The Role of Combination Antiplatelet and Anticoagulation ...Circulation. 2015. Adjusted Cumulative Incidence of Cardiovascular Death, MI or Stroke (%) Diabetes (Known Atherothrombosis,

The Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes and

Cardiovascular Disease: COMPASS DiabetesDeepak L. Bhatt MD, MPH, John W. Eikelboom MBBS, Stuart J. Connolly MD,

Ph. Gabriel Steg MD, Sonia S. Anand MD, Subodh Verma MD, PhD, Kelley R. H. Branch MD, Jeffrey Probstfield MD, Jackie Bosch PhD,

Olga Shestakovska MSc, Michael Szarek, Ph.D., Aldo Pietro Maggioni MD, Petr Widimský MD, Alvaro Avezum MD, Rafael Diaz MD, Basil S. Lewis MD,

Scott D. Berkowitz MD, Keith A. A. Fox MBChB, Lars Ryden MD, Salim Yusuf DPhil, for the COMPASS Steering Committee and Investigators

DisclosuresDr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), 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 (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda.

This presentation may discuss off label and investigational uses of drugs.

COMPASS was funded by Bayer.

Impact of Prior Ischemic Events or Stable Atherosclerosis on CV Events at 4 Years

*All event rates adjusted for age and sex.Bhatt DL, Eagle KA, Ohman EM, et al., and Steg PG. JAMA 2010; 304:1350-1357.

CV

deat

h, M

I, or

str

oke

at 4

yea

rs (%

)*

18.3

12.2

9.1

0

5

10

15

20

25

30

Prior ischemic event Stable atherosclerotic disease Risk factor only

All

Risk factor only

Impact of Polyvascular Disease on CV Events at 4 years


CV

deat

h, M

I, or

str

oke

at 4

yea

rs (%

)*

18.3

12.2

9.1

25.0

17.715.7

11.5

0

5

10

15

20

25

30


All+ Polyvascular disease- Polyvascular disease

Risk factor only

Impact of Diabetes on CV Events at 4 years


CV

deat

h, M

I, or

str

oke

at 4

yea

rs (%

)*

18.3

12.2

9.1

25.0

17.715.7

11.5

22.5

15.5

9.9

15.9

10.2

7.1

0

5

10

15

20

25

30


All+ Polyvascular disease- Polyvascular disease

+ Diabetes- Diabetes

Risk factor only

0

5

10

15

20

25

0 10 20 30 40 50

Y-ValuesREACH - Diabetes

Cavender MA, Steg PG, Smith SC, et al, Bhatt DL. Circulation 2015.

Adj

uste

d C

umul

ativ

e In

cide

nce

of

Car

diov

ascu

lar D

eath

, MI o

r Str

oke

(%) Diabetes (Known Atherothrombosis,

Prior Ischemic Event)

Diabetes (Known Atherothrombosis)

Diabetes (Overall)Diabetes (Known Atherothrombosis, No Prior Ischemic Event)No Diabetes (Overall)

Diabetes(Risk Factors Only)

Months

Bhatt DL. Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.212. 2018. Nature Reviews | Cardiology

Dual Pathway Inhibition:Antiplatelet plus Anticoagulant

www.phri.ca

Stable CAD or PAD27,395 participants randomized

*excluding patients enrolled 4-14 days post CABGBosch JJ, et al. Can J Cardiol 2017; 33:1027-1035.

Rivaroxaban 2.5 mg bid + Aspirin 100 mg od

Aspirin 100 mg od

Rivaroxaban 5 mg bid

Expected mean follow up: 3-4 years

Run-in* (aspirin plus rivaroxaban) placebo)

R

COMPASS Design

www.phri.ca

0.00

0.02

0.04

0.06

0.08

0.10

0 1 2 3

Eikelboom JW, et al. N Engl J Med 2017; 377:1319-30.

COMPASS Trial Primary outcomeC

umul

ativ

e R

isk

of C

ardi

ovas

cula

r Dea

th,

Myo

card

ial I

nfar

ctio

n, o

r Str

oke

Year

Hazard ratio, 0.90 (95% CI, 0.79-1.03)P=0.12

Rivaroxaban alone vs. placebo plus aspirin

Hazard ratio, 0.76 (95% CI, 0.66-0.86)P<0.001

Rivaroxaban + aspirin vs. placebo plus aspirin

Aspirin alone

Rivaroxaban aloneRivaroxaban + aspirin

Effects in patients with diabetes at baseline (N=6,922) versus without diabetes (N=11,356)

COMPASS Diabetes Analysis

Bhatt DL, Eikelboom JW, Connolly SJ, et al, Yusuf S. Circulation. 2020.

