SPAF

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SPAF Investigators. "Stroke Prevention in Atrial Fibrillation Study. Final results". Circulation. 1991. 84(2):527-39.
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Clinical Question

Among patients with non-valvular atrial fibrillation, does the use of warfarin or aspirin reduce the risk of stroke compared to placebo?

Bottom Line

Among patients with non-valvular atrial fibrillation, aspirin and warfarin both reduce stroke risk. Warfarin appears to have a stronger protective effect.

Major Points

We take for granted that aspirin, warfarin, and other anticoagulants reduce the risk of stroke in patients with AF. Yet establishing these as standards of care required thoughtfully designed, large, placebo-controlled studies. In the 1980s, there was sufficient clinical equipoise to carry out such a placebo-controlled trial, which led to the SPAF group of studies.

The 1991 Stroke Prevention in Atrial Fibrillation (SPAF) study evaluated the comparative efficacy of warfarin, aspirin, and placebo for stroke prevention in patients with nonvalvular AF. 1,330 patients were stratified by eligibility for warfarin: Warfarin-eligible patients (Group 1) were randomized to warfarin (goal INR 2.0-4.5), aspirin 325 mg/day, or placebo, while warfarin-ineligible patients (Group 2) were randomized to aspirin 325 mg/day or placebo. At a mean follow-up of 1.3 years, the rate of ischemic stroke or systemic embolism was reduced in patients receiving warfarin compared with those receiving placebo (2.3% vs. 7.4% per year), yielding a relative risk reduction of 67% (NNT=20). Comparing aspirin and placebo, primary events were less frequent in the aspirin group (3.6% vs. 6.3% per year) for a 42% relative risk reduction (NNT=37). Of note, SPAF did not directly compare warfarin versus aspirin, since the efficacy of these agents was not known at the time of the study; this was later addressed in multiple subsequent studies which demonstrated the superiority of warfarin over aspirin for stroke prevention.[1] Major complications, mostly in the form of major bleeding, occurred in 1-2% per year in each group and was not significantly different among groups. CNS bleeding occurred in all arms including warfarin (n=2), aspirin (n=2), and placebo (n=2).

As a result of the SPAF and subsequent trials, therapeutic anticoagulation with warfarin (and subsequently novel oral anticoagulants) has become the standard of care for stroke prevention in eligible patients with nonvalvular AF. In patients deemed to be at prohibitive bleeding risk, full-dose aspirin is often utilized despite its lower efficacy.

Guidelines

AHA/ACC/HRS AF (April 2014, adapted)[2]

  • In patients with nonvalvular AF with prior stroke, TIA, or CHA2DS2-VASc score ≥2, recommend oral anticoagulation with:
    • Warfarin, goal INR 2-3 (class I, level A)
    • Dabigatran (class I, level B)
    • Rivaroxaban (class I, level B)
    • Apixaban (class I, level B)
  • In patients with nonvalvular AF unable to maintain INR 2-3 with warfarin, recommend dabigatran, rivaroxaban, or apixaban (class I, level C)
  • In patients with nonvalvular AF with moderate or severe CKD with CHA2DS2-VASc score ≥2, consider treatment with reduced doses of dabigatran, rivaroxaban, or apixaban, although safety has not yet been clearly delineated (class IIb, level C)
  • In patients with ESRD, dabigatran and rivaroxaban are untested and are not recommended (class III, level C)
  • In patients with a mechanical heart valve, do not use dabigatran (class III, level B)

Design

  • Multicenter, randomized, placebo-controlled trial
  • N=1,330 patients with nonvalvular AF
    • Warfarin-eligible (Group 1)
      • Warfarin (n=210)
      • Aspirin (n=206)
      • Placebo (n=211)
    • Warfarin-ineligible (Group 2)
      • Aspirin (n=346)
      • Placebo (n=357)
  • Setting: 15 US centers
  • Enrollment: 1987-1989
  • Mean follow-up: 1.3 years
  • Analysis: Intention-to-treat
  • Primary outcome: Ischemic stroke or systemic embolism

Population

Inclusion Criteria

  • Age ≥18 years
  • EKG documentation of constant or intermittent AF in the prior 12 months

Exclusion Criteria

  • Symptoms of TIA/stroke in prior 2 years
  • ECG evidence of rheumatic heart disease
  • Presence of mitral valve disease
  • Prior thromboembolism
  • HF due to severe MR or idiopathic dilated CM
  • Requirement for or contraindication to aspirin or warfarin therapy

