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Natriuretic Peptide-Based Inclusion Criteria in COMMANDER-HF Trial
Quick Takes
- It is important to include biomarkers (natriuretic peptides) in the design of clinical trials of HF to minimize enrollment of low-risk patients who had not truly been hospitalized for decompensated HF.
- And instead, enroll HF patients with higher event rates (e.g., death, MI, or stroke; CV death, rehospitalization for HF), thereby, increasing statistical power that allows for more rapid completion of event-driven trials.
Study Questions:
What are the effects of a mid-trial protocol amendment requiring elevated natriuretic peptides for inclusion in the COMMANDER-HF trial?
Methods:
COMMANDER-HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) was an international, double-blind, randomized trial comparing the factor Xa inhibitor rivaroxaban 2.5 mg twice daily (a low dose) and placebo. Based on review of patient characteristics and the blinded event rate for 1,155 patients, the steering committee amended the enrollment criteria to require a plasma N-terminal pro–B-type natriuretic peptide (NT-proBNP) level ≥800 ng/L or BNP level ≥200 ng/L at any time between the index admission for decompensated HF and randomization. This study compares the baseline characteristics, event rates, and treatment effects for patients enrolled before and after the natriuretic peptide protocol amendment. The primary endpoint was all-cause death, myocardial infarction (MI), or stroke. Secondary endpoints included HF rehospitalization and cardiovascular (CV) death. In this analysis, the study authors compared baseline characteristics and crude event rates per 100 patient-years for clinical outcomes in patients enrolled before and after the natriuretic peptide amendment.
Results:
The study cohort was comprised of 5,022 patients with left ventricular ejection fraction (LVEF) ≤40% and coronary artery disease. Compared to patients enrolled before the natriuretic peptide protocol amendment, those enrolled post-amendment (n = 3,867, 77%) were older (67 years vs. 65 years), with more prevalent diabetes (43% vs. 34%) and anemia (34% vs. 22%), higher heart rate (72 bpm vs. 69 bpm), and lower systolic blood pressure (122 mm Hg vs. 124 mm Hg). LVEF was lower (33% vs. 36%), estimated glomerular filtration rate was lower (67 ml/min/1.73 m2 vs. 71 ml/min/1.73 m2), D-dimer was higher (380 mg/L vs. 310 mg/L), and event rates were higher: primary endpoint (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16-1.50), CV death (HR, 1.29; 95% CI, 1.11-1.50), HF rehospitalization (HR, 1.31; 95% CI, 1.15-1.49), and major bleeding (HR, 1.71; 95% CI, 1.11-2.65). Differences between pre- and post-amendment rates were confined to and driven by Eastern Europe (enrolled 89% of patients before the protocol amendment and 57% afterwards). In Eastern Europe, the amendment increased the primary endpoint event rate by 35% (13.64 events per 100 patient-years post-amendment vs. 10.11 events per 100 patient-years pre-amendment; HR, 1.33; 95% CI, 1.14-1.56). Comparison of event rates pre-/post-amendment in other regions was limited as >93% of patients in these regions were enrolled post-amendment; however, there was no signal for an increase in event rate. This protocol amendment did not modify the neutral effect of rivaroxaban on the primary endpoint (p interaction = 0.36) or secondary endpoints.
Conclusions:
The authors concluded that in an event-driven trial of rivaroxaban in HF, requiring elevated natriuretic peptides for inclusion increased event rates allowing earlier completion of the trial, but did not modify treatment effect. Also, these data inform future HF trials regarding the expected impact of natriuretic-based inclusion criteria on patient characteristics and event rates.
Perspective:
The protocol amendment brings important perspectives in the design of HF clinical trials. The amendment resulted in: 1) enrollment of patients with more comorbidities; 2) about 30% higher rates of the primary endpoint (mortality, MI, or stroke); and 3) higher rates of rehospitalization for HF, bleeding, and death (both CV and non-CV). By doing this amendment, it minimized the admission of low-risk HF patients. The 32% increase in primary endpoint event rate after the neuropeptide protocol amendment allowed more rapid completion of this event-driven trial. The use of biomarker-based inclusion criteria in future HF trials to enrich events is important so that HF patients with increased risk for endpoint events are enrolled, which then increases the rate of events that are potentially modifiable, thereby increasing statistical power. This allows earlier completion of clinical trials and this is particularly true in trials where HF is mainly ascertained by a history of HF hospitalization.
Clinical Topics: Anticoagulation Management, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Anemia, Anticoagulants, Blood Pressure, Clinical Trials as Topic, Coronary Artery Disease, Diabetes Mellitus, Glomerular Filtration Rate, Heart Failure, Heart Rate, Hemorrhage, Myocardial Infarction, Natriuretic Peptide, Brain, Natriuretic Peptides, Secondary Prevention, Stroke, Stroke Volume, Vascular Diseases, Ventricular Function, Left
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