Effects in patients with diabetes at baseline (N=6,922) versus without diabetes (N=11,356)Patients randomized to rivaroxaban plus aspirin (N=9,126) versus placebo plus aspirin (N=9,126)

• 1° efficacy: CV death, MI, stroke• 2° efficacy:

- All-cause mortality- CV death, MI, stroke, MALE, including amputation

• 1° safety: modified ISTH criteria - major bleeding • Prespecified net clinical benefit: CV death, MI, stroke,

fatal bleeding, symptomatic bleeding into a critical organ

COMPASS Diabetes Analysis


0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 6 12 18 24 30 36

10.7%

7.2%

8.4%

5.8%

No DiabetesHR 0.77, 95% CI: 0.64-0.93, p=0.005

ARR 1.4%

DiabetesHR 0.74, 95% CI: 0.61-0.90, p=0.002

ARR 2.3%Aspirin AloneRivaroxaban plus Aspirin

No Diabetes (N=11,356)

Aspirin AloneRivaroxaban plus Aspirin

Diabetes (N=6,922)

CV Death, Myocardial Infarction, or StrokeC

umul

ativ

e H

azar

d

Months

P value for interaction=0.77


0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 6 12 18 24 30 36

All-Cause Death

8.6%

5.7%

6.8%

5.1%

Cum

ulat

ive

Haz

ard

Months


ARR 0.6%

DiabetesHR 0.81, 95% CI: 0.65-1.00, p=0.05

ARR 1.9%





Diabetes (N=6,922)


0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 6 12 18 24 30 36

12.1%

7.8%

9.4%

6.1%

CV Death, Myocardial Infarction, Stroke, MALE, or Major Vascular Amputation

Cum

ulat

ive

Haz

ard

Months


ARR 1.7%

DiabetesHR 0.73, 95% CI: 0.61-0.88, p=0.0007

ARR 2.7%





Diabetes (N=6,922)


Rivaroxaban plus Aspirin Aspirin AloneNo. of

first events/ patients

(%)

Kaplan-Meier risk

at 36 months

No. of first events/

patients (%)

Kaplan-Meier risk

at 36 months

Hazard Ratio (95% CI)

P value

P value for

interaction

Major bleeding 0.97

No diabetes at baseline 178/5704 (3.1) 4.4 105/5652 (1.9) 3.2 1.69 (1.33-2.15) <0.0001

Diabetes at baseline 110/3448 (3.2) 4.5 65/3474 (1.9) 3.4 1.70 (1.25-2.31) 0.0006

Intracranial bleeding 0.44

No diabetes at baseline 17/5704 (0.3) 0.4 17/5652 (0.3) 0.7 0.99 (0.51-1.95) 0.98

Diabetes at baseline 11/3448 (0.3) 0.4 7/3474 (0.2) 0.4 1.57 (0.61-4.05) 0.35

Fatal bleeding 0.87

No diabetes at baseline 10/5704 (0.2) 0.4 7/5652 (0.1) 0.2 1.43 (0.55-3.77) 0.46

Diabetes at baseline 5/3448 (0.1) 0.2 3/3474 (<0.1) 0.2 1.66 (0.40-6.93) 0.48

Safety Outcomes


0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 6 12 18 24 30 36

CV Death, MI, Stroke, Fatal Bleeding, or Symptomatic Bleeding into Critical Organ

7.6%

9.1%

6.6%

Cum

ulat

ive

Haz

ard

Months


ARR 1.0%

DiabetesHR 0.78, 95% CI: 0.65-0.94, p=0.02

ARR 2.7%





Diabetes (N=6,922)

11.8%


Rivaroxaban plus Aspirin Aspirin AloneNo. of

first events/ patients

(%)

Kaplan-Meier risk

at 36 months

No. of first events/

patients (%)

Kaplan-Meier risk

at 36 months

Hazard Ratio (95% CI)

