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BAATAF

The Effect of Low-Dose Warfarin on the Risk of Stroke in Patients with Nonrheumatic Atrial Fibrillation

Year of Publication: 1990

Authors: The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators (Singer DE, Hughes RA, Gress DR, et al.; principal investigator J.P. Kistler)

Journal: New England Journal of Medicine

Citation: N Engl J Med 1990;323(22):1505-1511. DOI: 10.1056/NEJM199011293232201

Link: https://doi.org/10.1056/NEJM199011293232201

Bottom Line

Long-term low-dose warfarin reduced the risk of ischemic stroke by 86% and all-cause mortality by 62% in patients with nonrheumatic atrial fibrillation, with an acceptable bleeding profile when carefully monitored.

        Major Points
        Randomized 420 patients with nonrheumatic AF to low-dose warfarin (target PT ratio 1.2-1.5) or no warfarin (aspirin permitted).
Warfarin reduced ischemic stroke: 2 vs 13 events (0.41%/yr vs 2.98%/yr); incidence ratio 0.14 (95% CI 0.04-0.49); P=0.0022; 86% relative risk reduction.
All-cause mortality also reduced with warfarin: 11 vs 26 deaths (2.25%/yr vs 5.97%/yr); RR 0.38 (95% CI 0.17-0.82); P=0.005.
Prothrombin-time ratios were in the 1.2-1.5 target range on 83% of days; only 10% of warfarin patients permanently discontinued the drug.
Bleeding: one fatal intracranial hemorrhage in warfarin group and one fatal pulmonary hemorrhage in control group; minor bleeding higher with warfarin (38 vs 21 patients; incidence ratio 1.62, 95% CI 0.95-2.74).
Aspirin (used by 46% of control patient-years, most at ≥325 mg/d) did not appear protective: 8 of 13 control-arm strokes occurred in patients taking aspirin (rate 3.99%/yr).
Data Monitoring Committee terminated the trial early (April 13, 1990) for demonstrated benefit of warfarin.
Landmark study alongside AFASAK and SPAF establishing warfarin as the standard-of-care stroke prevention therapy for nonvalvular AF.

      

Design

Study Type: Randomized Controlled Trial (open-label, blinded endpoint adjudication - PROBE-like)

Randomization: 1

Blinding: Unblinded (open-label) treatment assignment; endpoint assessment (Neurologic and Medical End-Point Committees) was blinded to treatment.

Enrollment Period: September 1985 - June 1989

Follow-up Duration: Mean 2.2 years (up to ~4 years); trial terminated early April 1990

Centers: 30

Countries: USA

Sample Size: 420

Analysis: Intention-to-treat; Kaplan-Meier survival analysis with log-rank test; proportional-hazards regression for adjusted comparisons.

Inclusion Criteria

Adults with chronic sustained or intermittent atrial fibrillation.
No echocardiographic evidence of mitral stenosis (i.e., nonrheumatic AF).
At least two separate electrocardiograms documenting atrial fibrillation.
For intermittent AF: an ECG documenting AF within 18 months of entry.
Normal serum indexes of thyroid function measured after AF onset.
Baseline two-dimensional echocardiogram (obtained within 6 months of entry, reviewed centrally).

Exclusion Criteria

Transient atrial fibrillation during acute illness (e.g., pneumonia) or planned cardioversion.
Echocardiographic evidence of intracardiac thrombus, left ventricular aneurysm, severe congestive heart failure, or prosthetic heart valves.
Stroke within the previous six months.
Transient ischemic attacks for which the patient was being treated.
Any neurologic condition predisposing the patient to intracranial hemorrhage.
Clinical indication (e.g., recent thrombophlebitis) or contraindication (e.g., peptic ulcer disease or liver disease) for anticoagulation.
Required aspirin therapy (as aspirin could not be continued during warfarin).

Baseline Characteristics

Characteristic	Warfarin	Control
N	212	208
Male	75%	70%
Mean Age (yr)	68.5 ± 8.5	67.5 ± 9.3
Age <60 yr	15%	16%
Age 60-69 yr	38%	42%
Age 70-79 yr	39%	35%
Age ≥80 yr	8%	7%
Intermittent AF	17%	16%
Duration of AF ≤12 mo	32%	32%
Hypertension	51%	51%
Cholesterol (mmol/L)	5.35 ± 1.1	5.33 ± 1.2
Current smoker	7%	10%
Former smoker	51%	54%
Never smoker	42%	36%
Diabetes	14%	16%
Angina	23%	25%
History of MI	10%	16%
Congestive heart failure	24%	28%
No clinical heart disease	50%	47%
Previous stroke	3%	3%
Fully independent functional status	95%	94%
Left atrial diameter (mm)	41.9 ± 6.4	40.5 ± 5.8
Mitral regurgitation >1+	25%	21%
Mitral annular calcification	33%	28%

Arms

Field	Warfarin	Control
Intervention	Low-dose warfarin titrated to target prothrombin-time ratio 1.2-1.5 (INR ~1.5-2.7). Mean weekly dose 29.7 mg. PT monitored ~every 3 weeks by a centralized computer-based dosing protocol. No aspirin allowed.	No warfarin. Aspirin was permitted at the patient's/physician's discretion; frequency and dose recorded at follow-up. Aspirin was used during 46% of control patient-years, most commonly ≥325 mg/day.
Duration	Mean 2.3 years (indefinite as clinically indicated); 487 patient-years total, 444 while actually receiving drug.	Mean follow-up 2.1 years; 435 patient-years total.

