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