New-onset atrial fibrillation in patients with worsening heart failure and coronary artery disease:an analysis from the COMMANDER-HF trial

Background: Atrial fibrillation (AF) in the presence of heart failure (HF) is associated with poor outcomes including a high-risk of stroke and other thromboembolic events. Identifying patients without AF who are at high-risk of developing this arrhythmia has important clinical implications. Aims: To develop a risk score to identify HF patients at high risk of developing AF. Methods: The COMMANDER-HF trial enrolled 5022 patients with HF and a LVEF ≤ 40%, history of coronary artery disease, and absence of AF at baseline (confirmed with an electrocardiogram). Patients were randomized to either rivaroxaban (2.5 mg bid) or placebo. New-onset AF was confirmed by the investigator at study visits. Results 241 (4.8%) patients developed AF during the follow-up (median 21 months). Older age (≥ 65 years), LVEF < 35%, history of PCI or CABG, White race, SBP < 110 mmHg, and higher BMI (≥ 25 kg/m2) were independently associated with risk of new-onset AF, whereas the use of DAPT was associated with a lower risk of new-onset AF. We then built a risk score from these variables (with good accuracy C-index = 0.71) and calibration across observed and predicted tertiles of risk. New-onset AF events rates increased steeply by increasing tertiles of the risk-score. Compared to tertile 1, the risk of new-onset AF was 2.5-fold higher in tertile 2, and 6.3-fold higher in tertile 3. Rivaroxaban had no effect in reducing new-onset AF. In time-updated models, new-onset AF was associated with a higher risk of subsequent all-cause death: HR (95%CI) 1.38 (1.11–1.73). Conclusions: A well-calibrated risk-score identified patients at risk of new-onset AF in the COMMANDER-HF trial. Patients who developed AF had a higher risk of subsequent death

Rivaroxaban in patients with heart failure, sinus rhythm, and coronary disease

Background: Heart failure is associated with activation of thrombin-related pathways, which predicts a poor prognosis. We hypothesized that treatment with rivaroxaban, a factor Xa inhibitor, could reduce thrombin generation and improve outcomes for patients with worsening chronic heart failure and underlying coronary artery disease. Methods: In this double-blind, randomized trial, 5022 patients who had chronic heart failure, a left ventricular ejection fraction of 40% or less, coronary artery disease, and elevated plasma concentrations of natriuretic peptides and who did not have atrial fibrillation were randomly assigned to receive rivaroxaban at a dose of 2.5 mg twice daily or placebo in addition to standard care after treatment for an episode of worsening heart failure. The primary efficacy outcome was the composite of death from any cause, myocardial infarction, or stroke. The principal safety outcome was fatal bleeding or bleeding into a critical space with a potential for causing permanent disability. Results: Over a median follow-up period of 21.1 months, the primary end point occurred in 626 (25.0%) of 2507 patients assigned to rivaroxaban and in 658 (26.2%) of 2515 patients assigned to placebo (hazard ratio, 0.94; 95% confidence interval [CI], 0.84 to 1.05; P=0.27). No significant difference in all-cause mortality was noted between the rivaroxaban group and the placebo group (21.8% and 22.1%, respectively; hazard ratio, 0.98; 95% CI, 0.87 to 1.10). The principal safety outcome occurred in 18 patients who took rivaroxaban and in 23 who took placebo (hazard ratio, 0.80; 95% CI, 0.43 to 1.49; P=0.48). Conclusions: Rivaroxaban at a dose of 2.5 mg twice daily was not associated with a significantly lower rate of death, myocardial infarction, or stroke than placebo among patients with worsening chronic heart failure, reduced left ventricular ejection fraction, coronary artery disease, and no atrial fibrillation. (Funded by Janssen Research and Development; COMMANDER HF ClinicalTrials.gov number, NCT01877915.

