Cardiovascular outcome trials in patients with chronic kidney disease: challenges associated with selection of patients and endpoints.

Although cardiovascular disease is a major health burden for patients with chronic kidney disease, most cardiovascular outcome trials have excluded patients with advanced chronic kidney disease. Moreover, the major cardiovascular outcome trials that have been conducted in patients with end-stage renal disease have not demonstrated a treatment benefit. Thus, clinicians have limited evidence to guide the management of cardiovascular disease in patients with chronic kidney disease, particularly those on dialysis. Several factors contribute to both the paucity of trials and the apparent lack of observed treatment effect in completed studies. Challenges associated with conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), an international organization of academic cardiovascular and renal clinical trialists, held a meeting of regulators and experts in nephrology, cardiology, and clinical trial methodology. The group identified several research priorities, summarized in this paper, that should be pursued to advance the field towards achieving improved cardiovascular outcomes for these patients. Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease.

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.

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.

Evolution of natriuretic peptide biomarkers in heart failure: Implications for clinical care and clinical trials.

Natriuretic peptides (NPs) are recommended by international guidelines to exclude non-heart failure causes of acute dyspnea and to assess prognosis. NPs are commonly used as an entry criterion for clinical trials, to minimize enrollment of misdiagnosed patients, or to ensure enrollment of a sufficiently at-risk population. NP values used to select trial populations to date have been inconsistent across studies. Future trials should consider using standardized thresholds for NP levels, with protocol-specified adaptations appropriate for the specific study and patient population to account for factors that can influence the NP level. NPs have been used as an endpoint for proof-of-concept or phase 2 clinical trials, although it is important to remember that positive results in early phase studies may be unstable due to small numbers and the play of chance, and they are not always reproducible in phase 3 trials. Likewise, failure to reduce NP in phase 2 may not necessarily indicate that a drug will be ineffective on clinical outcomes in phase 3. NP guided therapy has been intensively studied, but the clinical outcome benefits of this approach remain uncertain. Neprilysin inhibitors have stimulated further exploration of the NP system and how it influences, and is potentially influenced by, heart failure therapies. This paper discusses the utility of NPs in the current clinical research and practice environment and addresses areas in need of further research from the perspectives of academic clinical trialists, clinicians, biostatisticians, regulators, and pharmaceutical industry scientists who participated in the 13th Global Cardiovascular Clinical Trialists Forum.

New strategies for the development of lipid-lowering therapies to reduce cardiovascular risk.

The very high occurrence of cardiovascular events presents a major public health issue, because treatment remains suboptimal. Lowering LDL cholesterol (LDL-C) with statins or ezetimibe in combination with a statin reduces major adverse cardiovascular events. The cardiovascular risk reduction in relation to the absolute LDL-C reduction is linear for most interventions without evidence of attenuation or increase in risk at low LDL-C levels. Opportunities for innovation in dyslipidaemia treatment should address the substantial risk of lipid-associated cardiovascular events among patients optimally treated per guidelines but who cannot achieve LDL-C goals and who could benefit from additional LDL-C-lowering therapy or experience side effects of statins. Fresh approaches are needed to identify promising drug targets early and develop them efficiently. The Cardiovascular Round Table of the European Society of Cardiology (ESC) convened a workshop to discuss new lipid-lowering strategies for cardiovascular risk reduction. Opportunities to improve treatment approaches and the efficient study of new therapies were explored. Circulating biomarkers may not be fully reliable proxy indicators of the relationship between treatment effect and clinical outcome. Mendelian randomization studies may better inform development strategies and refine treatment targets before Phase 3. Trials should match the drug to appropriate lipid and patient profile, and guidelines may move towards a precision-based approach to individual patient management. Stakeholder collaboration is needed to ensure continued innovation and better international coordination of both regulatory aspects and guidelines. It should be noted that risk may also be addressed through increased attention to other risk factors such as smoking, hypertension, overweight, and inactivity.

Role of Payers in the Development of Cardiovascular Therapeutics: Misalignment Between Approval and Reimbursement.

Regulators and payers have contrasting priorities that can lead to divergent decisions and delays in patient access to new treatments. Those involved in coverage decisions have not routinely been integrated in the drug development process. Theoretically, inclusion of payer representatives early in development could help discern discordance among stakeholder priorities; facilitate cooperation to align objectives; foster agreement on the evidence required for approval and reimbursement; improve transparency, accountability, and consistency of payer decision making; and ideally, minimize delays in patient access to new therapies. However, early participation by payers may not provide these expected benefits if payers' decision-making processes are not evidence based or cannot be reliably predicted. This paper describes current interactions among regulatory agencies, payers, sponsors, and investigators and proposes collaboration among all stakeholders earlier in the development process. The premise that a priori discussions might facilitate the delivery of advances in cardiovascular care is a hypothesis worth testing.

