The effect of aspirin on the risk of stroke in patients with nonrheumatic atrial fibrillation: The BAATAF study Recent randomized trials have consistently demonstrated the marked efficacy of warfarin in reducing the risk of stroke caused by nonrheumatic atrial fibrillation. These trials have provided conflicting evidence on the effect of aspirin. We report the aspirin analysis from the BAATAF study, a trial in which control patients could choose to take aspirin. There were two strokes in 446 person-years with warfarin (annual rate of 0.45%); eight strokes in 206 person-years with aspirin, most at 325 mg per day (annual rate of 3.9%); and five strokes in 271 person-years among patients taking neither aspirin nor warfarin (annual rate of 1.6%). Simultaneously controlling for the other significant determinants of stroke in the BAATAF study (age, mitral annular calcification, and clinical heart disease), the relative rates (95% confidence interval) of stroke were: (1) warfarinjaspirin = 0.135 (0.029 to 0.64); (2) aspirin/(no aspirin and no warfarin) = 1.95 (0.64 to 5.97); and (3) warfarin/(no aspirin and no warfarin) = 0.263 (0.051 to 1.36). Our “treatment received” analysis argues that warfarin is strikingly more effective than aspirin in preventing stroke in nonrheumatic atrial fibrillation. (AM HEART J 1992;124:1567.)

Daniel E. Singer, MD, Robert A. Hughes, MD, Daryl R. Gress, MD, Mary A. Sheehan, RN, Lynn B. Oertel, RN-C, Sue Ward Maraventano, RN, Dyan Ryan Blewett, MS, Bernard Rosner, PhD, and J. Philip Kistler, MD, for the BAATAF Investigators* Boston, Muss.

Patients with nonrheumatic atria1 fibrillation face an approximately fivefold increase in risk of stroke.l, 2 All four recently published randomized trials of long-term warfarin therapy (including two testing low-dose warfarin) have clearly demonstrated the marked efficacy of warfarin in preventing stroke in nonrheumatic atria1 fibrillation.3-6 These trials have also demonstrated that warfarin therapy can be quite safe when monitored carefully. Unfortunately, such monitoring, which involves frequent blood tests and patient contacts with medical care providers, is demanding for both patients and physicians. Aspirin From the General Service, Neurology Medical School.

Internal Medicine Unit, Service, Massachusetts

Medical General

Services, Hospital

and the Stroke and Harvard

Supported by a grant (HL 33233.05) from the National Heart, Lung, and Blood Institute, and by generous gifts from the Eliot B. Shoolman Fund, from the Hastings Fund, from Louise U. Snell, and from the Vera and J. W. G&land Fund. Dr. Singer was supported in part as a Henry J. Kaiser Family Foundation Scholar in General Internal Medicine. Received

for publication

Reprint Bulfinch

requests: Daniel 1. Massachusetts

*See Appendix 4/l/41313

May

13, 1992;

E. Singer, General

for participants.

accepted

July

10, 1992.

MD, General Internal Hospital, Boston MA

Medicine 02114.

Unit,

therapy would be a preferable alternative if its efficacy were comparable to that of warfarin. Guidelines published before the completion of the randomized trials suggested that warfarin, but not aspirin, might be effective in preventing stroke in atria1 fibrillation.7 Three of the randomized trials have published evidence bearing on the efficacy of aspirin. The Danish Atria1 Fibrillation, Aspirin, Anticoagulation (AFASAK) trial found no benefit from aspirin given at 75 mg per day.4 The Stroke Prevention in Atria1 Fibrillation (SPAF) trial found aspirin at 325 mg per day to be effective, although this effect was not consistent in the two parts of their trial (groups 1 and 2), and aspirin was not found to be effective among older patients.5v8 Our Boston Area Anticoagulation Trial in Atria1 Fibrillation (BAATAF) randomly assigned patients to warfarin (“low-dose” with a target prothrombin time ratio of 1.2 to 1.5), or no warfarin (our control group). The control patients could choose to take aspirin on a nonrandomized basis, and approximately half did. We have previously reported that in the control group, the crude rate of stroke among patients taking aspirin was actually higher than the rate among

1567

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Singer et al.

