Using DOACs in CAD Patients in Sinus Ryhthm Results of the ATLAS ACS 2, COMPASS and COMMANDER-HF Trials

Using DOACs in CAD Patients in Sinus Ryhthm Results of the ATLAS ACS 2, COMPASS and COMMANDER-HF Trials 19 th Annual San Diego Heart Failure Symposium for Primary Care Physicians January 11-12, 2019 La Jolla, CA Barry Greenberg M.D. Distinguished Professor of Medicine Director, Advanced Heart Failure Treatement Program University of California, San Diego La Jolla, CA

Vascular Protection Using Direct Thrombin Inhibitors Patients with atherosclerotic CV disease remain at increased risk for thrombotic events and death despite current treatment strategies including use of anti-platelet agents. Use of anti-coagulant agents has been limited by bleeding complications. Compared with warfarin, direct oral anticoagulants (DOACs) have a lower bleeding risk. Can DOACs improve outcomes in patients with atherosclerotic disease with acceptable risk of bleeding?

Trials in Atherosclerotic CV Disease with Low Dose Rivaroxaban Enrolled patients with atherosclerotic CV disease who were in normal sinus rhythm. Each study included a group that was randomized to low dose rivaroxaban (2.5 mg twice daily). Assessed safety and efficacy of this regimen in: - ATLAS ACS 2 TIMI 51 - patients with ACS (unstable angina and MI) - COMPASS - patients with stable atherosclerotic disease (CAD and/or PVD) - COMMANDER patients with chronic HFrEF and CAD following HF hospitalization

ATLAS ACS 2 TIMI 51

ATLAS ACS 2 TIMI 51 Assigned 15,526 patients with a recent ACS to either twice daily 2.5 mg or 5 mg of rivaroxaban or placebo on top of anti-platelet therapy. The primary efficacy MACE end point of CV death, MI and stroke was significantly reduced risk with both doses of rivaroxaban.

ATLAS ACS2 TIMI 51 Primary Efficacy Outcome Mega JL, N Engl J Med. 2012;366:9-19

Cumulative Incidence of Efficacy End Points, According to Rivaroxaban Dose Mega JL, N Engl J Med. 2012;366:9-19

Non-CABG TIMI Major Bleeding In ATLAS ACS 2 TIMI 51 Study N Engl J Med. 2012;366:9-19

Stent Thrombosis in ATLAS ACS 2 TIMI 51 J Am Coll Cardiol. 2013;62:286-90

Effects of Rivaroxaban in HF Patients Included in ATLAS ACS 2 TIMI 51

ATLAS ACS 2 TIMI 51 The study met its primary endpoint, demonstrating a 15% RRR in CVD/MI/Stroke for the 2.5mg BID rivaroxaban dose, driven by a 35% RRR in CVD and all cause mortality. Compared with anti-platelet therapy alone, 2.5 mg rivaroxaban bid increased rates of major bleeding not related to CABG (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other AEs. Enhanced efficacy in HF patients? ATLAS served as the basis for approval of 2.5mg BID in Europe.

COMPASS

COMPASS Study Design Cardiovascular Outcomes for People Using Anticoagulation Strategies Randomized, placebo controlled, double blinded trial 27,325 patients with stable CAD or PAD 1,323 with a primary outcome event Rivaroxaban 2.5 mg bid + aspirin 100 mg daily Run-in (aspirin) R Rivaroxaban 5 mg bid Aspirin 100 mg daily Median Follow Up: 23 months Ongoing arm testing proton pump inhibitor pantoprazole versus placebo (PPI arm) Eikelboom JW, et al. NEJM 2017; 377:1319-1330.

COMPASS Main Trial Outcomes Primary Outcome: CV death, stroke or MI Median 23 month follow up Riva 2.5 BID + ASA vs ASA MACE 24% Mortality 18% Net benefit 20% No benefit for Riva alone Time (years) Eikelboom JW, et al. NEJM 2017; 377:1319-1330.