Early diagnosis of acute coronary syndrome.

The diagnostic evaluation of acute chest pain has been augmented in recent years by advances in the sensitivity and precision of cardiac troponin assays, new biomarkers, improvements in imaging modalities, and release of new clinical decision algorithms. This progress has enabled physicians to diagnose or rule-out acute myocardial infarction earlier after the initial patient presentation, usually in emergency department settings, which may facilitate prompt initiation of evidence-based treatments, investigation of alternative diagnoses for chest pain, or discharge, and permit better utilization of healthcare resources. A non-trivial proportion of patients fall in an indeterminate category according to rule-out algorithms, and minimal evidence-based guidance exists for the optimal evaluation, monitoring, and treatment of these patients. The Cardiovascular Round Table of the ESC proposes approaches for the optimal application of early strategies in clinical practice to improve patient care following the review of recent advances in the early diagnosis of acute coronary syndrome. The following specific 'indeterminate' patient categories were considered: (i) patients with symptoms and high-sensitivity cardiac troponin <99th percentile; (ii) patients with symptoms and high-sensitivity troponin <99th percentile but above the limit of detection; (iii) patients with symptoms and high-sensitivity troponin >99th percentile but without dynamic change; and (iv) patients with symptoms and high-sensitivity troponin >99th percentile and dynamic change but without coronary plaque rupture/erosion/dissection. Definitive evidence is currently lacking to manage these patients whose early diagnosis is 'indeterminate' and these areas of uncertainty should be assigned a high priority for research.

Streamlining cardiovascular clinical trials to improve efficiency and generalisability.

Controlled trials provide the most valid determination of the efficacy and safety of an intervention, but large cardiovascular clinical trials have become extremely costly and complex, making it difficult to study many important clinical questions. A critical question, and the main objective of this review, is how trials might be simplified while maintaining randomisation to preserve scientific integrity and unbiased efficacy assessments. Experience with alternative approaches is accumulating, specifically with registry-based randomised controlled trials that make use of data already collected. This approach addresses bias concerns while still capitalising on the benefits and efficiencies of a registry. Several completed or ongoing trials illustrate the feasibility of using registry-based controlled trials to answer important questions relevant to daily clinical practice. Randomised trials within healthcare organisation databases may also represent streamlined solutions for some types of investigations, although data quality (endpoint assessment) is likely to be a greater concern in those settings. These approaches are not without challenges, and issues pertaining to informed consent, blinding, data quality and regulatory standards remain to be fully explored. Collaboration among stakeholders is necessary to achieve standards for data management and analysis, to validate large data sources for use in randomised trials, and to re-evaluate ethical standards to encourage research while also ensuring that patients are protected. The rapidly evolving efforts to streamline cardiovascular clinical trials have the potential to lead to major advances in promoting better care and outcomes for patients with cardiovascular disease.

Independent academic Data Monitoring Committees for clinical trials in cardiovascular and cardiometabolic diseases.

Data Monitoring Committees (DMCs) play a crucial role in the conducting of clinical trials to ensure the safety of study participants and to maintain a trial's scientific integrity. Generally accepted standards exist for DMC composition and operational conduct. However, some relevant issues are not specifically addressed in current guidance documents, resulting in uncertainties regarding optimal approaches for communication between the DMC, steering committee, and sponsors, release of information, and liability protection for DMC members. The Heart Failure Association (HFA) of the European Society of Cardiology (ESC), in collaboration with the Clinical Trials Unit of the European Heart Agency (EHA) of the ESC convened a meeting of international experts in DMCs for cardiovascular and cardiometabolic clinical trials to identify specific issues and develop steps to resolve challenges faced by DMCs.The main recommendations from the meeting relate to methodological consistency, independence, managing conflicts of interest, liability protection, and training of future DMC members. This paper summarizes the key outcomes from this expert meeting, and describes the core set of activities that might be further developed and ultimately implemented by the ESC, HFA, and other interested ESC constituent bodies. The HFA will continue to work with stakeholders in cardiovascular and cardiometabolic clinical research to promote these goals.

