managing patients who cannot take anticoagulants kenneth w. mahaffey, md, facc professor of...

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