Natriuretic peptide-based inclusion criteria in a heart failure clinical trial: insights from COMMANDER HF

Objectives: This study investigated the effects of a mid-trial protocol amendment requiring elevated natriuretic peptides for inclusion in the 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) trial. Background: Heart failure (HF) trials that select patients based on history of HF hospitalization alone are susceptible to regional variations in event rates. Elevated plasma concentrations of natriuretic peptides (NPs) as selection criteria may help HF ascertainment and risk enrichment. In the COMMANDER-HF trial, B-type natriuretic peptide greater than or equal to 200 ng/l or N-terminal pro–B-type natriuretic peptide greater than or equal to 800 ng/l were added to inclusion criteria as a mid-trial protocol amendment, providing a unique case-study of NP-based inclusion criteria. Methods: We compared the baseline characteristics, event rates, and treatment effects for patients enrolled before and after the NP protocol amendment. The primary endpoint was all-cause death, myocardial infarction, or stroke. Secondary endpoints included HF rehospitalization and cardiovascular death. Results: A total of 5,022 patients with left ventricular ejection fraction less than or equal to 40% and coronary artery disease were included. Compared to patients enrolled before the NP protocol amendment, those enrolled post-amendment (n = 3,867, 77%) were older, more often had diabetes, and had lower values for body mass index, left ventricular ejection fraction, and estimated glomerular filtration rate, higher heart rate, and higher event rates: primary endpoint (hazard ratio [HR]: 1.32; 95% confidence interval [CI]: 1.16 to 1.50), cardiovascular death (HR: 1.29; 95% CI: 1.11 to 1.50), HF rehospitalization (HR: 1.31; 95% CI: 1.15 to 1.49), and major bleeding (HR: 1.71; 95% CI: 1.11 to 2.65). Differences between pre- and post-amendment rates were confined to and driven by Eastern Europe. This protocol amendment did not modify the neutral effect of rivaroxaban on the primary endpoint (p interaction = 0.36) or secondary endpoints. Conclusions: In a global event-driven trial of rivaroxaban in HF, requiring elevated NPs for inclusion increased event rates allowing earlier completion of the trial but did not modify treatment effect. These data inform future HF trials regarding the expected impact of NP-based inclusion criteria on patient characteristics and event rates. (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] NCT01877915

Rationale and design of a randomized, double-blind, event-driven, multicentre study comparing the efficacy and safety of oral rivaroxaban with placebo for reducing the risk of death, myocardial infarction or stroke in subjects with heart failure and significant coronary artery disease following an exacerbation of heart failure: the COMMANDER HF trial.

AimsThrombin is a critical element of crosstalk between pathways contributing to worsening of established heart failure (HF). The aim of this study is to explore the efficacy and safety of rivaroxaban 2.5 mg bid compared with placebo (with standard care) after an exacerbation of HF in patients with reduced ejection fraction (HF-rEF) and documented coronary artery disease.MethodsThis is an international prospective, multicentre, randomized, double-blind, placebo-controlled, event-driven study of approximately 5000 patients for a targeted 984 events. Patients must have a recent symptomatic exacerbation of HF, increased plasma concentrations of natriuretic peptides (B-type natriuretic peptide ≥200 pg/mL or N-terminal pro-B-type natriuretic peptide ≥800 pg/mL), with left ventricular ejection fraction ≤40% and coronary artery disease. Patients requiring anticoagulation for atrial fibrillation or other conditions will be excluded. After an index event (overnight hospitalization, emergency department or observation unit admission, or unscheduled outpatient parenteral treatment for worsening HF), patients will be randomized 1:1 to rivaroxaban or placebo (with standard of care). The primary efficacy outcome event is a composite of all-cause mortality, myocardial infarction or stroke. The principal safety outcome events are the composite of fatal bleeding or bleeding into a critical space with potential permanent disability, bleeding events requiring hospitalization and major bleeding events according to International Society on Thrombosis and Haemostasis bleeding criteria.ConclusionCOMMANDER HF is the first prospective study of a target-specific oral antithrombotic agent in HF. It will provide important information regarding rivaroxaban use following an HF event in an HF-rEF patient population with coronary artery disease

Rationale and design of a randomized, double‐blind, event‐driven, multicentre study comparing the efficacy and safety of oral rivaroxaban with placebo for reducing the risk of death, myocardial infarction or stroke in subjects with heart failure and significant coronary artery disease following an exacerbation of heart failure: the COMMANDER HF trial

