Background To avert major hemorrhage, physicians need to knowthe lowest intensity of anticoagulation that is effective inpreventing stroke in patients with atrial fibrillation. Sincethe low rate of stroke has made it difficult to perform prospectivestudies to resolve this issue, we conducted a case–controlstudy.
Methods We studied 74 consecutive patients with atrial fibrillationwho were admitted to our hospital from 1989 through 1994 afterhaving an ischemic stroke while taking warfarin. For each patientwith stroke, three controls with nonrheumatic atrial fibrillationwho were treated as outpatients were randomly selected fromthe 1994 registry of the anticoagulant-therapy unit (222 controls).We used the international normalized ratio (INR) to measurethe intensity of anticoagulation. For the patients with stroke,we used the INR at admission; for the controls, we selectedthe INR that was measured closest to the month and day of thematched case patient's hospital admission.
Results The risk of stroke rose steeply at INRs below 2.0. Atan INR of 1.7, the adjusted odds ratio for stroke, as comparedwith the risk at an INR of 2.0, was 2.0 (95 percent confidenceinterval, 1.6 to 2.4); at an INR of 1.5, it was 3.3 (95 percentconfidence interval, 2.4 to 4.6); and at an INR of 1.3, it was6.0 (95 percent confidence interval, 3.6 to 9.8). Other independentrisk factors were previous stroke (odds ratio, 10.4; 95 percentconfidence interval, 4.4 to 24.5), diabetes mellitus (odds ratio,2.9; 95 percent confidence interval, 1.3 to 6.5), hypertension(odds ratio, 2.5; 95 percent confidence interval, 1.1 to 5.7),and current smoking (odds ratio, 5.7; 95 percent confidenceinterval, 1.4 to 24.0).
Conclusions Among patients with atrial fibrillation, anticoagulantprophylaxis is effective at INRs of 2.0 or greater. Since previousstudies have indicated that the risk of hemorrhage rises rapidlyat INRs greater than 4.0 to 5.0, tight control of anticoagulanttherapy to maintain the INR between 2.0 and 3.0 is a betterstrategy than targeting lower, less effective levels of anticoagulation.
Atrial fibrillation is a common risk factor for ischemic stroke,particularly among the elderly.1 Randomized trials have demonstratedthat a relatively low intensity of anticoagulant therapy canlargely eliminate the risk of stroke attributable to atrialfibrillation.2,3,4,5,6,7,8 In the trials, the rates of bleedingcomplications were acceptably low. However, there is concernthat in actual medical practice the risk of hemorrhage associatedwith the use of anticoagulants, particularly among the elderly,may be higher than that in the initial group of randomized trials.9,10Since the risk of major hemorrhage in patients treated withanticoagulants rises steeply with the intensity of anticoagulation,11,12,13it would be valuable to determine the lowest effective intensitythat still prevents ischemic stroke in patients with atrialfibrillation.
Ischemic strokes are rare among patients who are truly takinganticoagulant agents. For example, in the first five trialsof anticoagulant therapy in patients with atrial fibrillation,there were a total of only 27 ischemic strokes in almost 1900person-years of follow-up of patients randomly assigned to anticoagulanttherapy, and 29 percent of the strokes occurred in patientswho were not taking their assigned medication.8 This low rateof events makes it difficult to conduct prospective studiesto determine the relation between the level of anticoagulationas indicated by the international normalized ratio (INR) andthe risk of stroke. We chose instead to use a case–controlapproach similar to that used in our previous study of intracranialhemorrhage among patients taking anticoagulant drugs.12 In thepresent study, the case subjects were patients with atrial fibrillationwho had ischemic strokes despite receiving anticoagulants, andthe controls were patients with atrial fibrillation who didnot have strokes and whose treatment was managed by our anticoagulant-therapyunit.
Methods
Identification and Eligibility of Patients with Stroke
Using a log of consecutive patients discharged from MassachusettsGeneral Hospital from January 1, 1989, through December 31,1994, we identified 669 patients with codes from the InternationalClassification of Diseases, Ninth Revision (ICD-9)14 that indicateddischarge diagnoses of both atrial fibrillation (ICD-9 code427.31) and ischemic stroke (codes 436.0, 434.91, 434.9, 434.11,434.1, 434.01, 434.00, 434.0, 433.11, 433.01, and 432.9). Weused January 1, 1989, as the starting date for the identificationof patients discharged after hospitalization for ischemic strokebecause 1989 was the first full year during which values forthe international sensitivity index (ISI) were known for allthe thromboplastin preparations used in the prothrombin-timeassay at our hospital. The medical records of 6 of the 669 potentiallyeligible patients (1 percent) were not available for review.