New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment.

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.

Improving public health by improving clinical trial guidelines and their application.

Evidence generated from randomized controlled trials forms the foundation of cardiovascular therapeutics and has led to the adoption of numerous drugs and devices that prolong survival and reduce morbidity, as well as the avoidance of interventions that have been shown to be ineffective or even unsafe. Many aspects of cardiovascular research have evolved considerably since the first randomized trials in cardiology were conducted. In order to be large enough to provide reliable evidence about effects on major outcomes, cardiovascular trials may now involve thousands of patients recruited from hundreds of clinical sites in many different countries. Costly infrastructure has developed to meet the increasingly complex organizational and operational requirements of these clinical trials. Concerns have been raised that this approach is unsustainable, inhibiting the reliable evaluation of new and existing treatments, to the detriment of patient care. These issues were considered by patients, regulators, funders, and trialists at a meeting of the European Society of Cardiology Cardiovascular Roundtable in October 2015. This paper summarizes the key insights and discussions from the workshop, highlights subsequent progress, and identifies next steps to produce meaningful change in the conduct of cardiovascular clinical research.

Electronic health records to facilitate clinical research.

Electronic health records (EHRs) provide opportunities to enhance patient care, embed performance measures in clinical practice, and facilitate clinical research. Concerns have been raised about the increasing recruitment challenges in trials, burdensome and obtrusive data collection, and uncertain generalizability of the results. Leveraging electronic health records to counterbalance these trends is an area of intense interest. The initial applications of electronic health records, as the primary data source is envisioned for observational studies, embedded pragmatic or post-marketing registry-based randomized studies, or comparative effectiveness studies. Advancing this approach to randomized clinical trials, electronic health records may potentially be used to assess study feasibility, to facilitate patient recruitment, and streamline data collection at baseline and follow-up. Ensuring data security and privacy, overcoming the challenges associated with linking diverse systems and maintaining infrastructure for repeat use of high quality data, are some of the challenges associated with using electronic health records in clinical research. Collaboration between academia, industry, regulatory bodies, policy makers, patients, and electronic health record vendors is critical for the greater use of electronic health records in clinical research. This manuscript identifies the key steps required to advance the role of electronic health records in cardiovascular clinical research.

Emergency management of severe hyperkalemia: Guideline for best practice and opportunities for the future.

Hyperkalemia is a common electrolyte disorder, especially in chronic kidney disease, diabetes mellitus, or heart failure. Hyperkalemia can lead to potentially fatal cardiac dysrhythmias, and it is associated with increased mortality. Determining whether emergency therapy is warranted is largely based on subjective clinical judgment. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT) aimed to evaluate the current knowledge pertaining to the emergency treatment of hyperkalemia. The INI-CRCT developed a treatment algorithm reflecting expert opinion of best practices in the context of current evidence, identified gaps in knowledge, and set priorities for future research. We searched PubMed (to August 4, 2015) for consensus guidelines, reviews, randomized clinical trials, and observational studies, limited to English language but not by publication date. Treatment approaches are based on small studies, anecdotal experience, and traditional practice patterns. The safety and real-world effectiveness of standard therapies remain unproven. Prospective research is needed and should include studies to better characterize the population, define the serum potassium thresholds where life-threatening arrhythmias are imminent, assess the potassium and electrocardiogram response to standard interventions. Randomized, controlled trials are needed to test the safety and efficacy of new potassium binders for the emergency treatment of severe hyperkalemia in hemodynamically stable patients. Existing emergency treatments for severe hyperkalemia are not supported by a compelling body of evidence, and they are used inconsistently across institutions, with potentially significant associated side effects. Further research is needed to fill knowledge gaps, and definitive clinical trials are needed to better define optimal management strategies, and ultimately to improve outcomes in these patients.

Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion.

The Food and Drug Administration issued guidance for evaluating the cardiovascular risk of new diabetes mellitus drugs in 2008. Accumulating evidence from several completed trials conducted within this framework raises questions as to whether requiring safety outcome studies for all new diabetes mellitus therapies remains justified. Given the burden of cardiovascular disease in patients with diabetes, the focus should shift towards cardiovascular outcome studies designed to evaluate efficacy (i.e. to determine the efficacy of a drug over placebo or standard care) rather than demonstrating that risk is not increased by a pre-specified safety margin. All stakeholders are responsible for ensuring that new drug approvals occur under conditions of appropriate safety and effectiveness. It is also a shared responsibility to avoid unnecessary hurdles that may compromise access to useful drugs and threaten the sustainability of health systems. It is critical to renew this debate so that stakeholders can collectively determine the optimal approach for developing new drugs to treat type 2 diabetes mellitus.

