Generalizability Of Trial Findings Research Articles

Implications of trial eligibility in patients with heart failure with mildly reduced or preserved ejection fraction.

Clinical trials in heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) commonly have detailed eligibility criteria. This may contribute to challenges with efficient enrolment and questions regarding the generalizability of trial findings. Patients with HFmrEF/HFpEF from a large US healthcare system were identified through a computable phenotype applied in linked imaging and electronic health record databases. We evaluated shared eligibility criteria from five recent/ongoing HFmrEF/HFpEF trials (PARAGON-HF, EMPEROR-Preserved, DELIVER, FINE-ARTS, and SPIRRIT-HFpEF) and compared clinical and echocardiographic features as well as outcomes between trial-eligible and trial-ineligible patients. Among 5552 patients with HFpEF/HFmrEF, 792 (14%) were eligible for trial consideration, having met all criteria assessed. Causes of ineligibility included lack of recent loop diuretics (37%), significant pulmonary disease (24%), reduced estimated glomerular filtration rate (17%), recent stroke/transient ischaemic attack (13%), or low natriuretic peptides (12%); 53% of ineligible patients had >1 reason for exclusion. Compared with eligible patients, ineligible patients were younger (age 71 vs. 75years, P<0.001) with higher rates of coronary artery disease (66% vs. 59%, P<0.001) and peripheral vascular disease (40% vs. 33%, P<0.001), but less mitral regurgitation, lower E/e' ratio, and smaller left atrial sizes. Both eligible and ineligible patients demonstrated high rates of structural heart disease consistent with HFpEF [elevated left atrial size or left ventricular (LV) hypertrophy/increased LV mass], although this was slightly higher among eligible patients (95% vs. 92%, P=0.001). The two cohorts demonstrated similar LV global longitudinal strain along with a similar prevalence of atrial fibrillation/flutter, hypertension, and obesity. Ineligible patients had similar all-cause mortality (33% vs. 33% at 3years) to those eligible but lower rates of heart failure hospitalization (20% vs. 28% at 3years, P<0.001). Among patients with HFmrEF/HFpEF from a large health system, approximately one in seven were eligible for major trials based on key criteria applied through a clinical computable phenotype. These findings highlight the large proportion of patients with HFmrEF/HFpEF ineligible for contemporary trials for whom the generalizability of trial findings may be questioned and further investigation would be beneficial.

Regional Differences in Outcomes with Ablation Versus Drug Therapy for Atrial Fibrillation: Results from the CABANA Trial

The finding of unexpected variations in treatment benefits by geographic region in international clinical trials raises complex questions about the interpretation and generalizability of trial findings. We observed such geographical variations in outcome and in the effectiveness of atrial fibrillation (AF) ablation versus drug therapy in the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial. This paper describes these differences and investigates potential causes. The examination of treatment effects by geographic region was a prespecified analysis. CABANA enrolled patients from 10 countries, with 1,285 patients at 85 North American (NA) sites and 919 at 41 non-NA sites. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Death and first atrial fibrillation recurrence were secondary endpoints. At least 1 primary endpoint event occurred in 157 patients (12.2%) from NA and 33 (3.6%) from non-NA sites over a median 54.9 and 40.5 months of follow-up, respectively (NA/non-NA adjusted hazard ratio (HR) 2.18, 95% confidence interval (CI) 1.48-3.21, P < .001). In NA patients, 78 events occurred in the ablation and 79 in the drug arm, (HR 0.91, 95% CI 0.66, 1.24) while 11 and 22 events occurred in non-NA patients (HR 0.51, 95% CI 0.25,1.05, interaction P = .154). Death occurred in 53 ablation and 51 drug therapy patients in the NA group (HR 0.96, 95% CI 0.65,1.42) and in 5 ablation and 16 drug therapy patients in the non-NA group (HR 0.32, 95% CI 0.12,0.86, interaction P = .044). Adjusting for baseline regional differences or prognostic risk variables did not account for the regional differences in treatment effects. Atrial fibrillation recurrence was reduced by ablation in both regions (NA: HR 0.54, 95% CI 0.46, 0.63; non-NA: HR 0.44, 95% CI 0.30, 0.64, interaction P = .322). In CABANA, primary outcome events occurred significantly more often in the NA group but assignment to ablation significantly reduced all-cause mortality in the non-NA group only. These differences were not explained by regional variations in procedure effectiveness, safety, or patient characteristics. ClinicalTrials.gov Identifier: NCT0091150; https://clinicaltrials.gov/study/NCT00911508.

Fifteen-year mortality outcomes in the APEX-AMI trial compared to the general ST-elevation myocardial infarction population in Canada: Exploring lessons from numerators and denominators