The remaining 663 patients' medical records were reviewed toconfirm that the patients were at least 18 years old, had avalidated diagnosis of ischemic stroke occurring before admission,had electrocardiographic evidence of atrial fibrillation, andwere taking warfarin at the time of the stroke. Patients withmitral stenosis or prosthetic heart valves were not eligible.Whether the patients were taking warfarin at the time of admissionwas determined from reviews of admission notes made by the residentand attending physicians. The diagnosis of ischemic stroke wasconfirmed by a clinical history of the sudden development ofa major neurologic deficit lasting more than 24 hours that wascorrelated with a cerebrovascular territory. Seventy-four patientsmet the eligibility criteria. The vast majority of those excludedwere not taking warfarin at the time of the stroke. In 64 cases,the diagnosis of ischemic stroke was confirmed by positive evidenceof cerebral infarction on computed tomography (CT) or magneticresonance imaging (MRI). In nine cases, the initial CT scanof the head showed no evidence of primary intracerebral hemorrhageand no follow-up CT or MRI study was performed. In one case,the diagnosis was based solely on the clinical presentation,which was typical of ischemic stroke.
Identification and Eligibility of Controls
All the controls were randomly selected from the 1994 registryof the hospital's anticoagulant-therapy unit. We chose 1994because it was the first full year during which the resultsof all prothrombin-time tests performed at laboratories affiliatedwith the unit were expressed in terms of the INR. During 1994,this unit managed the treatment of 2680 patients, includingapproximately 700 with nonrheumatic atrial fibrillation. Threecontrols were matched to each patient with stroke. The medicalrecords of the controls were reviewed to confirm that the controlswere at least 18 years old, had nonrheumatic atrial fibrillation,and did not have a prosthetic heart valve. No patient servedas a control for more than one patient with stroke.
To validate the use of controls treated in 1994, we examinedthe distribution of INR values for each of the study years forpatients with nonrheumatic atrial fibrillation whose tests wereperformed at either the hospital laboratory or another largeclinical laboratory serving patients managed by the unit. Together,these two laboratories accounted for nearly 55 percent of theprothrombin-time tests for patients whose treatment was managedby the unit. Throughout the study period (1989 through 1994),both laboratories kept records of the ISI values of the thromboplastinthey used, thus allowing calculation of the INRs. For 1994,the distribution of INR values among all the patients with atrialfibrillation who were treated by the unit was essentially thesame as the distribution of values in the subgroup of patientsserved by these two laboratories. Similarly, the distributionsof INR values for patients with atrial fibrillation whose prothrombintimes were determined by these two laboratories during 1989through 1993 were not significantly different from the distributionfor 1994. Our analyses indicated that the INR values of thecontrol patients treated in 1994 were representative of theINR values of potential control patients from 1989 through 1994.
The mean INR was also consistent over time among the patientswith stroke; in 1989 the mean INR was 1.62 (n = 11); in 1990,1.58 (n = 6); in 1991, 1.49 (n = 14); in 1992, 1.87 (n = 10);in 1993, 1.41 (n = 16); and in 1994, 1.63 (n = 17). Logistic-regressionmodels assessing year-specific relations between the INR andthe occurrence of stroke were constructed for the subgroup ofpotential controls for whom INR values were available. A variablefor calendar year did not have a significant effect in the model.The estimated odds ratios for stroke as a function of the INRthat were generated by these models for each year fell within1 SE of the odds ratios estimated by the model including therandomly selected 1994 controls (see the Results section).
Sources of Data
Data on the characteristics of the patients with stroke andtheir controls were obtained primarily from hospital records,with supplementation in a few instances from physicians' officerecords. The information recorded for each patient includedthe INR and the duration of warfarin therapy, race, sex, anda variety of clinical characteristics. Echocardiographic variableswere also recorded, if available. For the patients with stroke,we included the staff neurologist's assessment of the likelymechanism and location of the stroke and the magnitude of theresulting neurologic deficit. For the controls, we recordedclinical data as of the time the selected INR was determined.
INRs were calculated on the basis of the prothrombin-time ratio(PTR) and the ISI of the thromboplastin used in the assay15as follows: INR = PTRISI. For the patients with stroke, we usedthe INR measured in blood drawn in the emergency room at admission.Since 1988, our hospital laboratory has used a thromboplastinwith a known ISI (Simplastin Automated, Organon Teknika, Durham,N.C.); the ISI values for different lots range from 1.9 to 2.2.Two patients with stroke had the PTR measured at a referringhospital's emergency room. Both of these hospitals' laboratorieswere using Thromboplastin C (Dade, Baxter Diagnostics, Deerfield,Ill.) with an ISI of 2.7. For the controls, the INR determinedon the date closest to the month and day of admission for thematched patient with stroke was obtained from the data baseof the anticoagulant-therapy unit. Such a method of selectingINRs for the controls avoided the bias toward out-of-range valuesthat is inherent in random selection of INR values (since morefrequent INR testing is done when patients have out-of-rangevalues) and accounts for possible seasonal changes in the INR.
Information on the duration of warfarin therapy was missingfor four patients with stroke. Echocardiographic data were availablefor 91 percent of the patients with stroke and 88 percent ofthe controls (echocardiography was performed during the studyperiod in 95 percent of the controls). All but seven of theechocardiograms (one in a patient with stroke and six in controls)were obtained at Massachusetts General Hospital. Data for patientswith stroke and controls were otherwise complete.