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Ischemic stroke - sudden onset of a neurologic deficit fitting a cerebroarterial distribution and lasting ≥24 hours, without hemorrhage on CT; adjudicated by a blinded Neurologic End-Point Committee.	Primary	13 strokes / 435 patient-years (2.98%/yr)	2 strokes / 487 patient-years (0.41%/yr)	0.14	0.0022
All-cause mortality	Secondary	26 deaths (5.97%/yr)	11 deaths (2.25%/yr)	0.38	0.005
Noncardiac death	Secondary	14	4		0.008
Cardiac death	Secondary	12	7		0.17
Severity of ischemic strokes (mild / moderate / severe / fatal)	Secondary	4 / 3 / 5 / 1 (total 13)	0 / 1 / 1 / 0 (total 2)
Stroke rate among control patients taking aspirin (nonrandomized)	Secondary	8 of 13 control-arm strokes occurred in patients on aspirin; rate 3.99%/yr (7 of 8 taking ≥325 mg/d)	N/A
Major hemorrhage (total)	Adverse	Warfarin 2 vs Control 1
Fatal intracranial hemorrhage	Adverse	Warfarin 1 (PT ratio 1.7) vs Control 0
Other fatal hemorrhage	Adverse	Warfarin 0 vs Control 1 (fatal pulmonary hemorrhage)
Nonfatal major hemorrhage	Adverse	Warfarin 1 (nonfatal GI bleed 7+ days after warfarin discontinuation) vs Control 0
Minor hemorrhage (patients)	Adverse	Warfarin 38 vs Control 21 (incidence ratio 1.62, 95% CI 0.95-2.74)
Minor bleeds leading to hospitalization	Adverse	Warfarin 4 vs Control 6
Minor bleeds leading to transfusion	Adverse	Warfarin 2 (2 units each) vs Control 1 (2 units)
Permanent warfarin discontinuation	Adverse	10% (21/212)

Subgroup Analysis

Univariate analyses (Table 3) identified age (74.2 vs 67.8 yr in stroke vs no-stroke, P=0.006), angina (53% vs 23%, P=0.02), and mitral annular calcification (67% vs 29%, P=0.003) as significantly associated with stroke. Intermittent vs sustained AF and duration of AF (≤1 vs >1 year) were not associated. In a proportional-hazards model controlling for age, MAC, clinical heart disease, and randomization strata, warfarin's relative risk for stroke remained 0.11 (95% CI 0.025-0.56).

Criticisms

Open-label (unblinded) treatment - though endpoint adjudication was blinded, patient/physician awareness could affect care.
Control patients were allowed to take aspirin (~46% of control patient-years), diluting comparison against 'true' placebo/no-therapy; findings suggest aspirin was ineffective but this is a nonrandomized comparison.
Trial terminated early by the Data-Monitoring Committee, which can overestimate treatment effect.
Modest sample size (n=420) and relatively small absolute number of stroke events (n=15), limiting power for subgroup analyses.
Predominantly white, U.S. tertiary-care population (30 mostly Boston-area sites); limited generalizability to other settings.
Target INR range (1.5-2.7) is lower than the current standard (INR 2-3), and warfarin dosing was managed by a centralized specialized anticoagulation service that may not be reproducible in community practice.
Excluded patients with prior recent stroke, contraindications to anticoagulation, or need for aspirin - narrowing applicability.

Funding

National Heart, Lung, and Blood Institute (grant HL 33233-05); Eliot B. Shoolman Fund; Louise U. Snell; the Vera and J.W. Gilliland Fund; Du Pont Pharmaceuticals Company provided Coumadin (warfarin) free of charge. Dr. Singer was supported in part as a Henry J. Kaiser Family Foundation Faculty Scholar.

Based on: BAATAF (New England Journal of Medicine, 1990)

Authors: The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators (Singer DE, Hughes RA, Gress DR, et al.; principal investigator J.P. Kistler)

Citation: N Engl J Med 1990;323(22):1505-1511. DOI: 10.1056/NEJM199011293232201

Content summarized and formatted by NeuroTrials.ai.

BAATAF

(1990)

Objective

Test whether long-term low-dose warfarin (target PT ratio 1.2-1.5; INR ~1.5-2.7) reduces ischemic stroke in patients with nonrheumatic atrial fibrillation.

