Improving clinical trials for cardiovascular diseases: a position paper from the Cardiovascular Round Table of the European Society of Cardiology.

AIMS: Cardiovascular disease is the most common cause of mortality and morbidity in the world, but the pharmaceutical industry's willingness to invest in this field has declined because of the many challenges involved with bringing new cardiovascular drugs to market, including late-stage failures, escalating regulatory requirements, bureaucracy of the clinical trial business enterprise, and limited patient access after approval. This contrasts with the remaining burden of cardiovascular disease in Europe and in the world. Thus, clinical cardiovascular research needs to adapt to address the impact of these challenges in order to ensure development of new cardiovascular medicines. METHODS AND RESULTS: The present paper is the outcome of a two-day workshop held by the Cardiovascular Round Table of the European Society of Cardiology. We propose strategies to improve development of effective new cardiovascular therapies. These can include (i) the use of biomarkers to describe patients who will benefit from new therapies more precisely, achieving better human target validation; (ii) targeted, mechanism-based approaches to drug development for defined populations; (iii) the use of information technology to simplify data collection and follow-up in clinical trials; (iv) streamlining adverse event collection and reducing monitoring; (v) extended patent protection or limited rapid approval of new agents to motivate investment in early phase development; and (vi) collecting data needed for health technology assessment continuously throughout the drug development process (before and after approval) to minimize delays in patient access. Collaboration across industry, academia, regulators, and payers will be necessary to enact change and to unlock the existing potential for cardiovascular clinical drug development. CONCLUSIONS: A coordinated effort involving academia, regulators, industry, and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.

Clinical trials in hospitalized heart failure patients: targeting interventions to optimal phenotypic subpopulations.

With one possible exception, the last decade of clinical trials in hospitalized heart failure (HHF) patients has failed to demonstrate improvement in long-term clinical outcomes. This trend necessitates a need to evaluate optimal drug development strategies and standards of trial conduct. It has become increasingly important to recognize the heterogeneity among HHF patients and the differential characterization of novel drug candidates. Targeting these agents to specific subpopulations may afford optimal net response related to the particular mode of action of the drug. Analyses of previous trials demonstrate profound differences in the baseline characteristics of patients enrolled across global regions and participating sites. Such differences may influence risks for events and interpretation of results. Therefore, the actual execution of trials and the epidemiology of HHF populations at the investigative sites must be taken into consideration. Collaboration among participating sites including the provision of registry data tailored to the planned development program will optimize trial conduct. Observational data prior to study initiation may enable sites to feedback and engage in protocol development to allow for feasible and valid clinical trial conduct. This site-centered, epidemiology-based network environment may facilitate studies in specific patient populations and promote optimal data collection and clear interpretation of drug safety and efficacy. This review summarizes the roundtable discussion held by a multidisciplinary team of representatives from academia, National Institutes of Health, industry, regulatory agencies, payers, and contract and academic research organizations to answer the question: Who should be targeted for novel therapies in HHF?

Site selection in global clinical trials in patients hospitalized for heart failure: perceived problems and potential solutions.

There are over 1 million hospitalizations for heart failure (HF) annually in the United States alone, and a similar number has been reported in Europe. Recent clinical trials investigating novel therapies in patients with hospitalized HF (HHF) have been negative, and the post-discharge event rate remains unacceptably high. The lack of success with HHF trials stem from problems with understanding the study drug, matching the drug to the appropriate HF subgroup, and study execution. Related to the concept of study execution is the importance of including appropriate study sites in HHF trials. Often overlooked issues include consideration of the geographic region and the number of patients enrolled at each study center. Marked differences in baseline patient co-morbidities, serum biomarkers, treatment utilization and outcomes have been demonstrated across geographic regions. Furthermore, patients from sites with low recruitment may have worse outcomes compared to sites with higher enrollment patterns. Consequently, sites with poor trial enrollment may influence key patient end points and likely do not justify the costs of site training and maintenance. Accordingly, there is an unmet need to develop strategies to identify the right study sites that have acceptable patient quantity and quality. Potential approaches include, but are not limited to, establishing a pre-trial registry, developing site performance metrics, identifying a local regionally involved leader and bolstering recruitment incentives. This manuscript summarizes the roundtable discussion hosted by the Food and Drug Administration between members of academia, the National Institutes of Health, industry partners, contract research organizations and academic research organizations on the importance of selecting optimal sites for successful trials in HHF.

