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Evolving Role of Antithrombotic Therapy in CAD and PAD:

The COMPASS Trial

DEEPAK L. BHATT, MD, MPH

Executive Director of Interventional Cardiovascular

Programs, BWH Heart and Vascular Center

Professor of Medicine, Harvard Medical School

Disclosures for Dr. Bhatt

Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado

Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care;

Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees:

Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic,

Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate

Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter),

Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute

(clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology),

Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health

Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology

Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME

steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering

Committee, VA CART Research and Publications Committee (Chair); Research Funding: Amarin,

Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood,

Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier

(Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator:

Biotronik, Boston Scientific, St. Jude Medical; Trustee: American College of Cardiology; Unfunded

Research: FlowCo, Merck, PLx Pharma, Takeda.

This presentation discusses off-label and/or investigational uses of various drugs and devices.

Bhatt DL, Hulot J-S, Moliterno, DJ, Harrington RA. Circ Res 2014; 114:1929-1943. In Fuster V, Kovacic J. Compendium on ACS.

Recent ACS: STEMI, NSTEMI, UAStabilized 1-7 Days Post-Index Event

Exclusions: increased bleeding risk, warfarin use, ICH, prior

stroke or TIA if on ASA + thienopyridine

PRIMARY ENDPOINTS:

EFFICACY: CV Death, MI, Stroke (Ischemic, Hemorrhagic, or Uncertain Origin)

SAFETY: TIMI major bleeding not associated with CABG

Rivaroxaban

5.0 mg BID

Stratified by Thienopyridine Use at MD Discretion

ASA 75 to 100 mg/day

Placebo Rivaroxaban

2.5 mg BID

N=15,526

ATLAS ACS 2 TIMI 51 Trial

Months After Randomization

Primary Efficacy Endpoint:

CV Death / MI / Stroke

Rivaroxaban(both doses)

HR 0.84

(0.74-0.96)

ARR 1.8%

NNT = 56

tive I

Placebo

5113 4307 3470 2664 1831 1079 421

10229 8502 6753 5137 3554 2084 831

Placebo

Rivaroxaban

2 Yr KM Estimate

No. at Risk

Mega et al and Gibson CM. NEJM 2011.

Placebo

Rivaroxaban

2.5 mg BID

All Cause Death

Cardiovascular Death

Months

CV Death / MI / StrokeE

0 24Months Months

HR 0.85

p=0.04

p=0.01

HR 0.62

p<0.001

Rivaroxaban

2.5 mg BID

Rivaroxaban

2.5 mg BID

PlaceboPlacebo HR 0.64

p<0.001

NNT = 56NNT = 71 NNT = 5912 12 12

Efficacy Endpoints:Very Low Dose 2.5 mg BID

Patients Treated with ASA + Thienopyridine

Mega et al and Gibson CM. NEJM 2011.

COMPASS Design

Rivaroxaban 2.5 mg bid

+ aspirin 100 mg od

Aspirin 100 mg od

Rivaroxaban 5 mg bid Expected follow up

3-4 years

Run-in

(aspirin)

Stable CAD or PAD

2,200 with a primary outcome event

Outcomes

Primary

• CV death, stroke or myocardial infarction

Secondary

• CHD death, ischemic stroke, myocardial infarction, or acute limb ischemia

• CV death, ischemic stroke, myocardial infarction, or acute limb ischemia

• Mortality

Safety and net benefit

• ISTH major bleeding (modified)

• Primary plus fatal or critical organ bleeding

33 Countries, 602 Sites, 27,395 Participants

Canada

N=2443

United States

N=1475

Brazil

N=1515

Argentina N=2789

Netherlands

N=2522

N=1086 Japan N=1556

Czech RepublicN=1553

ItalyN=1018

Follow-up, Adherence

• On February 6, 2017 the Data and Safety Monitoring Board recommended discontinuation of rivaroxaban/aspirin arms for clear evidence of efficacy (combination: Z= -4.59, P<0.00001; rivaroxaban: Z= -2.44, P=0.01)

• Close-out between March and June 2017

• Mean follow up 23 months

• Follow-up 99.8% complete

Baseline Characteristics

CharacteristicRivaroxaban +

aspirin N=9,152

RivaroxabanN=9,117

AspirinN=9,126

Age, yr 68 68 68

Blood pressure, mmHg 136/77 136/78 136/78

Total cholesterol, mmol/L

4.2 4.2 4.2

CAD 91% 90% 90%

PAD 27% 27% 27%

Diabetes 38% 38% 38%

Lipid-lowering 90% 90% 89%

ACE-I or ARB 71% 72% 71%

Primary: CV Death, Stroke, MI

Outcome

R + A R ARivaroxaban +

aspirin vs. aspirin

Rivaroxaban vs. aspirin

HR(95% CI)