patients not taking aspirin.3 The rate of stroke for the entire control group was markedly higher than that for patients taking warfarin, leading to the early stopping of the trial after only 15 strokes had occurred (13 strokes in the control group versus two in the warfarin group). Because of the importance of accurately assessing the benefit of aspirin in atria1 fibrillation, and because of concern that our reported crude rate of stroke with aspirin was confounded by other risk factors for stroke, we now provide analyses of the BAATAF data that estimate the efficacy of aspirin in preventing stroke, independent of the risk factors for stroke found in our study. METHODS The detailed methods of the BAATAF study have been reported previously.3 In brief, patients were recruited from a variety of clinical settings (see Appendix). Patients were eligible if they had chronic sustained or intermittent atria1 fibrillation, and had no clinical or echocardiographic evidence for mitral stenosis (the defining characteristic of “rheumatic” atria1 fibrillation). Patients who had firm indications for or contraindications against warfarin therapy were ineligible. Similarly, patients who could not stop aspirin therapy were ineligible, since such therapy could not be continued in patients assigned to warfarin. Patients were randomly allocated to warfarin or no warfarin, with a 50% chance for either category. Patients and their treating physicians were not blinded as to therapy assignment. Patients receiving warfarin were managed by a central anticoagulant therapy unit using a prothrombin time of 1.2 to 1.5 times control as the target range (corresponding to an international normalized ratio of 1.5 to 2.6 for a North American thromboplastin with an international sensitivity index of 2.4g Patients in the no warfarin group could choose to take aspirin. Institutional review board approval was obtained in all participating institutions. At entry and annually, a medical history and physical examination were obtained. Every year, beginning at 6 months, patients were sent a questionnaire requesting information on neurologic symptoms, episodes of bleeding, and other medical conditions. Study nurses then telephoned all patients to review their responses. At 3 months and 9 months during each year of follow-up, each patient’s referring physician was contacted. Patients and their physicians were reminded to contact the investigators if any important medical problems developed. Aspirin frequency and dose were recorded as part of the 6-month questionnaire and follow-up telephone call, and were also part of the yearly history and physical examination. The specific questions asked were whether patients took aspirin, how frequently, how many tablets per day, and whether the tablets were “adult” (325 mg), or “baby” (80 mg) aspirin size. An additional question asked what medication patients took for pain, and how often they took this medicine. One further question asked patients to list all their medicines. These questions plus the telephone

American

December 1992 Heart Journal

follow-up reviewing these responses allowed us to characterize each patient, every 6 months, as to their aspirin status. Through the termination date of the study, follow-up was complete regarding the use of aspirin or warfarin, the occurrence of embolic complications, and death. The study’s primary end point was ischemic stroke (defined as the sudden onset of a neurologic deficit fitting a cerebrovascular distribution, lasting ab least 24 hours, without hemorrhage evident on initial imaging studies) or visceral embolus. No definite visceral embolus actually occurred. For the primary analysis there was no attempt to specify which strokes resulted from cardiac emboli. Primary hemorrhagic stroke was to be counted as a bleeding complication. In fact, there were no hemorrhagic strokes in the study. Reported symptoms and events were evaluated and summarized for end point committee ruling. End point committee summaries provided no information about the patient’s therapy, ensuring blinded evaluation. We have previously reported evidence that older age, “clinical heart disease,” and mitral annular calcification are risk factors for stroke among patients with at,rial fibrillation.” As such, they may be confounding factors in the current analysis. Clinical heart disease was defined as t,he presence of diagnosed coronary artery disease, congestive heart failure, cardiomyopathy, an artificial pacemaker, a treated ventricular rhythm disorder, left bundle branch block, or congenital heart disease. Patients without clinical heart disease could be of any age, have diagnosed hypertension, or diagnosed diabetes mellitus. Mitral annular calcification was considered to be present when there was an area of increased reflectivity within the mitral annular region consistent with calcium deposition. These features were characterized at entry to the study. The focus of this communication is the efficacy of aspirin in preventing stroke. The analysis is based on the actual treatment received: warfarin, aspirin, or neither warfarin nor aspirin. Patients were characterized as taking aspirin if they reported at a given 6-month evaluation that they were taking aspirin on a regular basis. Prevention of stroke was the reason usually cited for aspirin use, although relief of chronic painful conditions was also cited. Patients were characterized as taking warfarin if they reported regularly taking the medication and if they were participating in regular follow-up prothrombin time measurements. Ninet,y percent of patients assigned to warfarin remained compliant over the course of the study (average follow-up of 2.3 years). For such patients, control of anticoagulation was excellent, with prothrombin time tests in t,he desired range over 80Vr of the time.” Because patients’ treatment status could change over the course of the study and because patients were followed for differing lengths of observation, the analysis is based on an incidence rate’” or person-time comparison. Patient-years on aspirin were calculated by summing the time following a follow-up assessment in which the patient reported taking aspirin regularly. Thus on average each time a patient reported taking aspirin at a standard follow-up, he or she would contribute 6 patient-months to the aspirin category.