Aims Thrombin is a critical element of crosstalk between pathways contributing to worsening of established heart failure (HF). The aim of this study is to explore the efficacy and safety of rivaroxaban 2.5 mg bid compared with placebo (with standard care) after an exacerbation of HF in patients with reduced ejection fraction (HF‐rEF) and documented coronary artery disease. Methods: This is an international prospective, multicentre, randomized, double‐blind, placebo‐controlled, event‐driven study of approximately 5000 patients for a targeted 984 events. Patients must have a recent symptomatic exacerbation of HF, increased plasma concentrations of natriuretic peptides (B‐type natriuretic peptide ≥200 pg/mL or N‐terminal pro–B‐type natriuretic peptide ≥800 pg/mL), with left ventricular ejection fraction ≤40% and coronary artery disease. Patients requiring anticoagulation for atrial fibrillation or other conditions will be excluded. After an index event (overnight hospitalization, emergency department or observation unit admission, or unscheduled outpatient parenteral treatment for worsening HF), patients will be randomized 1:1 to rivaroxaban or placebo (with standard of care). The primary efficacy outcome event is a composite of all‐cause mortality, myocardial infarction or stroke. The principal safety outcome events are the composite of fatal bleeding or bleeding into a critical space with potential permanent disability, bleeding events requiring hospitalization and major bleeding events according to International Society on Thrombosis and Haemostasis bleeding criteria. Conclusion: COMMANDER HF is the first prospective study of a target‐specific oral antithrombotic agent in HF. It will provide important information regarding rivaroxaban use following an HF event in an HF‐rEF patient population with coronary artery disease

Plasma D‐dimer concentrations predicting stroke risk and rivaroxaban benefit in patients with heart failure and sinus rhythm: an analysis from the COMMANDER‐HF trial

Background: D‐dimer is a marker of fibrin degradation that reflects intra‐vascular coagulation. Therefore, plasma concentrations of D‐dimer might predict thromboembolic risk and rivaroxaban treatment effect. Aims: To investigate the association between D‐dimer levels and the risk of stroke and other thrombotic, bleeding and fatal events, and whether D‐dimer concentrations could predict rivaroxaban 2.5mg/bd (vs. placebo) effect in patients enrolled in the COMMANDER‐HF trial who were in sinus rhythm, had HFrEF and coronary artery disease. Methods: Survival models with treatment‐by‐plasma D‐dimer interaction. Baseline measurement of D‐dimer was available in 4,107 (82%) of 5,022 patients enrolled. Median (percentile25‐75) follow‐up was 21 (12.9‐32.8) months. Results: The median (percentile25‐75) plasma concentration of D‐dimer was 360 (215‐665)ng/mL. The D‐dimer tertiles were: 1) ≤255; 2) 256‐515; 3) >515ng/mL. Patients within the tertile‐3 were older, and had lower BMI, blood pressure, hemoglobin, eGFR, and LVEF. Higher plasma D‐dimer concentrations were independently associated with higher rates of death, stroke, and venous thromboembolism. For example, the all‐cause death adjusted HR (95%CI) of tertile‐3 vs. tertile‐1 was 1.77 (1.48‐2.11), p<0.001. The effect of rivaroxaban was similar in each tertile of D‐dimer for all outcomes except stroke. Patients within the tertile‐3 had the greatest absolute and relative stroke reduction (HR [95%CI] tertile‐1=1.16 [0.49‐2.74], tertile‐2=1.45 [0.77‐2.73], and tertile‐3=0.36 [0.18‐0.70]; interactionp=0.008). The number‐needed‐to‐treat to prevent one stroke in tertile‐3 was 36. Conclusion: In COMMANDER‐HF, rivaroxaban reduced the risk of stroke but the benefit may be confined to patients with D‐dimer concentrations above 515ng/mL. Prospective trials are warranted to confirm these findings

Heart failure re-hospitalizations and subsequent fatal events in coronary artery disease: insights from COMMANDER-HF, EPHESUS, and EXAMINE