Study Summary

• Warfarin cut ischemic stroke by 86%: 0.41%/yr vs 2.98%/yr in controls (incidence ratio 0.14, 95% CI 0.04-0.49; P=0.0022).
• All-cause mortality was also lower with warfarin: 2.25%/yr vs 5.97%/yr (rate ratio 0.38, 95% CI 0.17-0.82; P=0.005).
• Safety was favorable: 1 fatal intracranial hemorrhage on warfarin vs 1 fatal pulmonary hemorrhage on control; minor bleeding higher with warfarin (38 vs 21 patients; IR 1.62, 95% CI 0.95-2.74).

Intervention

Low-dose warfarin (target prothrombin-time ratio 1.2-1.5; corresponding INR ~1.5-2.7); mean weekly dose 29.7 mg.

Inclusion Criteria

Adults with chronic sustained or intermittent nonrheumatic atrial fibrillation, documented on ≥2 ECGs, without mitral stenosis on echocardiogram.

Study Design

Arms: Warfarin (low-dose, PT ratio 1.2-1.5) vs Control (no warfarin; aspirin permitted, used during 46% of control patient-years).

Patients per Arm: Warfarin 212; Control 208 (total N=420).

Outcome

• Primary (ischemic stroke): 2 vs 13 events; 0.41%/yr vs 2.98%/yr; IR 0.14 (0.04-0.49); 86% relative risk reduction; P=0.0022.
• Death: 11 vs 26; 2.25%/yr vs 5.97%/yr; RR 0.38 (0.17-0.82); P=0.005.
• Major hemorrhage: 2 (warfarin) vs 1 (control), including 1 fatal ICH in warfarin group; minor bleeding 38 vs 21.

Clinical Question

In patients with nonrheumatic atrial fibrillation, does long-term low-dose warfarin (target PT ratio 1.2-1.5) reduce the risk of ischemic stroke compared with no anticoagulation?

Bottom Line

Major Points

Randomized 420 patients with nonrheumatic AF to low-dose warfarin (target PT ratio 1.2-1.5) or no warfarin (aspirin permitted).
Warfarin reduced ischemic stroke: 2 vs 13 events (0.41%/yr vs 2.98%/yr); incidence ratio 0.14 (95% CI 0.04-0.49); P=0.0022; 86% relative risk reduction.
All-cause mortality also reduced with warfarin: 11 vs 26 deaths (2.25%/yr vs 5.97%/yr); RR 0.38 (95% CI 0.17-0.82); P=0.005.
Prothrombin-time ratios were in the 1.2-1.5 target range on 83% of days; only 10% of warfarin patients permanently discontinued the drug.
Bleeding: one fatal intracranial hemorrhage in warfarin group and one fatal pulmonary hemorrhage in control group; minor bleeding higher with warfarin (38 vs 21 patients; incidence ratio 1.62, 95% CI 0.95-2.74).
Aspirin (used by 46% of control patient-years, most at ≥325 mg/d) did not appear protective: 8 of 13 control-arm strokes occurred in patients taking aspirin (rate 3.99%/yr).
Data Monitoring Committee terminated the trial early (April 13, 1990) for demonstrated benefit of warfarin.
Landmark study alongside AFASAK and SPAF establishing warfarin as the standard-of-care stroke prevention therapy for nonvalvular AF.

Study Design

Study Type: Randomized Controlled Trial (open-label, blinded endpoint adjudication - PROBE-like)
Randomization: Yes
Blinding: Unblinded (open-label) treatment assignment; endpoint assessment (Neurologic and Medical End-Point Committees) was blinded to treatment.
Sample Size: 420
Follow-up: Mean 2.2 years (up to ~4 years); trial terminated early April 1990
Centers: 30
Countries: USA

Primary Outcome

Definition: Ischemic stroke - sudden onset of a neurologic deficit fitting a cerebroarterial distribution and lasting ≥24 hours, without hemorrhage on CT; adjudicated by a blinded Neurologic End-Point Committee.

Control	Intervention	HR/OR	P-value
13 strokes / 435 patient-years (2.98%/yr)	2 strokes / 487 patient-years (0.41%/yr)	0.14 (0.04-0.49)	0.0022

Limitations & Criticisms

Open-label (unblinded) treatment - though endpoint adjudication was blinded, patient/physician awareness could affect care.
Control patients were allowed to take aspirin (~46% of control patient-years), diluting comparison against 'true' placebo/no-therapy; findings suggest aspirin was ineffective but this is a nonrandomized comparison.
Trial terminated early by the Data-Monitoring Committee, which can overestimate treatment effect.
Modest sample size (n=420) and relatively small absolute number of stroke events (n=15), limiting power for subgroup analyses.
Predominantly white, U.S. tertiary-care population (30 mostly Boston-area sites); limited generalizability to other settings.
Target INR range (1.5-2.7) is lower than the current standard (INR 2-3), and warfarin dosing was managed by a centralized specialized anticoagulation service that may not be reproducible in community practice.
Excluded patients with prior recent stroke, contraindications to anticoagulation, or need for aspirin - narrowing applicability.

Citation

N Engl J Med 1990;323(22):1505-1511. DOI: 10.1056/NEJM199011293232201

View Original Publication →

BAATAF

The Effect of Low-Dose Warfarin on the Risk of Stroke in Patients with Nonrheumatic Atrial Fibrillation

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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