(95% CI)

CV death, stroke, MI

379(4.1%)

448(4.9%)

496(5.4%)

0.76 <0.0001 0.90 0.12

Primary: CV Death, Stroke, MI

Primary Components

Outcome

R + A N=9,152

AN=9,126

Rivaroxaban + Aspirinvs. Aspirin

HR(95% CI)

CV death160

(1.7%)203

(2.2%)0.78

(0.64-0.96)0.02

Stroke83

(0.9%)142

(1.6%)0.58

(0.44-0.76)<0.0001

(1.9%)205

(2.2%)0.86

(0.70-1.05)0.14

Secondary Outcomes

Outcome

R + A N=9,152

AN=9,126

HR(95% CI)

CHD death, IS,

MI, ALI

329(3.6%)

450(4.9%)

0.72(0.63-0.83)

<0.0001

CV death, IS,

MI, ALI

389(4.3%)

516(5.7%)

0.74(0.65-0.85)

<0.0001

Mortality313

(3.4%)378

(4.1%)0.82

(0.71-0.96)0.01

* pre-specified threshold P=0.0025

CAD and PADSubgroups for Primary Outcome

Outcome

R + A N=9,152

AN=9,126

Rivaroxaban +Aspirin

vs. Aspirin

HR(95% CI)

CAD347

(4.2%)

(5.6%)

(0.65-0.86)

PAD126

(5.1%)174

(6.9%)0.72

(0.57-0.90)

Major Bleeding

OutcomeR + A R A

Rivaroxaban +Aspirin

vs. Aspirin

Rivaroxaban vs. Aspirin

HR(95% CI)

(95% CI)P

Major bleeding

288(3.1%)

255(2.8%)

170(1.9%)

1.70(1.40-2.05)

<0.00011.51

(1.25-1.84)

<0.0001

Fatal15

(0.2%)14

(0.2%)10

(0.1%)1.49

(0.67-3.33)

0.321.40

(0.62-3.15)

Non fatal ICH*

21(0.2%)

32(0.4%)

19(0.2%)

1.10(0.59-2.04)

0.771.69

(0.96-2.98)

Non-fatalother

critical organ*

42(0.5%)

45(0.5%)

29(0.3%)

1.43(0.89-2.29)

0.141.57

(0.98-2.50)

0.06* symptomatic

Net Clinical Benefit

Outcome

R + A N=9,152

AN=9,126

HR(95% CI)

Net clinical benefit (Primary + Severebleeding events)

431(4.7%)

534(5.9%)

0.80(0.70-0.91)

0.0005

Eligibility: PAD

• Peripheral artery revascularization

• Limb or foot amputation for arterial vascular disease

• Intermittent claudication plus:

Low ABI (<0.90), or

Significant peripheral artery stenosis (≥50%)

• Previous carotid revascularization, asymptomatic carotid artery stenosis ≥50%

• CAD + low ABI (<0.90)

Anand et Lancet (in press)

Key Efficacy Outcomes

•Primary Cardiovascular Outcome (MACE):

‒ CV death, Stroke, or MI

•Major Adverse Limb Events (MALE):

‒ Severe limb ischemia leading to an intervention (angioplasty, bypass surgery, amputation, thrombolysis)

‒ Major Amputation above forefoot due to vascular cause

Primary Safety Outcome

•Major Bleeding: Modified ISTH

•Net Clinical Benefit: MACE, MALE, major amputation, fatal bleeding, or symptomatic bleeding into a critical organ

PAD Patients in COMPASS

PAD Groups Number of patients

All Patients 7,470

Symptomatic PAD Limbs 4,129

Carotid Disease 1,919

CAD + Low ABI (<0.90) only 1,422

Mean Follow-up: 21 months

Primary Outcome & Components

Outcome

R + AN=2,492

R N=2,474

AN=2,504

Riva + aspirin vs. aspirin

Riva vs. aspirin

HR(95% CI)

(95% CI)P

MACE126(5.1)

149(6.0)

174(6.9)

0.72 0.005 0.86 0.19

(2.0)56

(2.3)67

(2.7)0.76 - 0.84 -

Stroke25

(1.0)43

(1.7)47

(1.9)0.54 - 0.93 -

CV Death64

(2.6)66

(2.7)78

(3.1)0.82 - 0.86 -

Limb Outcomes

R + AN=2,492

R N=2,474

AN=2,504

Riva vs. aspirin

HR(95%

30(1.2)

35(1.4)

56(2.2)

0.54(0.35-0.84)

0.0050.63

(0.41-0.96)