Background: Patients with coronary artery disease (CAD) are at increased risk of developing and being hospitalised for heart failure (HFH). However, the risk of HFH versus ischemic events may vary among patients with CAD, depending on whether acute myocardial infarction (MI), left ventricular dysfunction or decompensated HF is present at baseline. Aims: We aim to explore the risk of non-fatal events (HFH, MI, stroke) and subsequent death in 3 landmark trials, COMMANDER-HF, EPHESUS and EXAMINE that, together, included patients with CAD with and without reduced ejection fraction and acute MI. Methods: Events, person-time metrics and time-updated Cox models. Results: In COMMANDER-HF the event-rate for the composite of AMI, stroke or all-cause death was 13.5 (12.8–14.3) events/100 py. Rates for AMI and stroke were much lower (2.2 [2.0–2.6] and 1.3 [1.1–1.6] events/100 py, respectively) than the rate of HFH (16.9 [16.1–17.9] events/100 py). In EPHESUS, the rates of MI and stroke were also lower than the rate of HFH: 7.2 (6.7–7.8), 1.9 (1.7–2.3), and 10.6 (9.9–11.3) events/100 py, but this was not true for EXAMINE with 4.4 (4.0–4.9), 0.7 (0.6–0.9), and 2.4 (2.0–2.7) events/100 py, respectively. In all 3 trials, a non-fatal event (HFH, MI or stroke) during follow-up doubled the risk of subsequent mortality. This most commonly followed a HFH. Conclusions: A first or recurrent HFH is common in patients with CAD and AMI or HFrEF and indicates a poor prognosis. Preventing the development of heart failure after AMI and control of congestion in patients with CAD and HFrEF are key unmet needs and therapeutic targets. Registration: ClinicalTrials.gov Identifier: NCT01877915. URL: https://clinicaltrials.gov/ct2/show/NCT01877915

A comprehensive analysis of the effects of rivaroxaban on stroke or transient ischaemic attack in patients with heart failure, coronary artery disease, and sinus rhythm: the COMMANDER HF trial.

AimsStroke is often a devastating event among patients with heart failure with reduced ejection (HFrEF). In COMMANDER HF, rivaroxaban 2.5 mg b.i.d. did not reduce the composite of first occurrence of death, stroke, or myocardial infarction compared with placebo in patients with HFrEF, coronary artery disease (CAD), and sinus rhythm. We now examine the incidence, timing, type, severity, and predictors of stroke or a transient ischaemic attack (TIA), and seek to establish the net clinical benefit of treatment with low-dose rivaroxaban.Methods and resultsIn this double-blind, randomized trial, 5022 patients who had HFrEF(≤40%), elevated natriuretic peptides, CAD, and who were in sinus rhythm were treated with rivaroxaban 2.5 mg b.i.d. or placebo in addition to antiplatelet therapy, after an episode of worsening HF. The primary neurological outcome for this post hoc analysis was time to first event of any stroke or TIA. Over a median follow-up of 20.5 (25th-75th percentiles 20.0-20.9) months, 150 all-cause stroke (127) or TIA (23) events occurred (ischaemic stroke in 82% and haemorrhagic stroke in 11% of stroke events). Overall, 47.5% of first-time strokes were either disabling (16.5%) or fatal (31%). Prior stroke, low body mass index, geographic region, and the CHA2DS2-VASc score were predictors of stroke/TIA. Rivaroxaban significantly reduced the primary neurological endpoint of all-cause stroke or TIA compared with placebo by 32% (1.29 events vs. 1.90 events per 100 patient-years), adjusted for the time from index HF event to randomization and stratified by geographic region (adjusted hazard ratio 0.68, 95% confidence interval 0.49-0.94), with a number needed to treat of 164 patients per year to prevent one stroke/TIA event. The principal safety endpoint of fatal bleeding or bleeding into a critical space, occurred at a similar rate on rivaroxaban and placebo (0.44 events vs. 0.55 events per 100 patient-years).ConclusionsPatients with HFrEF and CAD are at risk for stroke or TIA in the period following an episode of worsening heart failure in the absence of atrial fibrillation. Most strokes are of ischaemic origin and nearly half are either disabling or fatal. Rivaroxaban at a dose of 2.5 mg b.i.d. reduced rates of stroke or TIA compared with placebo in this population.Trial registrationCOMMANDER 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); ClinicalTrials.gov NCT01877915