:ume 124 Number

Aspirin

6

Table

I. Clinical

features

of patients

treated

with

aspirin

No ASA & no warjarin Total person-years Clinical features: I, I’; of total person-years in treatment Age 2~70 years Male Mitral annular calcification Clinical heart disease Prior myocardial infarction Sustained AF AF duration >l year Hypertension Congestive heart failure Left atria1 size >40 mm* Mitral regurgitation more than l+*

versus warfarin

in atria1 fibrillation

1569

or warfarin* Less than 7 ASAlwrek

At least 7 ASAIweek

Warfarin

271.29

36.23

169.43

446.43

43.5 64.9 28.9 52.1 12.1 81.1 67.6 52.4 31.0 50.9 24.6

45.1 64.8 35.5 60.1 12.4 77.6 71.2 45.6 35.8 37.5 17.2

45.8 80.7 35.6 56.1 21.1 84.6 69.3 49.4 20.3 42.6 26.9

44.9 77.2 30.6 47.5 11.4 82.9 67.9 49.9 19.1 62.1 26.6

column)

Aspirin. *All person-years of observation in the BAATAF study are divided into four categories of treatment actually received: (1) No aspirin and no warfarin; (2) aspirin, at less than seven 325 mg tablets per week, and no warfarin; (3) aspirin, at seven or more 325 mg tablets per week, and no warfarin; and (4) warfarin and no aspirin. The total person-years accumulated in each treatment category is given in the first row of the table. The percentage of this total accumulated by patients with the listed clinical features is given in the subsequent rows. Left atrial size could not be read in three subjects, who contributed 4.8 personyears (0.52”; of total). Mitral regurgitation could not be adequately assessed in 50 subjects, who contributed 111.6 person-years (12% of total). Person-years contributed by patients with these missing values are not included in the total for that variable. ASA,

The sum of such patient-years in the aspirin, warfarin, and “no aspirin and no warfarin” categories formed the denominator of their respective incidence rates of stroke. The numerators were the sum of patients taking the given therapy who had a stroke. Confidence intervals for individual rates were read from tables for the expectation of a Poisson variab1e.l’ Adjustment for covariates was accomplished using the technique of Greenland and Robins,12 and by Poisson regression modeling.13 These latter two methods were in close agreement. RESULTS There warfarin

were 446 person-years of observation in the category (Table I). All but 4 person-years

were contributed by patients initially randomized to warfarin therapy. We divided aspirin therapy into categories of less than seven 325 mg tablets per week (or its equivalent in different dosages), and seven or more tablets per week. There were 169 person-years of observation in the seven or more tablets per week category, and 36 person-years in the less than seven tablets per week category. Six person-years in the aspirin categories were contributed by patients originally randomized to warfarin, after these patients stopped t,aking warfarin. There were 271 personyears of observation among patients taking neither aspirin nor warfarin; 39 of these were contributed by patients originally randomized to warfarin. Table I displays the clinical features (at entry into the BAATAF study) of each of the treatment categories. The t,able entries are the percent of person-years

in each treatment category contributed by patients with the given clinical feature. Older age, mitral annular calcification, and clinical heart disease were the only characteristics previously demonstrated to have a univariate statistically significant association with the subsequent occurrence of stroke.3 Mitral annular calcification and clinical heart disease, including a prior myocardial infarction, were somewhat more common in the aspirin categories. A total of 15 strokes occurred over the 923 personyears of observation, for an overall rate of stroke of 1.62% per year (Table II). The rate of stroke was markedly lower among patients treated with warfarin, 0.45% per year, compared with those in the other treatment categories. Of greatest interest for the current analysis, there was no evidence for a reduced rate of stroke with aspirin. Indeed, the rate of stroke was highest in the aspirin categories. Table III presents these comparisons in strata where each of the most important correlates of stroke are sequentially held constant. The two aspirin categories are merged for this and further analyses to provide more powerful analyses. In each stratum, the rate of stroke was lowest for warfarin treatment. The comparison between aspirin treatment and the “no aspirin and no warfarin” category is less clear-cut, but in each of the higher risk strata (age 70 or greater, mitral annular calcification present, and clinical heart disease present) the rate of stroke is higher in the aspirin treatment category. The adjusted inci-

December

1570

Singer et al.