Major amp. 5

(0.2)8

(0.3)17

0.30(0.11-0.80)

0.010.46

(0.20-1.08)

Key Composite Outcome

Outcome

R + AN=2,492

RN=2,474

AN=2,504

Riva vs. aspirin

HR(95%

MACE, MALE, or Major amputation

157 (6.3)

188(7.6)

225 (9.0)

0.69 0.0003 0.84 0.08

lative

0 1 2 3

Rivaroxaban + Aspirin

Rivaroxaban

Aspirin

2492 2069 893 124

2474 2023 864 147

2504 2034 911 113

No. at Risk

Riva + ASA

Rivaroxaban + Aspirin vs. Aspirin HR: 0.69 (0.56-0.85) P=0.0003

Rivaroxaban vs. Aspirin HR: 0.84 (0.69-1.02) P=0.08

MACE or MALE or Major Amputation

Major Bleeding

Outcome

R + AN=2,492

R N=2,474

AN=2,504

Riva + aspirin vs. aspirin Riva vs. aspirin

HR(95% CI)

(95% CI)P

Major Bleeding77

(3.1)79

(3.2)48

(1.9)1.61

(1.12-2.31)0.009

1.68(1.17-2.40)

Fatal4

(0.2)5

(0.2)3

(0.1)- - - -

Non-Fatal ICH4

(0.2)3

(0.1)8

(0.3)- - - -

Non-fatal othercritical site*

13(0.5)

18(0.7)

8(0.3)

1.55(0.64-3.74)

0.332.15

(0.94-4.96)0.06

* symptomatic

Net Clinical Benefit in PAD

Outcome

R + AN=2,492

R N=2,474

AN=2,504

Riva vs. aspirin

HR(95%

Net Clinical Benefit

169 (6.8)207 (8.4)

234 (9.3)

0.72 (0.59-0.87)

0.00080.89

(0.74-1.07)

Overall COMPASS

Overall PAD

Symptomatic PAD

PAD Lower Extremeties

Carotid Artery Disease

0 0.5 1.0 1.5

Riva 2.5 + ASA

better

ASA only

better

MACE, MALE, or Major Amputation

Prevalence of atherothrombosis at baseline

Atherothrombotic status of REACH

Registry patients at baseline:

– 18.2% RFO (n=12 389)

– 59.3% CAD (n=40 258)

– 27.8% CVD (n=18 843)

– 12.2% PAD (n=8273)

(single bed disease and overlap in patients with

polyvascular disease shown to left)

Cardiovascular risk-factor profiles

were consistent across patient types

and across all participating regions.

Bhatt DL, et al. JAMA 2006;296:180.

CAD, coronary artery disease; CVD, cerebrovascular disease;

PAD, peripheral artery disease; RFO, Risk Factors Only.

*All event rates adjusted for age and sex.

Impact of diabetes on CV events at 4 years

9.19.9

Stable atherosclerotic disease

Prior ischemic event Risk factor only

+ Polyvascular disease

- Polyvascular disease

+ Diabetes

- Diabetes

Bhatt DL, Eagle KA, Ohman EM, et al. JAMA 2010; 304:1350-1357.

Eligibility for the COMPASS Trial Among 31,873 Evaluable REACH Registry Patients

Excluded29.9%

Non-included

Eligible52.9%

60High bleeding risk

Oral anticoagulant treatment

DAPT for ACS/PCI <12 months

Ischaemic stroke <1 year

Severe renal failure

Darmon A, Bhatt DL,…Steg PG (EHJ in press)

4.2[4.0–4.3]

3.2[3.1–3.4]

1.9[1.8–2.1]

1.2[1.1–1.3]

2.9[2.6–3.2]

2.2[1.9–2.4]

1.2[1.0–1.3] 1.0

[0.9–1.2]

CV death, MI or stroke All-cause mortality CV death Non-CV death

COMPASS-eligible COMPASS participants

p<0.001

p<0.0001

p=0.711

Comparison of Main CV Event Rate per 100 Patient/Years for the COMPASS-Eligible Patients from REACH, and COMPASS

Participants from the Aspirin Treatment Arm (%)

CAD alone PAD alone CAD & PAD

Non-eligible

Eligible

n=22,969 n=8825 n=5079

Eligibility for the COMPASS Trial among REACH Participants According to the Presence of CAD, PAD, or Both

www.brighamandwomens.org/heart

Deepak L. Bhatt, MD, MPHExecutive Director of Interventional Cardiovascular Programs, BWH Heart & Vascular CenterProfessor of Medicine, Harvard Medical School1 (857) 307-1992dlbhattmd@post.harvard.edu

Thank You!

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