Interleukin-1ß inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).

BACKGROUND: Inflammation contributes to all phases of the atherothrombotic process, and patients with elevated inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have increased vascular risk. Yet, it remains unknown whether direct inhibition of inflammation will reduce cardiovascular event rates. DESIGN: The CANTOS will evaluate whether interleukin-1ß (IL-1ß) inhibition as compared with placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable patients with coronary artery disease who remain at high vascular risk due to persistent elevations of hsCRP (>2 mg/L) despite contemporary secondary prevention strategies. Canakinumab is a human monoclonal antibody that selectively neutralizes IL-1ß, a proinflammatory cytokine that plays multiple roles in the atherothrombotic process and that undergoes activation by the nucleotide-binding leucine-rich repeat-containing pyrin receptor 3 inflammasome, a process promoted by cholesterol crystals. Canakinumab significantly reduces systemic C-reactive protein and other inflammatory biomarker levels, is generally well tolerated, and is currently indicated for the treatment of inherited IL-1ß driven inflammatory diseases such as the Muckle-Wells syndrome. In a multinational collaborative effort using an event-driven intention-to-treat protocol, CANTOS will randomly allocate 17,200 stable postmyocardial infarction patients with persistent elevation of hsCRP to either placebo or to canakinumab at doses of 50, 150, or 300 mg every 3 months, administered subcutaneously. All participants will be followed up over an estimated period of up to 4 years for the trial primary end point (nonfatal myocardial infarction, nonfatal stroke, cardiovascular death) as well as for other vascular events, total mortality, adverse events, and specific clinical end points associated with inflammation including new onset diabetes, venous thrombosis, and atrial fibrillation. SUMMARY: If positive, CANTOS would confirm the inflammatory hypothesis of atherothrombosis and provide a novel cytokine-based therapy for the secondary prevention of cardiovascular disease and new-onset diabetes.

Peripheral artery disease, biomarkers, and darapladib.

OBJECTIVE: Subjects with peripheral artery disease (PAD) are at increased risk of cardiovascular morbidity and mortality, perhaps in part, related to increased levels of inflammation, platelet activity, and lipids. We therefore sought to investigate the relationship between PAD and levels of inflammatory, platelet, and lipid biomarkers and the treatment effect of darapladib, a novel lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) inhibitor. METHODS: This is a post hoc analysis of the 959 patients with coronary disease or their risk equivalent receiving atorvastatin who were randomized to receive darapladib or placebo to examine the effects of an Lp-PLA(2) inhibitor on the biomarkers of cardiovascular risk. We conducted an exploratory analysis evaluating the levels of biomarkers in subjects with PAD (n = 172) compared with those without PAD (n = 787). RESULTS: After adjustment for age, sex, smoking, body mass index, and diabetes, subjects with PAD had greater levels of matrix metalloproteinase-9 (between group comparisons 22%, 95% confidence interval [10-31], P < .01), myeloperoxidase (12% [2-20], P = .01), interleukin-6 (13% [4-21], P = .01), adiponectin (17% [7-26], P < .01), intercellular adhesion molecule-1 (7% [2-11], P < .01), osteoprotegrin (6% [1-10], P = .02), CD40 ligand (15% [1-28], P = .04), high-sensitivity C-reactive protein (17% [1-31], P = .04), and triglycerides (11% [0.2-21], P = .05). No significant difference was detected for Lp-PLA(2) activity, P-selectin, urinary 11-dehydrothroboxane B2, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol between subjects with and without PAD. Darapladib produced highly significant inhibition of Lp-PLA(2) activity when compared with placebo at weeks 4 and 12 (P < .01) in patients with and without PAD. CONCLUSIONS: Subjects with PAD had elevated levels of matrix metalloproteinase-9, myeloperoxidase, interleukin-6, adiponectin, intercellular adhesion molecule-1, osteoprotegrin, CD40 ligand, high-sensitivity C-reactive protein, and triglycerides compared with those without PAD. Darapladib, a novel Lp-PLA(2) inhibitor, was equally effective in reducing Lp-PLA(2) activity levels in subjects with and without PAD.

Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque.

BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture. METHODS AND RESULTS: This study compared the effects of 12 months of treatment with darapladib (an oral Lp-PLA(2) inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (intravascular ultrasound palpography) and plasma high-sensitivity C-reactive protein in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (intravascular ultrasound radiofrequency), atheroma size (intravascular ultrasound gray scale), and blood biomarkers. BACKGROUND: =0.37). In contrast, Lp-PLA(2) activity was inhibited by 59% with darapladib (P<0.001 versus placebo). After 12 months, there were no significant differences between groups in plaque deformability (P=0.22) or plasma high-sensitivity C-reactive protein (P=0.35). In the placebo-treated group, however, necrotic core volume increased significantly (4.5+/-17.9 mm(3); P=0.009), whereas darapladib halted this increase (-0.5+/-13.9 mm(3); P=0.71), resulting in a significant treatment difference of -5.2 mm(3) (P=0.012). These intraplaque compositional changes occurred without a significant treatment difference in total atheroma volume (P=0.95). CONCLUSIONS: Despite adherence to a high level of standard-of-care treatment, the necrotic core continued to expand among patients receiving placebo. In contrast, Lp-PLA(2) inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability. These findings suggest that Lp-PLA(2) inhibition may represent a novel therapeutic approach.

Site-specific atherogenic gene expression correlates with subsequent variable lesion development in coronary and peripheral vasculature.

OBJECTIVE: The relationship between specific gene regulation and subsequent development and progression of atherosclerosis is incompletely understood. We hypothesized that genes in the vasculature related to cholesterol metabolism, inflammation, and insulin signaling pathways are differentially regulated in a site-specific and time-dependent manner. METHODS AND RESULTS: Expression of 59 genes obtained from coronary, carotid, and thoracic aortic arteries were characterized from diabetic (DM)/hypercholesterolemic (HC) swine (n=52) 1, 3, and 6 months after induction. Lesion development in the 3 arterial beds was quantified and characterized at 1, 3, 6, and 9 months. Progressive lesion development was observed in the coronary>thoracic aorta>>carotid arteries. Genes involved in cholesterol metabolism and insulin pathways were upregulated in coronaries>thoracic aortae>carotids. Inflammatory genes were more markedly upregulated in coronary arteries than the other 2 arteries. Genes implicated in plaque instability (eg, matrix metalloproteinase-9, CCL2 and Lp-PLA(2) mRNAs) were only upregulated at 6 months in coronary arteries. CONCLUSIONS: Variable gene expression, both in regard to the arterial bed and duration of disease, was associated with variable plaque development and progression. These findings may provide further insight into the atherosclerotic process and development of potential therapeutic targets.

Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in diabetes patients with Cardiovascular History (APPROACH): study design and baseline characteristics.