Table

II. Rates of stroke among patients

American

receiving

warfarin,

No ASA & no warfarin

Number of strokes Total person-years Annual rate of stroke 95 GCconfidence interval for annual rate of stroke Abbreviations as in Table I. *Aspirin therapy is characterized

by the number

5 271.3 0.018 0.0060

aspirin,

or no antithrombotic

Less than 7 ASAlweek

to 0.043

0.028 0.00070

7

to 0.15

of 325 mg pills taken per week; 7 ASA/week

dence rate ratios12 with their corresponding 95% confidence intervals are presented below the stratified display. The three analyses controlling for each potential confounding variable provide similar results. The rate of stroke in the warfarin category is about one fourth of that in the no aspirin and no warfarin category, and less than one seventh of that in the aspirin category. Despite the small number of events, the warfarin/aspirin comparison is clearly statistically significant. To simultaneously account for the three potentially confounding features, we constructed an additive Poisson regression model13 of the rate of stroke that included terms for age (for simplicity, the quartiles presented in Table III were reduced to tertiles that were represented by two indicator variables), mitral annular calcification (present or absent), clinical heart disease (present or absent), as well as treatment category (the three treatment categories represented by two indicator variables). This model had satisfactory goodness-of-fit (assessed by scaled deviance), and two-way interaction terms did not add significant predictive ability. The estimated relative annual rates of stroke (and their 95 % confidence intervals) from the model were as follows: (1) warfarinl (no aspirin and no warfarin) = 0.263 (0.051 to 1.36); (2) aspirin/(no aspirin and no warfarin) = 1.95 (0.64 to 5.97); and (3) warfarimaspirin = 0.135 (0.029 to 0.64). These results are in substantial agreement with the results of the stratified analyses. DISCUSSION

Patients with atria1 fibrillation face a fivefold increase in the risk of stroke.2 Because atria1 fibrillation is such a common rhythm disorder among older people (2% to 4% of people over 60 years of age), it accounts for approximately 15 % of all strokes.2 It has been widely assumed that atria1 fibrillation predisposes to the formation of atria1 thrombi, which give rise to emboli producing stroke.14 While this mechanism may not account for all strokes attributable to

therapy*

At /east 7 ASAfweek

1 36.2

Heart

169.4 0.041 0.017 to 0.085

1992 Journal

-.Warfarin

2 446.4 0.0045 0.00054

to 0.016

is seven 325 mg pills per week.

atria1 fibrillation, it provides the conceptual basis for prophylactic therapy with anticoagulants. Long-term warfarin therapy has demonstrated remarkable efficacy in preventing strokes among patients with atria1 fibrillation in all published randomized trials and in observational studies.3-6, l5 Warfarin has also been quite safe in the randomized trials3-” and, in the BAATAF study, warfarin did not impair patients’ functioning or health perceptions.16 Nonetheless, warfarin, even at low doses, is not a popular longterm therapy for many patients or physicians.17 The frequent tests of prothrombin time and medical care visits, plus concern about serious bleeding, are unacceptable for many people. A simple regimen of aspirin prophylaxis would be preferable if it were effective. Because of the attractiveness of aspirin as an alternative to warfarin, it is particularly important to report and scrutinize evidence bearing on its efficacy. There are only three studies that have collected data on the efficacy of aspirin in atria1 fibrillation, and this evidence has been inconsistent. Patients randomized to aspirin (at 75 mg per day) in the AFASAK trial were not protected from stroke.4 In the SPAF trial,5, 8 aspirin (at 325 mg per day) reduced the rate of stroke by 44 % . However, aspirin was much less effective in preventing “nonminimal” stroke: the rate of moderately to severely disabling or fatal stroke was reduced by only 26% (statistically not significant). In addition, the efficacy of aspirin was not reproduced in both subgroups of the SPAF study,5s 8 a finding perhaps explained by a lack of efficacy among patients over age 75. Our “treatment received” analysis of the BAATAF study provides no support for the efficacy of aspirin in preventing stroke in atria1 fibrillation. The unadjusted annual rate of stroke among patients taking aspirin was 3.9 @O, nearly nine times the rate among patients taking warfarin, and actually two times the rate of patients taking neither aspirin nor warfarin. The latter comparison was not statistically significant. Since aspirin therapy was not randomly assigned in