P value

P value for

interaction

Prior ischemic events 0.85

No 42/937 (4.5) 8.8 57/981 (5.8) 10.1 0.76 (0.51-1.14) 0.18

Yes 137/2511 (5.5) 8.3 182/2493 (7.3) 11.0 0.73 (0.59-0.91) 0.006

Prior revasc 0.87

No 58/978 (5.9) 10.0 85/1068 (8.0) 12.8 0.73 (0.52-1.02) 0.06

Yes 121 / 2470 (4.9) 7.9 154/2406 (6.4) 9.9 0.75 (0.59-0.95) 0.02

Prior ischemic events, revasc 0.88

No 18/416 (4.3) 11.0 26/435 (6.0) 12.3 0.71 (0.39-1.30) 0.27

Yes 161/3032 (5.3) 8.3 213/3039 (7.0) 10.6 0.74 (0.61-0.91) 0.004

Benefits in Diabetes +/- Prior Ischemic Events or Revascularization: CV Death/MI/Stroke


LimitationsDiabetes subgroup not specifically powered for efficacy or safety


Diabetes subgroup not specifically powered for efficacy or safety

• Though the analysis was prespecified, with sufficient power to show a significant reduction in the primary endpoint in the overall trial, and with or without diabetes

Limitations




Early stopping of the trial further limits the power of subgroup analysis

Limitations




Early stopping of the trial further limits the power of subgroup analysis

• Though the independent DSMB felt the trial needed to be stopped due to overwhelming efficacy, including a reduction in all-cause mortality

Limitations


Low-dose rivaroxaban + aspirin reduced major CV events in stable atherosclerosis, irrespective of the presence or absence of diabetes, though absolute risk reductions were numerically larger with diabetes, including for all-cause mortality.

Conclusions


Low-dose rivaroxaban + aspirin reduced major CV events in stable atherosclerosis, irrespective of the presence or absence of diabetes, though absolute risk reductions were numerically larger with diabetes, including for all-cause mortality.As in the overall trial, there was a significant increase in major bleeding, but not in fatal or intracranial bleeding.

Conclusions


Low-dose rivaroxaban + aspirin reduced major CV events in stable atherosclerosis, irrespective of the presence or absence of diabetes, though absolute risk reductions were numerically larger with diabetes, including for all-cause mortality.As in the overall trial, there was a significant increase in major bleeding, but not in fatal or intracranial bleeding.The net clinical benefit when examining irreversible outcomes appeared numerically greater in those with diabetes.

Conclusions


Low-dose rivaroxaban + aspirin reduced major CV events in stable atherosclerosis, irrespective of the presence or absence of diabetes, though absolute risk reductions were numerically larger with diabetes, including for all-cause mortality.As in the overall trial, there was a significant increase in major bleeding, but not in fatal or intracranial bleeding.The net clinical benefit when examining irreversible outcomes appeared numerically greater in those with diabetes. Use of dual pathway inhibition with low-dose rivaroxaban + aspirin is particularly attractive in high-risk patients, such as those with diabetes.

Conclusions


Circulation

The Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes and

Cardiovascular Disease: COMPASS DiabetesDeepak L. Bhatt MD, MPH, John W. Eikelboom MBBS, Stuart J. Connolly MD,

Ph. Gabriel Steg MD, Sonia S. Anand MD, Subodh Verma MD, PhD, Kelley R. H. Branch MD, Jeffrey Probstfield MD, Jackie Bosch PhD,

Olga Shestakovska MSc, Michael Szarek, Ph.D., Aldo Pietro Maggioni MD, Petr Widimský MD, Alvaro Avezum MD, Rafael Diaz MD, Basil S. Lewis MD,

Scott D. Berkowitz MD, Keith A. A. Fox MBChB, Lars Ryden MD, Salim Yusuf DPhil, for the COMPASS Steering Committee and Investigators

Circulation. 2020; [published online ahead of print]. DOI: 10.1161/CIRCULATIONAHA.119.044586

Circulationhttps://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.046448


Deepak L. Bhatt, MD, MPHExecutive Director,Interventional Cardiovascular Programs, BWH Heart & Vascular Center;Professor of Medicine, Harvard Medical SchoolEmail: [email protected] Twitter: @DLBhattMD

www.brighamandwomens.org/heart

Thank You!

Documents

The Role of Combination Antiplatelet and Anticoagulation ...Circulation. 2015. Adjusted Cumulative Incidence of Cardiovascular Death, MI or Stroke (%) Diabetes (Known Atherothrombosis,