BACKGROUND: Rosiglitazone, a thiazolidinedione, has effects on insulin sensitivity and cardiovascular risk factors that may favorably impact the progression of coronary atherosclerosis. METHODS: APPROACH is a double-blind randomized clinical trial comparing the effects of the insulin sensitizer rosiglitazone with the insulin secretagogue glipizide on the progression of coronary atherosclerosis. Patients with type 2 diabetes and coronary artery disease undergoing clinically indicated coronary angiography or percutaneous coronary intervention are randomized to receive rosiglitazone or glipizide for 18 months using a titration algorithm designed to provide comparable glycemic control between treatment groups. The primary end point is change in percent atheroma volume from baseline to study completion in a nonintervened coronary artery, as measured by intravascular ultrasound. Cardiovascular events are adjudicated by an end point committee. RESULTS: A total of 672 patients were randomized. The mean age was 61 years, hemoglobin A(1c) (HbA(1c)) 7.2%, body mass index 29.5 kg/m(2), and median duration of diabetes 4.8 years. At baseline, approximately half of the participants were receiving oral antidiabetic monotherapy (53.9%) with 27.5% receiving dual combination therapy and 17.9% treated with diet and exercise alone. Approximately two thirds of the participants (68%) had dyslipidemia, 79.9% hypertension, and 24% prior myocardial infarction. CONCLUSIONS: APPROACH has fully enrolled a high-risk patient population and will compare the glucose-independent effects of rosiglitazone and glipizide on the progression of coronary atherosclerosis, as well as provide additional data on the cardiovascular safety of rosiglitazone in patients with type 2 diabetes and coronary artery disease.

Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging cardiovascular risk marker. To explore the biologic role of Lp-PLA2 in atherosclerosis, we examined its expression and contribution to leukocyte activation under proatherogenic conditions. METHODS AND RESULTS: Following the induction of diabetes and hypercholesterolemia in a porcine model, a rapid increase in plasma Lp-PLA2 activity was observed at 1 month. This was accompanied by upregulated Lp-PLA2 mRNA expression by peripheral blood mononuclear cells (PBMC) at 3 months, and elevated Lp-PLA2 mRNA expression in coronary arteries at 6 months. These changes were paralleled by increased inflammatory responses by circulating PBMC (ICAM-1, IL-6), in coronary tissues (ICAM-1, VCAM-1), and the subsequent accumulation of inflammatory cells. In human PBMC, proinflammatory mediators augmented the synthesis and release of functional Lp-PLA2. Furthermore, lysophosphatidylcholine (lysoPC), a product of Lp-PLA2 activity, induced an increase in several inflammatory cytokines (IL-1beta, IL-6, TNF-alpha) in a concentration-dependent manner. In contrast, Lp-PLA2 inhibition (SB677116; 1 microM) abrogated the inflammatory response elicited by oxidized LDL. CONCLUSIONS: In an experimental model of diabetes and hypercholesterolemia, leukocyte activation was associated with augmented Lp-PLA2 expression. In vitro, Lp-PLA2 activity mediated leukocyte activation and inflammatory responses, whereas Lp-PLA2 inhibition abolished inflammatory responses induced by oxidized LDL. Collectively, these observations support a proatherogenic role for Lp-PLA2.

Role of lipoprotein-associated phospholipase A2 in atherosclerosis and its potential as a therapeutic target.

Despite substantial progress in preventing adverse cardiovascular events with current therapeutic strategies, there remains an extensive residual risk of clinical events, particularly in high-risk patients. Because of the evidence implicating inflammation in the pathogenesis of atherosclerosis, identifying and targeting inflammatory pathways could help further reduce cardiovascular risk. There has been controversy regarding the role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in atherosclerosis, partly because of the lack of simple animal models with a human-like pattern of Lp-PLA2 lipoprotein distribution. However, accumulating evidence from pathology, biology and epidemiology studies favors a pro-atherogenic rather than an atheroprotective role for the enzyme. In particular, Lp-PLA2 might play an important role in plaque vulnerability. As a result, additional studies are warranted to determine whether Lp-PLA2 inhibition improves plaque stability and ultimately clinical outcomes for high-risk patients.

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.

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.

Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target.