Volume Number

124 6

the BAATAF study, there is the concern that patients taking aspirin were at higher risk of stroke, independent of therapy. Risk factors for stroke among patients with nonrheumatic atria1 fibrillation have not been reliably established, and are the object of considerable research.2, 18-z2 In the BAATAF study itself, three univariate risk factors were identified: age, clinical heart disease, and mitral annular calcification.3 There was somewhat more clinical heart disease and mitral annular calcification in the aspirin groups. Nonetheless, the rate of stroke in the aspirin-treated group was still almost sevenfold that in the warfarin group, even after controlling for the impact of imbalances in these other correlates of stroke risk. This analysis shows that the BAATAF data do not support the hypothesis that aspirin is comparable to warfarin in stroke preventive efficacy among patients with atria1 fibrillation. Some perspective on the strength of these results is provided by contrasting the eight strokes observed with aspirin in the BAATAF study alone with the total of seven ischemic strokes among patients who were actually anticoagulated with warfarin in all four published trials.3-6, 23 The BAATAF data do not rule out some efficacy for aspirin. The number of strokes are too small to powerfully compare aspirin to no anticoagulant therapy. But even with this comparison, the estimated rate ratio, aspirin/(no aspirin and no warfarin), is actually greater than one. We do not interpret these data as indicating that aspirin raises the risk of stroke, but rather that they make unlikely any substantial preventive benefit of aspirin. One possible reason for the lack of efficacy of aspirin in the AFASAK trial was the low dose used, 75 mg per day. The BAATAF data primarily address the efficacy of higher doses of aspirin, since the vast majority of person-years with aspirin occurred at doses of at least 325 mg per day. Our assessmentof the stroke preventive efficacy of aspirin in nonrheumatic atria1 fibrillation derives from nonrandomized “treatment received” analyses from within a randomized trial. This assessmentdoes benefit from the other features of our study design besides randomization, which include adherence to a prospectively developed protocol of procedures and definitions, detailed description of patients at entry, careful and close prospective follow-up, and structured, blinded evaluation of outcomes. Randomization serves to balance determinants of outcome other than t,he experimental variable. Randomization is important in assessing therapies, since physicians often choose a particular therapy based on clinical risk factors for a bad outcome,24 with the result that treated patients are at higher risk than untreated

Aspirin

versus warfarin

in atria1 fibrillation

1571

III. Rates of stroke among patients receiving warfarin, aspirin, or no therapy: Stratified by clinical features associatedwith stroke

Table

No ASA & no warfarin

Aspirin

Warfarin

0 30.56

0 75.65

0

0

1 81.15 0.012

0 170.38

6 80.84 0.074

1

1

1 36.21

Age(yr)’ = 80 Events 1 Person-years 23.46 Annual rate 0.043 Mitral annular calcification+ Absent Events 2 Person-years 192.66 Annual rate 0.010 Present Events 3 Person-years 78.64 Annual rate 0.038 Clinical heart diseaset Absent Events 1 Person-years 130.04 Annual rate 0.0077 Present Events 4 Person-years 141.25 Annual rate 0.028