COMPASS The primary efficacy outcome was a composite of CV death, stroke, or MI. COMPASS was stopped for superiority of rivaroxaban 2.5 mg BID + ASA vs ASA alone after a mean follow-up of 23 months. The primary outcome occurred in fewer patients in the rivaroxaban 2.5 mg BID + ASA vs ASA group (379 patients [4.1%] vs. 496 patients [5.4%]; HR, 0.76; 95% CI, 0.66 to 0.86; P<0.001), but major bleeding events occurred in more patients in the rivaroxaban-plus-asa group (288 patients [3.1%] vs. 170 patients [1.9%]; HR, 1.70; 95% CI, 1.40 to 2.05; P<0.001). No significant difference in intracranial or fatal bleeding between groups. Rivaroxaban alone did not reduce the primary outcome compared to the ASA-alone group, but had more major bleeding events than the ASA alone group. Eikelboom JW, et al. NEJM 2017; 377:1319-1330.

COMPASS No significant difference in intracranial or fatal bleeding between groups. Rivaroxaban alone did not reduce the primary outcome compared to the ASA-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. Eikelboom JW, et al. NEJM 2017; 377:1319-1330.

Primary MACE Outcome by HF Status Cumulative Hazard 0.16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0.00 No heart failure at baseline Rivaroxaban plus aspirin Aspirin alone Heart failure at baseline Rivaroxaban plus aspirin Aspirin alone HF, ASA No HF, ASA HF, R+A No HF, R+A HR 0.68 (95% CI 0.53-0.86) ARR 2.4% NNT 42 HR 0.79 (95% CI 0.68-0.93) ARR 0.9% NNT 111 0 6 12 18 24 30 36 Time (months) No. at Risk Kelly Branch et al. Presented at the ESC HFA Mtg No heart failure In Vienna, May 2018 Rivaroxaban p

COMMANDER HF

COMMANDER-HF: Rationale for Use in HFrEF About half of the patients hospitalized with decompensated heart failure (HF) have reduced EF and of these 50-70% have coronary artery disease. Activation of thrombin-related pathways may contribute to HF disease progression by influencing inflammation, endothelial dysfunction and thrombosis. Post-hoc analysis of the SOLVD studies suggest that anticoagulation improves outcomes in HF patients with reduced EF. However, clinical trials (e.g. WATCH, WARCEF) failed to demonstrate efficacy of warfarin in this population.

Background for COMMANDER HF (cont.) Unlike warfarin, rivaroxaban directly targets thrombin generation. Rivaroxaban (2.5 mg twice daily), in addition to antiplatelet agents reduced CV death, MI, and stroke in two trials: - ATLAS ACS 2 TIMI 51 (post-mi and unstable angina) 1 - COMPASS (stable CAD or PVD) 2 Both of these trials included patients with HF 3,4. 1. Mega JL, et al. N Engl J Med. 2012 2. Eikelboom JW, et al. N Engl J Med. 2017 3. Korjian et al Am J Cardiol. 2018 Sep 7. Published online ahead of print 4. Branch K et al. ESC HFA, Vienna

COMMANDER HF COMMANDER HF tested the hypothesis that, compared with placebo, rivaroxaban 2.5 mg twice daily added to background anti-platelet therapy, would reduce rates of death and CV events in patients with recent worsening of chronic HF, reduced EF, CAD, and sinus rhythm. The primary efficacy outcome was a composite of allcause mortality, MI, or stroke. The main secondary outcome was a composite of CV death and HF hospitalization.

Study Design Screening Period Double Blind Treatment Phase Follow-Up After GTED Rivaroxaban 2.5 mg bid + standard of care therapy 21 days of Index Event Patients with HFrEF and CAD are appropriate regardless of whether they are managed via the traditional inpatient hospital pathway or via the outpatient HF clinic pathway R N=5000 At Hospital Discharge & up to 30 Days Post Discharge Placebo bid + standard of care therapy Visits: Day 1 = R Week 4 Week 12 q 3 months Early Permanent Study Drug Discontinuation Continue Follow-Up q 12 weeks 30±15 days Global Treatment End Date (GTED) End of Study Visit Zannad F, et al. Eur J Heart Fail. 2015:17(7):735-742.