The development of atherosclerotic vascular disease is invariably linked to the formation of bioactive lipid mediators and accompanying vascular inflammation. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme that is produced by inflammatory cells, co-travels with circulating low-density lipoprotein (LDL), and hydrolyzes oxidized phospholipids in LDL. Its biological role has been controversial with initial reports purporting atheroprotective effects of Lp-PLA2 thought to be a consequence of degrading platelet-activating factor and removing polar phospholipids in modified LDL. Recent studies, however, focused on pro-inflammatory role of Lp-PLA2 mediated by products of the Lp-PLA2 reaction (lysophosphatidylcholine and oxidized nonesterified fatty acids). These bioactive lipid mediators, which are generated in lesion-prone vasculature and to a lesser extent in the circulation (eg, in electronegative LDL), are known to elicit several inflammatory responses. The proinflammatory action of Lp-PLA2 is also supported by a number of epidemiology studies suggesting that the circulating level of the enzyme is an independent predictor of cardiovascular events, despite some attenuation of the effect by inclusion of LDL, the primary carrier of Lp-PLA2, in the analysis. These observations provide a rationale to explore whether inhibiting Lp-PLA2 activity and consequent interference with the formation of bioactive lipid mediators will abrogate inflammation associated with atherosclerosis, produce favorable changes in intermediate cardiovascular end points (eg, biomarkers, imaging, and endothelial function), and ultimately reduce cardiovascular events in high-risk patients.

Diabetes-induced oxidative stress and low-grade inflammation in porcine coronary arteries.

BACKGROUND: Multiple pathways contribute to accelerated coronary atherosclerosis in diabetics, including increased oxidative stress and inflammatory burden. Accordingly, the mechanisms of abnormal formation of reactive oxygen species and the changes in inflammatory gene expression were examined in diabetic coronary arteries. METHODS AND RESULTS: In pigs with streptozotocin-induced diabetes, superoxide formation was augmented in coronary media and adventitia because of increased NAD(P)H oxidase activity (3 months) accompanied by upregulated expression of its cytosolic subunit, p22phox. Diabetes-induced oxidative stress resulted in the inflammatory response in the adventitia (increased expression of interleukin-6, tumor necrosis factor-alpha, monocyte chemotactic protein-1, vascular cell adhesion molecule-1 [VCAM-1]) and in the media (VCAM-1). To examine the mechanisms of these changes, studies with isolated coronary fibroblasts were undertaken. Advanced glycation end products (AGEs), rather than glucose itself, upregulated expression of interleukin-6, VCAM-1, and monocyte chemotactic protein-1 mRNAs. These results were paralleled by increased interleukin-6 secretion (P<0.01) and augmented leukocyte adhesion to AGE-stimulated coronary cells (P<0.001). AGEs increased expression of phosphorylated forms of mitogen-activated protein kinases in coronary cells (ERK1/2 and JNK) and resulted in redox-sensitive expression of inflammatory genes that was inhibited by several inhibitors of oxidative pathways [NAD(P)H oxidase inhibitors, N-acetylcysteine, and pyrrolidine dithiocarbamate]. CONCLUSIONS: Diabetes increased NAD(P)H oxidase activity and oxidative stress, producing inflammatory responses in porcine coronary media and adventitia. AGEs activated ERK1/2 and JNK signaling pathways and induced the expression of several inflammatory genes in coronary cells in a redox-sensitive manner. These results suggest the involvement of AGEs in the development of accelerated coronary atherosclerosis in diabetes.

Human epicardial adipose tissue is a source of inflammatory mediators.

BACKGROUND: Inflammatory mediators that originate in vascular and extravascular tissues promote coronary lesion formation. Adipose tissue may function as an endocrine organ that contributes to an inflammatory burden in patients at risk of cardiovascular complications. In this study, we sought to compare expression of inflammatory mediators in epicardial and subcutaneous adipose stores in patients with critical CAD. METHODS AND RESULTS: Paired samples of epicardial and subcutaneous adipose tissues were harvested at the outset of elective CABG surgery (n=42; age 65+/-10 years). Local expression of chemokine (monocyte chemotactic protein [MCP]-1) and inflammatory cytokines (interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha) was analyzed by TaqMan real-time reverse transcription-polymerase chain reaction (mRNA) and by ELISA (protein release over 3 hours). Significantly higher levels of IL-1beta, IL-6, MCP-1, and TNF-alpha mRNA and protein were observed in epicardial adipose stores. Proinflammatory properties of epicardial adipose tissue were noted irrespective of clinical variables (diabetes, body mass index, and chronic use of statins or ACE inhibitors/angiotensin II receptor blockers) or plasma concentrations of circulating biomarkers. In a subset of samples (n=11), global gene expression was explored by DNA microarray hybridization and confirmed the presence of a broad inflammatory reaction in epicardial adipose tissue in patients with coronary artery disease. The above findings were paralleled by the presence of inflammatory cell infiltrates in epicardial adipose stores. CONCLUSIONS: Epicardial adipose tissue is a source of several inflammatory mediators in high-risk cardiac patients. Plasma inflammatory biomarkers may not adequately reflect local tissue inflammation. Current therapies do not appear to eliminate local inflammatory signals in epicardial adipose tissue.