Baseline Characteristics

  • Patients (n): 1,330
  • Male sex (%): 71%
  • Current smoker (%): 16%
  • Mean age (yr): 67
  • Mean blood pressure (systolic/diastolic): 137/80
  • Onset of AF (%)
    • < 1 yr: 28%
    • ≥ 1 yr: 68%
    • No estimate: 4%
  • Pattern of AF (%)
    • Intermittent: 34%
    • Constant: 66%
  • HTN (%): 52%
  • Cervical bruits (%): 4%
  • Prior stroke or TIA (%): 7%
  • Definite CHF (%): 19%
  • Definite Angina (%): 10%
  • Definite MI (%): 8%
  • Echocardiography
    • LAD > 5 cm (%): 26%
    • Mean LAD (cm): 4.6 cm
    • MVP (%): 6%
    • Moderate-to-severe LV dysfunction (%): 12%

Interventions

  • Patients were stratified by their candidacy for warfarin therapy into warfarin-eligible (Group 1) or warfarin-ineligible (Group 2).
  • Patients were ineligible for warfarin if they had any of:
    • Patient or attending physician refused anticoagulant therapy (n=220)
    • Age >75 years (n=173)
    • Isolated AF complex, with age ≤50 years, LA size ≤2.1 cm/m2, and no cardiopulmonary disease (n=51)
    • Anticipated poor follow-up (n=50)
    • Predisposition to head trauma (n=37)
    • Positive stool test for occult blood (n=25)
    • Chronic alcoholism (n=19)
    • GI or GU bleeding in prior 6 months (n=19)
    • Uncontrolled HTN (n=17)
    • Occupational hazards to anticoagulant therapy (n=16)
    • Severe hemorrhage with prior anticoagulation despite therapeutic PT (n=10)
    • Intrinsic PT >2 seconds beyond control value (n=8)
    • Recurrent syncope or uncontrolled epilepsy (n=8)
    • Prior intracranial hemorrhage (n=3)
  • Warfarin-eligible patients were randomized to warfarin (target INR 2.0-4.5), aspirin 325 mg, or placebo.
  • Warfarin-ineligible patients were randomized to aspirin 325mg or placebo.
  • The placebo arms were terminated in November 1989 due to high rate of events compared to the aspirin and warfarin arms.

Outcomes

'Presented as therapy vs. placebo'

Primary Outcome

Ischemic stroke or systemic embolism
Warfarin: 2.3% vs. 7.4% (RR 0.67; 95% CI 0.27-0.85; P=0.01)
Aspirin: 3.6% vs. 6.3% (RR 0.42; 95% CI 0.09-0.63; P=0.02)

Secondary Outcomes

Ischemic stroke, systemic embolism, or death
Warfarin: 3.8% vs. 9.8% (RR 0.58; 95% CI 0.20-0.78; P=0.01)
Aspirin: 7.9% vs. 11.8% (RR 0.32; 95% CI 0.07-0.50; P=0.02)
All-cause mortality
Warfarin: 2.2% vs. 3.1% (RR 0.25; 95% CI -1.11-0.73; P=0.56)
Aspirin: 5.3% vs. 6.5% (RR 0.20; 95% CI -0.20-0.46; P=0.37)

Adverse Events

  • Major complications consisted of bleeding episodes with overall rates between 1% and 2% per year in the treatment arms
  • Of 6 total CNS hemorrhages, two were fatal primary intracerebral hemorrhages and 4 were subdural hematomas
  • The rate of major complications were sequelae was less than 1%/yr in all treatment arms

Criticisms

  • Study was not designed or powered to compare the efficacy of aspirin or warfarin directly
  • Patients > 75 years old were deemed ineligible for warfarin therapy despite no clear evidence that these patients are at prohibitive bleeding risk
  • Study terminated early due to achievement of primary efficacy endpoint in both aspirin and warfarin arms which limited power to detect a difference between aspirin and warfarin

Funding

No disclosures regarding study sponsor or funding source

Further Reading

  1. McNamara RL et al. Management of atrial fibrillation: Review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography 'Ann Int Med 2003';139(12):1018-1833
  2. January CT, et al. "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary." Circulation. 2014:epub April.