Rivaroxaban Failed to Improve Outcomes in COMMANDER HF Primary Efficacy Outcome Secondary Efficacy Outcome HR (95% CI) 0.94 (0.84, 1.05) HR (95% CI) 1.01 (0.92, 1.10) All cause mortality, MI and stroke CV mortality and HF hospitalization Zannad F et al. NEJM, 2018

Primary Efficacy Outcome & Components COMMANDER HF (ITT*) 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 626 (25.0) 13.44 658 (26.2) 14.27 0.94 (0.84, 1.05) 0.27 (composite) 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) - Primary outcome composite driven by mortality, a large proportion of whichwas due to worsening HF * ITT, Intent to Treat

Rationale for Analysis of Thromboembolic Events These findings suggest that in the high risk HF population enrolled in COMMANDER HF: -the primary composite was driven by events that were not influenced by rivaroxaban 2.5 mg twice daily. -an effect of rivaroxaban on thromboembolic events might have been masked by the preponderance of events related to worsening heart failure. Is low dose rivaroxaban superior to placebo in reducing the risk of thromboembolic events in patients enrolled in COMMANDER HF?

KM Estimates for the Post Hoc Thromboembolic Event Composite HR (95% CI) 0.83 (0.72, 0.96) p=0.013 Composite included: Myocardial Infarction Non-hemmorhagic stroke Sudden/Unwitnessed death Symptomatic DVT Pulmonary embolus Overall, 14.3% of patients experienced a thromboembolic event over a median follow-up of 19.6 months with the event rate of 7.0 and 8.5 per 100 patient years in the rivaroxaban and placebo groups, respectively.

Comparing HF Patient Outcomes COMMANDER HF 1 Post HF hospitalization Between Rivaroxaban Trials ATLAS (HF Subgroup) 2 History of CHF at Randomization Incidence rate COMPASS 3 Chronic Stable HF subgroup Stroke MI 3.0 2.0 4.7 3.9 Placebo Rivaroxaban 2.5 mg BID Stroke MI 1.8 1.7 9.0 6.4 Placebo Rivaroxaban 2.5 mg BID Stroke MI 2.0 1.0 2.7 2.1 ASA 100 mg Rivaroxaban 2.5 mg BID + ASA 100 mg CV death 18.9 18.1 CV death 9.0 4.1 CV death 4.5 3.0 Composite of CV Death, MI or Stroke 23.2 21.4 Composite of CV Death, MI or Stroke 17.2 10.5 Composite of CV Death, MI or Stroke 7.9 5.5 ITT up to GTED * 34.8% of patients received DAPT at baseline, while 93.1% received ASA alone at baseline mitt * 86.7% of patients received DAPT at baseline, while 13.3% received ASA alone at baseline ITT COMMANDER HF enrolled high risk HF patients after recent worsening and HF deaths, rather than deaths mediated by atherothrombotic events, likely contributed to a substantial proportion of all deaths. 1 Zannad F et al., N Engl J Med 2018; 2 Korjian S et al Am J Cardiol. 2018 Sep 7. Published online ahead of print; 3 Branch KR. COMPASS: low-dose rivaroxaban plus aspirin may benefit patients with chronic CAD, PAD, HF. Presented at Late-breaking Trial IV: Registries, Heart Failure 2018 and World Congress on Acute Heart Failure, Vienna, May 26-29, 2018

Summary Low dose rivaroxaban reduces MACE in patients with ACS and stable atherosclerotic CV disease (CAD and PVD) including patients with HF. The failure of rivaroxaban to improve outcomes in COMMANDER indicates that thrombin mediated events are not the main drivers of morbidity and mortality following a HF hospitalization. Results of ATLAS ACS 2 TIMI 51, COMPASS and COMMANDER demonstrate the on-going risk of MI and stroke in HF patients with CAD and post-hoc analyses support the possibility that low-dose rivaroxaban reduces thromboembolic risk in HF patients. However, confirmation of these results by a prospective trial is required in order to establish a role for low dose rivaroxaban in HF patients.