Interaction between baseline and early worsening of renal function and efficacy of renin-angiotensin-aldosterone system blockade in patients with heart failure: insights from the Val-HeFT study.

AIMS: We evaluated the effect of (dual) renin-angiotensin-aldosterone system (RAAS) blockade with valsartan and an ACE inhibitor [92.7% of patients were treated with an ACE inhibitor in the Valsartan in Heart Failure Trial (Val-HeFT)] in patients with NYHA class II-IV heart failure (HF) and reduced EF on cardiovascular (CV) death and HF hospitalization by subgroups and by presence of early worsening of renal function (EWRF) and according to baseline estimated glomerular filtration rate (eGFR). METHODS AND RESULTS: We analysed the data from 5010 patients enrolled in the Val-HeFT study. A total of 2346 (46.8%) patients had baseline renal impairment (i.e. baseline eGFR <60 mL/min/1.73 m(2)). Further, 425 patients (8.6%) had EWRF (i.e. eGFR decrease >20% within 1 month after randomization), whereas 4503 patients (91.4%) had ≤20% decline in eGFR. Overall, the difference between valsartan and placebo on the composite endpoint of CV death and HF hospitalization was significant [P = 0.0005; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.75-0.92)]. In patients with baseline renal impairment, the difference between the treatment groups was also significant (P = 0.0002; HR 0.76, 95% CI 0.66-0.88). Patients with EWRF had higher risk of CV death and HF hospitalization vs. those without ERWF (P < 0.0001; HR 1.44, 95% CI 1.21-1.71), and within the EWRF group a significant difference was also observed between valsartan and placebo (P = 0.0086; HR 0.63, 95% CI 0.45-0.89). However, the interaction between treatment and eGFR at Month 1 was not significant (P = 0.1160). CONCLUSION: Benefits were maintained in patients with renal dysfunction at baseline and those who experienced EWRF.

Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document.

Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and it also has important clinical and practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all-cause mortality, cause-specific mortality, relevant non-fatal morbidity (e.g., all-cause and cause-specific hospitalization), composites capturing both morbidity and mortality, safety, symptoms, functional capacity, and patient-reported outcomes. Each of these endpoints has strengths and weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consistency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronic heart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA-ESC) convened a group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 12-13 February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. This report summarizes the group's recommendations for achieving common views on heart failure endpoints in clinical trials.

Standardization of outcome measures in clinical trials of pharmacological treatment for abdominal aortic aneurysm.

An abdominal aortic aneurysm (AAA) is a common aortic wall disease with an increased prevalence in the elderly population (4-8% for those aged >65 years). Many AAAs are slow growing and remain insidious. Current standard of care for patients with small AAAs (<49 mm) is surveillance, with interventional therapy (open surgical repair or endovascular aneurysm repair) recommended for large (>50-55 mm), rapidly growing (>10 mm/year) or symptomatic AAAs. Although open surgical repair or endovascular aneurysm repair are effective, significant short- and long-term postoperative morbidity and mortality occurs. Currently, there is no pharmacological treatment specific for AAA; the need for the development of targeted pharmacological therapies based on clinically relevant and feasible outcomes acceptable to the medical community, regulatory agencies and third-party payers is high. A consensus on such end points will be critical to accelerating the development of pharmacological agents to prevent formation, arrest the expansion and reduce the rupture risk of AAA.