New approaches to hyperkalemia in patients with indications for renin angiotensin aldosterone inhibitors: Considerations for trial design and regulatory approval.

Hyperkalemia is a common clinical problem, especially in patients with chronic kidney disease, diabetes mellitus, or heart failure. Treatment with renin angiotensin aldosterone system inhibitors exacerbates the risk of hyperkalemia in these patients. Concern about hyperkalemia can result in the failure to initiate, suboptimal dosing, or discontinuation of renin angiotensin aldosterone system inhibitor therapy in patients; effective treatments for hyperkalemia might mitigate such undertreatment. New treatments for hyperkalemia in development may offer better efficacy, tolerability and safety profiles than do existing approved treatments. These compounds might enable more eligible patients to receive renin angiotensin aldosterone system inhibitor therapy or to receive renin angiotensin aldosterone system inhibitors at target doses. The evidence needed to support a treatment claim (reduction in serum potassium) differs from that needed to support a prevention claim (preventing hyperkalemia to allow renin angiotensin aldosterone system inhibitor treatment). Thus, several issues related to clinical trial design and drug development need to be considered. This paper summarizes and expands upon a discussion at the Global Cardiovascular Clinical Trialists 2014 Forum and examines methodologic considerations for trials of new potassium binders for the prevention and management of hyperkalemia in patients with renin angiotensin aldosterone system inhibitor indications.

Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency.

Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patient's burden of disease. Thus, novel methods for using composite endpoints in clinical trials (e.g. clinical status composite endpoints, recurrent event analyses) are being applied in current and planned trials. Endpoints that measure functional status or reflect the patient experience are important but used cautiously because heart failure treatments may improve function yet have adverse effects on mortality. This paper discusses the use of traditional and new composite endpoints, identifies qualities of robust composites, and outlines opportunities for future research.

Designing phase 3 sepsis trials: application of learned experiences from critical care trials in acute heart failure.

Substantial attention and resources have been directed to improving outcomes of patients with critical illnesses, in particular sepsis, but all recent clinical trials testing various interventions or strategies have failed to detect a robust benefit on mortality. Acute heart failure is also a critical illness, and although the underlying etiologies differ, acute heart failure and sepsis are critical care illnesses that have a high mortality in which clinical trials have been difficult to conduct and have not yielded effective treatments. Both conditions represent a syndrome that is often difficult to define with a wide variation in patient characteristics, presentation, and standard management across institutions. Referring to past experiences and lessons learned in acute heart failure may be informative and help frame research in the area of sepsis. Academic heart failure investigators and industry have worked closely with regulators for many years to transition acute heart failure trials away from relying on dyspnea assessments and all-cause mortality as the primary measures of efficacy, and recent trials have been designed to assess novel clinical composite endpoints assessing organ dysfunction and mortality while still assessing all-cause mortality as a separate measure of safety. Applying the lessons learned in acute heart failure trials to severe sepsis and septic shock trials might be useful to advance the field. Novel endpoints beyond all-cause mortality should be considered for future sepsis trials.

Heart Failure in Non-Caucasians, Women, and Older Adults: A White Paper on Special Populations From the Heart Failure Society of America Guideline Committee.

The presentation, natural history, clinical outcomes, and response to therapy in patients with heart failure differ in some ways across populations. Women, older adults, and non-Caucasian racial or ethnic groups compose a substantial proportion of the overall heart failure population, but they have typically been underrepresented in clinical trials. As a result, uncertainty exists about the efficacy of some guideline-directed medical therapies and devices in specific populations, which may result in the under- or overtreatment of these patients. Even when guideline-based treatments are prescribed, socioeconomic, physical, or psychologic factors may affect non-Caucasian and older adult patient groups to a different extent and affect the application, effectiveness, and tolerability of these therapies. Individualized therapy based on tailored biology (genetics, proteomics, metabolomics), socioeconomic and cultural considerations, and individual goals and preferences may be the optimal approach for managing diverse patients. This comprehensive approach to personalized medicine is evolving, but in the interim, the scientific community should continue efforts focused on intensifying research in special populations, prescribing guideline-directed medical therapy unless contraindicated, and implementing evidence-based strategies including patient and family education and multidisciplinary team care in the management of patients.