Coronary Artery Disease Following an Episode of Decompensated Heart - - PowerPoint PPT Presentation

COMMANDER HF – Randomized Study Comparing Rivaroxaban with Placebo in Subjects with Heart Failure and Significant Coronary Artery Disease Following an Episode of Decompensated Heart Failure

Funded by Janssen Research & Development, LLC Faiez Zannad, MD, PhD, FESC, Professor of Therapeutics and Cardiology, Université de Lorraine, Inserm U1116 and CIC 1433, FCRIN INI-CRCT, CHRU de Nancy, Vandoeuvre les Nancy, France

Declaration of Interest

• Faiez Zannad is co-chair of the steering committee of COMMANDER HF, consultant

to Bayer and has no other conflict of interest related to the current work.

Background

• The majority of patients with chronic heart failure (HF) with reduced ejection

fraction have significant coronary artery disease (CAD)

• For patients who suffer an episode of decompensated HF, the prognosis is poor

with a high rate of readmission and death, despite advances in treatment

• Thrombin-mediated pathways may play a critical role in the disease progression of

heart failure, but prior research with warfarin was inconclusive

• A randomized study was needed to determine whether the prevention of

thrombin-mediated events with a direct oral anticoagulant would improve

• utcomes for chronic HF patients with reduced ejection fraction and significant

CAD following an episode of decompensated HF

Study Outcomes

Primary Efficacy Outcome

• Composite of all-cause mortality,

myocardial infarction, or stroke following an index event Secondary Efficacy Outcomes

• Composite of CV mortality or

rehospitalization for worsening of HF

• CV mortality
• Rehospitalization for worsening of HF
• Rehospitalization for CV events

Principal Safety Outcome

• Composite of fatal bleeding, or bleeding into a

critical space (intracranial, intraspinal, intraocular, pericardial, intra-articular, retroperitoneal, intramuscular with compartment syndrome) with a potential for permanent disability Other Safety Outcomes

• Bleeding events requiring hospitalization
• Major bleeding events using the International

Society on Thrombosis and Haemostasis (ISTH) bleeding criteria

Study Design

Zannad F, et al. Eur J Heart Fail. 2015:17(7):735-742

Patients with HF-rEF and CAD are appropriate regardless

• f whether they are

managed via the traditional inpatient hospital pathway or via the outpatient HF clinic pathway N = 5000 Rivaroxaban 2.5 mg bid + standard of care therapy Placebo bid + standard of care therapy

R

At hospital discharge & up to 30 days post discharge

Double Blind Treatment Phase Screening Period

Early Permanent Study Drug Discontinuation Continue Follow-Up *Global Treatment End Date (GTED)

End of Study Visit

q 12 weeks 30 ±15 days

Follow-Up After GTED

Visits: Day 1 = R Week 4 Week 12 q 3 months

≤ 21 days of Index Event

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Primary Efficacy Outcome & Components (ITT, Up to GTED)

Rivaroxaban Placebo Rivaroxaban vs. Placebo

Event Rate Event Rate Log-rank Outcomes n (%) / (100 pt-yr) n (%) / (100 pt-yr) HR (95% CI) P-value N=2507 N=2515 Primary efficacy (composite) 626 (25.0) 13.44 658 (26.2) 14.27 0.94 (0.84, 1.05) 0.27 All-cause mortality 546 (21.8) 11.41 556 (22.1) 11.63 0.98 (0.87, 1.10)

• MI

98 ( 3.9) 2.08 118 ( 4.7) 2.52 0.83 (0.63, 1.08)

• Stroke

51 ( 2.0) 1.08 76 ( 3.0) 1.62 0.66 (0.47, 0.95)

• GTED = Global Treatment End Date; MI = myocardial infarction; HR = hazard ratio; CI = confidence interval

Note: HR (95% CI): Hazard ratios (95% confidence interval) are from a Cox proportional hazards model stratified by region with treatment assignment as the only effect.

Principal Safety Outcome (On-Treatment, Safety Analysis Set)

Rivaroxaban Placebo Rivaroxaban vs. Placebo P value

N=2499 N=2509 Principal safety (composite) 18 ( 0.7) 0.44 23 ( 0.9) 0.55 0.80 ( 0.43, 1.49) 0.484 Fatal bleeding 9 ( 0.4) 0.22 9 ( 0.4) 0.22 1.03 ( 0.41, 2.59) 0.951 Bleeding in critical space with potential for permanent disability 13 ( 0.5) 0.32 20 ( 0.8) 0.48 0.67 ( 0.33, 1.34) 0.253 ISTH major bleeding 82 ( 3.3) 2.04 50 ( 2.0) 1.21 1.68 ( 1.18, 2.39) 0.003 ISTH: HGB decreases ≥ 2g/dL 55 ( 2.2) 1.37 30 ( 1.2) 0.73 1.87 ( 1.20, 2.91) 0.005 ISTH: transfusions ≥ 2 Units 31 ( 1.2) 0.77 18 ( 0.7) 0.43 1.74 ( 0.98, 3.12) 0.058 ISTH: critical bleeding sites 25 ( 1.0) 0.62 23 ( 0.9) 0.56 1.12 ( 0.63, 1.97) 0.699 ISTH: fatal outcome 3 ( 0.1) 0.07 7 ( 0.3) 0.17 0.45 ( 0.12, 1.72) 0.228 Bleeding requiring hospitalization 61 ( 2.4) 1.52 48 ( 1.9) 1.16 1.30 ( 0.89, 1.90) 0.170

Conclusion

In patients with recent worsening of chronic HF and reduced ejection fraction who also have underlying CAD and are not in atrial fibrillation, low-dose rivaroxaban, when added to guideline-based therapy, does not improve the composite of all-cause mortality, myocardial infarction, or stroke, nor does it favorably influence heart failure rehospitalization

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Comments

1. Heart failure readmission was the single most frequent event in the trial 2. It is likely that heart failure, rather than deaths mediated by atherothrombotic events, contributed to a substantial proportion of all deaths. 3. Thrombin-mediated events are not the major driver of heart failure-related events in patients with recent heart failure hospitalization. 4. Whether a higher dose of rivaroxaban could have led to a more favorable

• utcome remains unknown.

5. In patients with chronic heart failure with reduced ejection fraction remain at high long-term risk for death and cardiovascular events despite treatments targeted at a variety of mechanistic pathways. Thus, there is an important unmet need to find novel approaches to reduce the morbidity and mortality in this population.