Abstract Background It is well established that patients enrolled in clinical trials tend to be younger, more likely male, and have fewer comorbidities. Moreover, sites that enroll patients in randomized trials (RT) are often tertiary care centres in urban areas especially in the setting of STEMI. The impact of these potential selection biases on clinical outcomes both within and well beyond the proscribed RT follow-up window have not been adequately explored. Objective To compare 15-year mortality of ST elevation myocardial infarction of Canadian (STEMI) patients with high-risk electrocardiographic findings enrolled within 6 hours of symptom onset undergoing primary PCI in the APEX-AMI clinical trial of Pexelizumab (APEX-AMI group) with STEMI patients presenting to 25 APEX-AMI enrolling sites (APEX-AMI sites group); and STEMI patients presenting to 400 other sites (non-APEX-AMI site group). Methods APEX-AMI enrolled patients between 07/13/2004 – 05/11/2006. We conducted a probabilistic linkage (based on admission date, discharge date, age, sex, province, diagnosis of MI, presence of comorbidities) between APEX-AMI and the Canadian national Discharge Abstract Database (DAD), excluding Quebec, for the same time period. These data were further linked to tax files (for socio-economic data) and vital statistics data to obtain mortality status as of 2020. Results Of the 335 Canadian participants in APEX-AMI, 143 were from Quebec and were excluded. Of the remaining 192 patients, 188 (97.9%) were linked with the DAD. There were 8,470 patients in the APEX-AMI sites and 10,940 in the non-APEX-AMI sites groups, respectively (Table 1). Patients enrolled in APEX-AMI were less likely to be female, more affluent, have a lower comorbidity burden as measured by the Charlson Comorbidity Index, and higher PCI rates. Ninety-day all-cause mortality in the three groups was 4.3%, 8.5%, 12.7% in the APEX-AMI, APEX-AMI site, and non-APEX-AMI site groups, respectively. At 15-years, mortality rates were 34.0%, 45.8%, and 52.2% in the three groups (p&amp;lt;0.01, Figure). Enrollment in APEX-AMI was associated with an unadjusted 45% reduction in risk of 15-year mortality (HR 0.55, 95% CI: 0.43-0.70). However, this association was attenuated after adjusting for demographic and clinical factors (adjusted HR (aHR), 0.69, 95% CI: 0.54-0.88), and completely nullified after adjusting for PCI (aHR, 0.82, 95% CI: 0.64-1.05). Conclusions Our study demonstrates the feasibility and value of extending clinical trial follow-up via linkage with routinely collected administrative data. While enrollment in clinical trials appears to be associated with better long-term outcomes, our findings highlight the need to be vigilant to the potential for selection bias, the generalizability of trial findings and the potential to more broadly enhance long-term STEMI outcomes.

Enrollment of Older Patients, Women, and Racial and Ethnic Minority Individuals in Valvular Heart Disease Clinical Trials: A Systematic Review.

Inadequate representation of older patients, women, and racial minority individuals in cardiovascular clinical trials limits both the generalizability of trial findings and inclusivity in access to novel therapies and therapeutic strategies. To report on temporal trends in the representation of older patients, women, and racial and ethnic minority individuals in clinical trials studying treatments for valvular heart disease. All published clinical trials enrolling more than 100 adults with any valvular heart disease published between 2005 and 2020 were included after searches with PubMed and ClinicalTrials.gov. Data on age, sex, race, and ethnicity reported in the included studies were collected. Trials were assigned to 4 time periods based on the publication date, and temporal trends were analyzed in the representation of older patients, women, and racial and ethnic minority individuals. A total of 139 clinical trials with 51 527 participants were identified. Of these trials, 103 (74%) investigated aortic valve disease and the remainder mitral valve disease. Overall, 63 trials (45.3%) enrolled patients only in Europe, 24 (17.3%) only in North America, and 19 (13.7%) in multiple geographical regions. The weighted mean (SD) age of enrolled patients was 68.4 (11.4) years, increasing nonsignificantly from 61.9 (5.9) years in 2005-2008 to 72.8 (9.6) years in 2017-2020 (P = .09 for trend). The overall proportion of women enrolled in valvular heart disease trials was 41.1%, with no significant changes over time. Data on race and ethnicity of trial participants were reported in 13 trials (9.4%), in which trial-level representation of American Indian/Alaska Native, Asian, Black/African American, Hispanic, and Native Hawaiian/Pacific Islander patients ranged from 0.27% to 43.9%. There were no significant temporal trends noted in the enrollment of racial and ethnic minority populations. The representation of women in clinical trials was positively associated with enrollment rates of older patients and underrepresented racial and ethnic groups. This review found that over the past 2 decades, women and racial and ethnic minority individuals have remained underrepresented in North American valvular heart disease clinical trials. Further work is needed to improve the reporting of race and ethnicity data and address barriers to trial enrollment for older patients, women, and racial and ethnic minority individuals.

Assessing the Eligibility Criteria in Phase III Randomized Controlled Trials of Drug Therapy in Heart Failure With Preserved Ejection Fraction: The Critical Play-Off Between a “Pure” Patient Phenotype and the Generalizability of Trial Findings

AimsTo investigate the effect of the different eligibility criteria used by phase III clinical studies in heart failure with preserved ejection fraction (HFpEF) on patient selection, phenotype, and survival. Methods and ResultsWe applied the key eligibility criteria of 7 phase III HFpEF studies (Digitalis Investigation Group Ancillary, Candesartan in Patients With Chronic Heart Failure and Preserved Left-Ventricular Ejection Fraction, Perindopril in Elderly People With Chronic Heart Failure, Irbesartan in Heart Failure With Preserved Systolic Function, Japanese Diastolic Heart Failure, Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist, and Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF; ongoing]) to a typical and well-characterized HFpEF population (n = 557) seen in modern European cardiological practice. Follow-up was available for a minimum of 24 months in each patient. Increasing the number of study eligibility criteria identifies a progressively smaller group of patients from real-life practice suitable for recruitment into clinical trials; using the J-DHF criteria, 81% of our clinic patients would have been eligible, whereas the PARAGON-HF criteria significantly reduced this proportion to 32%. The patients identified from our clinical population had similar mortality rates using the different criteria, which were consistently higher than those reported in the actual clinic trials. ConclusionsTrial eligibility criteria have become stricter with time, which reduces the number of eligible patients, affecting both generalizability of any findings and feasibility of completing an adequately powered trial. We could not find evidence that the additional criteria used in more recent randomized trials in HFpEF have identified patients at higher risk of all-cause mortality.