13.08 0.076

0

164.17 0.0061

0.028

2 132.48

1 309.64

0.015

0.0032

6

1 136.78

73.18 0.082

2 88.76 0.023 6

116.89 0.051

0.0073

0 234.22 0 2 212.22 0.0094

*Incidence rate ratio controlling for age’! (1) warfarin/(no ASA & no warfarin) = 0.246 (95 “; confidence interval: 0.047 to 1.27); (2) aspirin/(no ASA & no warfarin) = 2.12 (0.67 to 6.68); (3) warfariniaspirin = 0.112 (O.oZ2 to 0.543). tIncidence rate ratio controlling for mitral annular calcification’? (1) warfarin/(no ASA & no warfarin) = 0.239 (95’; confidence interval: 0.046 to 1.231; (2) aspirin/(no ASA & no warfarin) = 1.90 (0.62 to 5.86); (3) warfarini aspirin = 0.122 (0.025 to 0.59). elncidence rate ratio controlling for clinical heart disease’? (1) warfarin/(no ASA & no warfarin) = 0.263 (95% confidence interval: 0.05 to 1.33); (2) aspirin/(no ASA & no warfarin) = 2.02 (0.66 to 6.14); (3) warfarin/aspirin = 0.134 (0.03 to 0.60).

patients at the outset of the comparison. Such confounding might be less of a problem in nonrheumatic atria1 fibrillation since risk factors for stroke in this condition are still not well established, and few were substantiated at all before the completion of the BAATAF study. It is unlikely that imbalances in clinical features could explain the striking differ-

1572

Singer et al

American

ences in rates of stroke that we observed among patients treated with aspirin compared with those treated with warfarin. Indeed, one can preserve a fully randomized comparison by simply assuming that all patients randomized to the no warfarin arm of the study took aspirin. Although this artificially reduces the rate of stroke with aspirin by half, this rate is still fourfold higher than the rate with warfarin (l-tailed p < 0.05). Given the difficulties inherent in taking warfarin and the ease of taking aspirin, physicians and patients might choose aspirin to prevent stroke in nonrheumatic atria1 fibrillation. We feel that our results serve to highlight the uncertainty about aspirin therapy and contrast such uncertainty with the repeatedly demonstrated efficacy of warfarin.3-6 We thank

Terry

S. Field,

MPH,

for statistical

support.

REFERENCES

1. Wolf PA, Dawber TR, Thomas HE Jr, Kannel WB. Epidemiologic assessment of chronic atria1 fibrillation and risk of stroke: the Framingham study. Neurology 1978;28:9’73-7. 2. Wolf PA, Abbott RD, Kannel WB. Atria1 fibrillation: a major contributor to stroke in the elderly. Arch Intern Med 1987;147:1561-4. 3. The Boston Area Anticoagulation Trial for Atria1 Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with non-rheumatic atria1 fibrillation. N Engl J Med 1990;323:1505-11. 4. Petersen P, Godtfredsen J, Boysen G, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atria1 fibrillation: the Copenhagen AFASAK study. Lancet 1989;1:175-9. 5. Stroke Prevention in Atria1 Fibrillation study group investigators. Stroke Prevention in Atria1 Fibrillation study: final results. Circulation 1991;84:527-39. 6. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Jovner C. Canadian Atria1 Fibrillation (CAFA) studv. J Am Coil Cardiol 1991;18:349-55. 7. Dunn M, Alexander J, de Silva R, Hildner F. Antithrombotic therapy in atria1 fibrillation. Chest 1989;95(suppl):llBs-27s. 8. Stroke Prevention in Atria1 Fibrillation study group investigators. Preliminary report of the Stroke Prevention in Atria1 Fibrillation study. N Engl J Med 1990;322:863-8. 9. Hirsch J, Poller L, Deykin D, Levine M, Dalen JE. Optimal therapeutic range for oral anticoagulants. Chest 1989; 95(suppl):5s-11s. H, Kleinbaum DG, Kupper LL. Measures of 10. Morgenstern disease incidence used in epidemiologic research. Int J Epidemiol 1980;9:97-104. 11. Pearson ES, Hartley HO, eds. Biometrika tables for statisticians. vol. I. London: Biometrika Trust, 1984:227. 12. Greenland S, Robins JM. Estimation of a common effect parameter from sparse follow-up data. Biometrics 1985;41:55-68. 13. Aitkin M, Anderson D, Francis B, Hinde J. Statistical modeling in GLIM. New York: Oxford University Press, 1989. 14. Hinton RC, Kistler JP, Fallon JT, Friedlich AL, Fisher CM. Influence of etiology of atria1 fibrillation on incidence of systemic embolism. Am J Cardiol 1977;40:509-13. 15. Roy D, Marchand E, Gagne P, Chabot M, Cartier R. Usefulness of anticoagulant therapy in the prevention of embolic complications of atria1 fibrillation. AM HEART J 1986:112:103943.

