Quality of life/return to work ○ Economic evaluation (cost contention, cost-effectiveness) Collection of all data instead of first event Single trials spanning acute coronary syndromes and long-term prevention Strategies to replace old evidence-based treatments instead of incrementally adding new ones Use of registry information for post-marketing surveillance, comparative effectiveness, extending indications, new groups… In spite of major advances, our understanding of the pathophysiology of coronary atherosclerosis progression and triggers of recurrent thrombotic events after ACS remains limited. To enhance therapeutic development, a clearer picture of coronary atherothrombosis is required. For that, large collaborative consortia between Pharma and acadaemia focused on pathophysiology, genetic epidemiology, new biomarkers, and other intermediate measurements, as well as clinical research on traditional outcomes are needed to better understand the natural history of coronary artery disease. The identification of new pathways and therapeutic targets, as well as the genetic, phenotypic, or behavioural causes underlying the wide individual variations in responses to therapies, particularly antithrombotic treatments should be prioritized. Traditional and new ways of research will be essential to achieve these objectives (Table 1).3 Better ways are also needed to identify patients at high risk for coronary or other vascular recurrences as well as the individual response to treatment perhaps through the emergence of ‘personalized medicine’. Also, more attention should be devoted to the subpopulations whose responses are far from the ‘mean’ responses. The ‘outliers’ are usually diluted in the overall analyses and thus neglected, but may offer keys for interpretation of both atherothrombosis pathophysiology and drug response. Several approaches can be considered, including matching treatments to risk identified by selected phenotypic characteristics (e.g. ACS patients with diabetes, chronic kidney disease, or polyvascular disease), upstream pre-treatment biomarkers (or imaging), on-therapy biomarkers (e.g. response of targets to therapies, pharmacodynamic testing, such as bedside measures of platelet aggregation), or pharmacogenomics, which may help predict response to therapy. Randomized clinical trial populations should reflect the patients who will ultimately receive the study treatment in practice. Therefore, external validity is a major issue for RCTs. First, patients treated in routine clinical practice differ largely from trial participants, who tend to be younger and healthier.4,5 Yet the results of RCTs performed in these highly selected groups are extrapolated to higher risk populations despite the fact that the efficacy and safety of new therapies likely differ across such populations. Second, clinical research was frequently performed away from the most common patient care settings to more academic environments, although this trend may be reversing now.6 Third, large global studies conducted in different countries may not fully reflect regional differences in clinical presentation, patterns of care, and outcomes. Fourth, the scientific and ethical challenges of data from RCTs conducted mainly in developing countries―the so-called globalization of clinical research―are also matters of concern.7 Future RCTs should be ‘enriched’ through increased focus on the ‘underserved’ and higher risk population (Table 1),8 during both the early (Phase 1B and/or adaptive designed trials) and late phases of research. The external validity of new RCTs can also be improved by encouraging recruitment in typical patient clinical-care settings6 in a broad geographic outreach to achieve consistency and geographic validity. Attempts should also be made to reduce regional variations in processes of care and background therapies. Solutions to the problems raised by the conduct of trials in developing countries have been proposed.7 All-cause mortality is the single most important measure of clinical benefit for therapies, and remains the priority for regulators. Given the decline in mortality over recent decades, researchers now need to look beyond this endpoint and focus on non-fatal events. The use of composite endpoints has gained widespread acceptance among clinical trialists but their interpretation is often complex. The combination of ‘hard’ (death, myocardial infarction, stroke) and ‘soft’ (unstable angina, recurrent ischaemia, revascularization) endpoints, of which the latter are much more susceptible to bias, is controversial. If the results of all the components are concordant, interpretation is easier; but this is often not the case. In addition, researchers are attuned to the notion that hierarchy approaches ordinal scoring, but this may not be true for composite endpoints.9 Moreover, it is difficult to balance the trade-off of non-fatal events such as increased bleeding and reduced myocardial infarction risk. Despite these limitations, composite endpoints will continue to have a role. Therefore, the assessment and weighing of non-fatal endpoints have to be refined through the use of standardized definitions, such as those of myocardial infarction,10 stent thrombosis,11 or major bleeding.12 The input of scientific societies will be helpful in solving these problems. Finally, the traditional analysis of time-to-first event in composite endpoints leads to the loss of important information. For better clinical (i.e. competing risks) and economic decisions, it is critical to capture all clinically relevant information and not to dismiss any when there is more than one. The use of clinical scores developed by neurologists (with each outcome weighted individually)—such as the grading of strokes according to disability to communicate the impact on quality of life from the patient's perspective—rather than composite endpoints (with equal weight given to each outcome) has been proposed as alternatives to traditional endpoints. The number of days without symptoms, a variable that combines events and quality of life, has also been proposed.13 The role of novel endpoints, such as reducing side-effects, improving quality of life, cost contention, return to work, and cost-effectiveness, should be discussed. The use of surrogate endpoints (e.g., biomarkers, imaging, functional assessments) that capture patient risk and predict response to a new therapy should in theory make trials easier and less costly. However, they are often unreliable predictors of clinical outcomes and their role is limited as research tools. Much of the evidence for background therapies used after ACS such as aspirin or β-blockers is old, and was obtained in a clinical environment quite different from today's. Some argue that strategies to replace old evidence-based treatments instead of adding new ones on top should be facilitated. This approach faces substantial opposition from ethical committees and regulatory authorities. Scientific societies may assist in revisiting the possible discontinuation of older therapies and the introduction of potentially superior agents. The European Medicines Agency (EMEA) emphasize cardiovascular prevention from a ‘global approach’, and give recommendations based on a ‘continuum of risk’.14 A better knowledge of the similarities or differences in the determinants of early post-ACS events compared with those related to the long-term progression of the disease is needed. The therapeutic implications of the continuum of risk for secondary prevention both early and late after ACS for bridging acute and chronic therapy should be addressed. Also, the potential differences in managing clinical manifestations that may be sustained, such as heart failure, or discrete, such as myocardial infarction deserve attention. Treatments are usually tested in RCTs over relatively short periods (e.g. 12 months), rarely extending beyond 4–5 years. 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