Managing Patients Who Cannot Take Anticoagulants

Kenneth W. Mahaffey, MD, FACCProfessor of Medicine, Cardiology

Faculty Associate Director, DCRIDirector, DCRI MegaTrials & CECDuke Clinical Research InstituteDurham, NC

DisclosuresConsultant Fees/HonorariaAdolor; Amgen; AstraZeneca; Bayer HealthCare; Biotronik, Inc.; Boehringer Ingelheim; Bristol-Myers Squibb; Daiichi Sankyo, Inc.; Eli Lilly; Elsevier; Exeter Group; Forest; Genentech; Gilead; GlaxoSmithKline; Haemonetics; Johnson and Johnson; Medtronic; Merck and Co., Inc.; Novartis; Orexigen Therapeutics; Ortho-McNeil; Pfizer Inc; sanofi-aventis U.S. Inc.; Sun Pharma; Springer Publishing; WebMD Research/Research GrantsAbbott Vascular; Amgen; Amylin; AstraZeneca; Baxter; Bayer HealthCare; Boehringer Ingelheim; Bristol-Myers Squibb; Cordis; Daiichi Sankyo, Inc.; Edwards Lifesciences; Eli Lilly; GlaxoSmithKline; Guidant; Ikaria; INC Research; Johnson and Johnson; Kai Pharmaceuticals; Luitpold; Merck and Co., Inc.; Portola Pharmaceuticals; Pozen; Regado Biosciences; Roche; sanofi-aventis U.S. Inc.; Schering Plough; The Medicines Company

Fibrin

Platelet aggregate

Hemostasis and Thrombosis

Atherosclerotic Plaque

Red Blood Cells

• Pathobiology is complex

• Understanding relationships is important

• Antiplatelet therapy

• Anticoagulant therapy

Antithrombotic Therapy for AF Overview:Antiplatelet Agents Compared with Placebo or Control

Hart RG, et al. Ann Intern Med. 2007;146:857-867.

Study, Year

Favors Antiplatelet Favors Placebo or Control

RRR (95% CI)

AFASAK I, 1989; 1990SPAF I, 1991 EAFT, 1993 ESPS II, 1997 LASAF, 1997 Daily Alternate dayUK-TIA, 1999 300 mg daily 1,200 mg dailyJAST, 2006

Aspirin trials (n = 7)

SAFT, 2003 ESPS II, 1997 Dipyridamole Combination

All antiplatelet trials (n = 10) 100% 50% 0% -50% -

100%

Contraindications to Oral Anticoagulation

1,409 / 10,124 (14%) with a contraindication

ACTIVE A: Primary Outcome (Stroke, MI, Non-CNS Systemic Embolism, Vascular Death)

Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151.

0

HR = 0.89 (0.81-0.98) p = 0.014

Placebo + Aspirin

Clopidogrel + Aspirin

Years

Cum

ula

tive H

aza

rd R

ate

s

1 2 3 4

0.0

0.1

0.2

0.3

0.4

No. at RiskC + A 3772 3456 3180

2522 1179ASA 3782 3426 3103

2460 1156

Apixaban 5 mg twice daily

ASA (81-324 mg/d)

AF and ≥ 1 risk factor and

demonstrated or expected

unsuitable for VKA

Primary Outcome: Stroke or Systemic Embolic Event

5,599 patients

2.5 mg twice daily in select patients

R

36 countries, 522 centres

Double-Blind

AVERROES Trial Design

Connolly SJ, et al. N Engl J Med. 2011;364:806-817.

AVERROES: Primary EndpointStroke or Systemic Embolic Event

Cu

mu

lati

ve

Ris

k0

.00

.01

0.0

30

.05

0 3 6 9 12 18 21

ASA

Apixaban

Months

HR = 0.4595% CI = 0.32-0.62P < 0.001

Connolly SJ, et al. N Engl J Med. 2011;364:806-817.

ESC Guidelines AF, EHJ 2012

Recommendations Classa Levelb Refc

Recommendations for prevention of thromboembolism in non-valvular AF─general

Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except in those patients (both male and female) who are at low risk (aged < 65 years and lone AF), or with contraindications.

I A21, 63,

104, 105, 106

The choice of antithrombotic therapy should be based upon the absolute risks of stroke/thromboembolism and bleeding and the net clinical benefit for a given patient.

I A 21, 63, 105

The CHA2DS2-VASc score is recommended as a means of assessing stroke risk in non-valvular AF. I A 25, 36, 39

In patients with a CHA2DS2-VASc score of 0 (i.e., aged < 65 years with lone AF) who are at low risk, with none of the risk factors, no antithrombotic therapy is recommended.

I B 21, 36, 82

In patients with a CHA2DS2-VASc score of ≥ 2, OAC therapy with:•Adjusted-dose VKA (INR 2-3); or•A direct thrombin inhibitor (dabigatran); or•An oral factor Xa inhibitor (e.g., rivaroxaban, apixaban)d

…is recommended, unless contraindicated.

I A 3, 4, 70, 82

In patients with a CHA2DS2-VASc score of I, OAC therapy with:•Adjusted-dose VKA (INR 2-3); or•A direct thrombin inhibitor (dabigatran); or•An oral factor Xa inhibitor (e.g., rivaroxaban, apixaban)d

…should be considered, based upon an assessment of the risk of bleeding complications and patient preferences.

IIa A 33, 44

Female patients who are aged < 65 and have lone AF (but still have a CHA2DS2-VASc score of I by virtue of their gender), are low risk and no antithrombotic therapy should be considered.

IIa B 33, 44

When patients refuse the use of any OAC (whether VKAs or NOACs), antiplatelet therapy should be considered, using combination therapy with aspirin 75-100 mg plus clopidogrel 75 mg daily (where there is a low risk of bleeding or─less effectively─aspirin 75-325 mg daily.

IIa B21, 26, 51,

109

Recommendations for prevention of thromboembolism in non-valvular AF

Summary

• Few patients have true contraindications to anticoagulant therapy

• ASA vs. placebo─ Modest reduction in thromboembolic events─ Modest increase in bleeding

• ASA + clopidogrel vs. ASA─ Reduces thromboembolic events─ Increases bleeding

• Apixaban is a potentially attractive alternative in patients with VKA contraindications