December 1992 Hearl Journal

16. Lancaster TR, Singer DE, Sheehan MA, Oertel LB, Maraventano SW, Hughes RA, Kistler JP. The impact of long-term warfarin therapy on quality of life: evidence from a randomized trial. Arch Intern Med 1991;151:1944-9. 17. Kutner M. Nixon G. Silverstone F. Phvsicians’ attitudes toward anticoagulant ‘and antiplatelet agents for stroke prevention in elderly patients with atria1 fibrillation. Arch Intern Med 1991;151:1950-3. 18. Flegel KM, Hanley J. Risk factors for stroke and other embolit events in patients with nonrheumatic atria1 fibrillation. Stroke 1989;20:1000-4. 19. Petersen P, Kastrup J, Helweg-Larsen S, Boysen G, Godtfredsen J. Risk factors for thromboembolic complications in chronic atria1 fibrillation: the Copenhagen AFASAK study. Arch Intern Med 1990;150:819-217 20. Moulton AW, Singer DE, Haas J. A case-control study of risk factors for stroke in patients with non-rheumatic atria1 fibrillation. Am J Med 1991;91:156-61. 21. The Stroke Prevention in Atria1 Fibrillation investigators. Predictors of thromboembolism in atria1 fibrillation I. Clinical features of patients at risk. Ann Intern Med 1992;116:1-5. 22. The Stroke Prevention in Atria1 Fibrillation investigators. Predictors of thromboembolism in atria1 fibrillation II. Echocardiographic features of patients at risk. Ann Intern Med 1992;116:6-12. 23. Albers GW, Sherman DG, Gress DR, Paulseth JE, Petersen P. Stroke prevention in nonvalvular atria1 fibrillation: a review of prospective randomized trials. Ann Neurol 1991;30:511-8. 24. Miettinen OS. The need for randomization in the study of intended effects. Stat Med 1983;2:267-71.

APPENDIX Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF) Investigators A. Participating Medical Institutions (numbers of patients entered into the study at each center) Group I: 166 Patients Massachusetts General Hospital, Boston, Mass. (70), Coordinating Center: Daniel E. Singer, MD, Epidemiologist in charge of Study Design/Data Analysis; Robert A. Hughes, MD, Co-Principal Investigator; Daryl R. Gress, MD, Neurologist; Mary A. Sheehan, RN, Study Coordinator; Lynn B. Oertel, RN-C, MS, Sue Ward Maraventano, RN, Dyan Ryan Blewett, MS, Data Analysts; Bernard Rosner, PhD, Statistician; J. Philip Kistler, MD, Principal Investigator University of Utah, Salt Lake City, Utah (31): Gregory K. Call, MD (Local Principal Investigator); Jeffrey L. Anderson, MD, Thomas H. Caine, MD, Bruce Bray, MD, Susan Lyver, RN Boston City Hospital, Boston, Mass. (17): Rodney H. Falk, MD (Local Principal Investigator); Nancy Battinelli, RN, G. Gargas, MD, Naggopal Venna, MD, Sheila Hewett, RN, Michael McNeil, RN University Hospital-Boston University, Boston, Mass. (12): Michael D. Klein, MD (Local Principal Investigator); Philip A. Wolf, MD, Carlos S. Kase, MD, Eloise E. Licata-Gehr, RN, MS Penobscot Bay Medical Center, Rockland, Maine (12): Donald J. Weaver, MD (Local Principal Inves-

Volume Number

124 6

Aspirin

tigator); Robert W. Stein, MD, Ralph Hamill, MD, Patricia Cole, RN University of Connecticut Health Center, Farmington, Conn. (10): W. David Hager, MD (Local Principal Investigator); Hartwell G. Thompson, MD, Denise Raymond, RN Stanford University Medical Center, Stanford, Calif. (9): Tim A. F&hell, MD (Local Principal Investigator); Richard L. Popp, MD, Gregory Albers, MD, Ann Cline, RN, Pamela Galante, RN University of Pittsburgh Presbyterian Hospital, Pittsburgh, Pa. (4): Lawrence R. Wechsler, MD (Local Principal Investigator); Richard Fogoros, MD, Nancy Kosanovich, RN-C, Nancy Nagel, RN Columbia Presbyt,erian Medical Center, New York, N.Y. (1): George Petty, MD Group

II: 210 Patients

Dartmouth Hitchcock Medical Center-White River ,Junction Veterans Affairs Hospital, White River Junction, Vt. (69): Arthur E. Sauvigne, MD (Local Principal Investigator); John Wasson, MD, Ann Choquette, James Bell, MD Mary Hitchcock Memorial Hospital, Hanover, N.H. (18): Andrew T. Torkelson, MD (Local Principal Investigator); John Plehn. MD, Alexander G. Reeves, MD, Vera Deveau, RN Brown University-Affiliated Hospitals Providence Veterans Affairs Medical Center, Providence, RI (18): Satish C. Sharma, MD (Local Principal Investigator); Donna Wiberg NP, RN-C Miriam Hospital, Providence RI. (17): Ara Sadaniantz, MD (Local Principal Investigator), William Stone, MD, Donna Fitzpatrick, RN, Ann Nugent, RN Memorial Hospit,al, Pawtucket, R.I. (14): Gary V. Heller, MD (Local Principal Investigator); Candace Miklozek-McNulty, MD, Lisa Warren, MS Rhode Island Hospital, Providence, R.I. (6): Anne W. Moulton, MD (Local Principal Investigator); J. Donald Easton, MD, Alan J. Shurman, MD, Leslie Macksoud, RN Roger Williams General Hospital, Providence, R.I. (3): Jeffrey Austerlitz, MD (Local Principal Investigator); Jane Carter, MD, Nicole Aebisher, MD, Satish C. Sharma, MD, Joanne Austerlitz, RN Mary Imogene Basset Hospital, Cooperstown, N.Y. and Basset Hospital-Herkimer Health Center,

versus warfarin

in atria1 fibrillation

1573

Herkimer, N.Y. (28): Lewis L. Hamilton, MD (Local Principal Investigator); Stephen E. Szebenyi, MD, David W. Vaules, MD, Herbert J. Marx, MD, Alan Kozak, MD, Carol Bordley, RN, Richard Trimble, MD, Philip Dzwonczyk, MD, Mark Darrow, MD New Hampshire Heart Institute, Manchester, NH (15): J. Beatty Hunter, MD (Local Principal Investigator); Pamela Gagnon, RN Lown Cardiovascular Group, Brookline, Mass. (7): Charles M. Blatt, MD (Local Principal Investigator); Martha Constantino, RN Malden Hospital, Malden, Mass. (6): Farouk A. Pirzada, MD (Local Principal Investigator); Lawrence Moschitto, MD Medical Center Hospital of Vermont-University of Vermont, Burlington, Vt. (4): Mark A. Capeless, MD (Local Principal Investigator); Jonathan Dissin, MD Merrimack Valley Cardiology Associates, Chelsmsford, Mass. (3): Jose Carrion, MD (Local Principal Investigator); Elizabeth Terranova, RN Nashoba Community Hospital, Ayer, Mass. (2): James Barzun, MD (Local Principal Investigator); Gary Stanton, MD Group

III:

44 Patients

Harvard Community Health Plan, Boston, Mass. (18): Mark Stockman, MD (Local Principal Investigator) Newton-Wellesley Hospital, Newton, Mass. (5): Mark R. Goldman, MD (Local Principal Investigator); Joel Rubenstein, MD, Richard E. Toran, MD Emerson Hospital, Concord, Mass. (4): Charles S. Keevil, MD (Local Principal Investigator); Michael Moore, MD Brockton-West Roxbury Veterans Affairs Medical Center, West Roxbury, Mass. (3): William Strauss, MD Cambridge Hospital, Cambridge, Mass. (5): Thomas Risser, MD, Salim Jabbour, MD, Thomas Glick, MD Jordan Hospital, Plymouth, Mass. (3): Robert Timberlake, MD, Lee I. Corwin, MD Mount Auburn Hospital, Cambridge, Mass. (2): Stanley A. Forward, MD Atlanticare, Lynn, Mass. (1): Gerald M. Perlow, MD Private M.D. Offices (3): Leslie Selbovitz, MD, Westwood, Mass.; Charles Sykes, MD, New Bedford, Mass. Robert England, MD, East Boston, Mass.