Additional definitions used in the analysis included the following:
Nonrheumatic atrial fibrillation — electrocardiographicallydocumented atrial fibrillation, with no evidence of mitral stenosison echocardiography and no clinical history of mitral stenosis.For three patients with stroke, atrial fibrillation was firstdocumented during the initial 48 hours of hospitalization forstroke. For the controls, atrial fibrillation was documentedin the medical records before the date when the chosen INR wasmeasured.
Paroxysmal atrial fibrillation — atrial fibrillation documentedelectrocardiographically at least once in the preceding 24 months,but with intervening periods of normal sinus rhythm.
Hypertension — a diagnosis of hypertension listed in themedical record. Ninety-four percent of the patients with strokeand 96 percent of the controls who had been given a diagnosisof hypertension were taking antihypertensive medication.
Diabetes mellitus — a diagnosis of diabetes mellitus listedin the medical record. Seventy-five percent of the patientswith stroke and 64 percent of the controls who had been givena diagnosis of diabetes were being treated with insulin or oralhypoglycemic agents.
Mitral regurgitation — mild, moderate, or severe regurgitationas estimated from the echocardiogram.
Coronary artery disease — a history of myocardial infarction,bypass surgery, angioplasty, or angina.
Peripheral vascular disease — a history of intermittentclaudication or revascularization surgery.
Prior stroke — a diagnosis of previous stroke recordedin the medical record. In all instances, previous strokes occurredbefore the beginning of anticoagulant therapy.
The research protocol for this study was reviewed and approvedby the hospital's subcommittee on human studies.
Statistical Analysis
For univariate comparisons between the patients with strokeand the controls, we assessed statistical significance withthe chi-square test or Fisher's exact test, as appropriate.Odds ratios with 95 percent confidence intervals were calculatedby standard methods.16,17 A continuous probability-density functionfor INRs among both the patients with stroke and the controlswas constructed according to a nonparametric method (with thearea under the curve between any two INRs used to give an estimateof the proportion of patients whose INRs fell between thosevalues).18 The ratio of the probability densities among thecase patients to those among the controls, normalized to 1.0at an INR of 2.0, provided a nonparametric estimate of the oddsratio for stroke at any given INR level as compared with anINR of 2.0.
We used logistic-regression models to assess the independenteffect of multiple clinical characteristics on the risk of stroke.INRs were transformed with the natural logarithm to providea better linear fit. Models that provided an increase in therisk of stroke below an INR of 2.0 but no change in the oddsat 2.0 or higher were compared with models that included onlya single linear term for the log INR. The latter models provideda lower log likelihood as well as estimates of the effect ofthe INR that were more consistent with the results of the univariateanalysis and are therefore described in the Results section.Other predictive variables were chosen for inclusion in thelogistic models because they were significantly associated withrisk in the univariate analysis (P<0.05) or because theywere significant in the pooled analysis of the trials of anticoagulanttherapy in patients with atrial fibrillation.8 Variables thatwere not found to be significant independent predictors of therisk of stroke were eliminated, and the model refitted. Theresults of the matched case–control analysis19 differednegligibly from the estimates in the unmatched analysis; onlythe results of the unmatched analyses are presented here. Statisticalanalyses were performed with SAS (SAS Institute, Cary, N.C.),S-plus (Statistical Science, MathSoft, Seattle), and StatXact(Cytel Software, Cambridge, Mass.).
Results
Clinical Course of Patients with Stroke
We identified a total of 74 patients who were admitted to ourhospital from 1989 through 1994 with nonrheumatic atrial fibrillationand ischemic stroke who were taking warfarin at the time ofthe stroke (Table 1). Ninety-two percent of the patients hadembolic stroke, 84 percent in the anterior circulation and 8percent in the posterior circulation. Six patients (8 percent)were given a diagnosis of lacunar infarcts, three on the basisof CT scanning and three on the basis of MRI. Twenty percentof the patients with stroke died before discharge, and 19 percentsurvived with major neurologic deficits that prevented theirreturn to independent living.
Table 1. Clinical Characteristics of 74 Patients with Ischemic Stroke.
Comparison of Patients with Ischemic Stroke and Controls
A history of stroke was a powerful risk factor for stroke whilereceiving anticoagulant therapy (odds ratio, 6.8; 95 percentconfidence interval, 3.9 to 12.1) (Table 2). Other factors thatwere statistically significant in the univariate analysis wereage greater than 75 years, a history of peripheral vasculardisease, a history of transient ischemic attacks, diabetes mellitus,and current smoking (Table 2). Coronary artery disease was ofborderline significance. The patients with stroke and the controlsdid not differ significantly in terms of sex, race, the numberswith chronic as opposed to paroxysmal atrial fibrillation, theproportion with hypertension, and the proportion with congestiveheart failure.
Table 2. Characteristics of Patients with Ischemic Stroke and Controls.
Among the echocardiographic features, mitral annular calcificationand left ventricular hypertrophy were found more frequentlyamong the patients with stroke. Left atrial size had no relationto the risk of stroke. The vast majority of both patients withstroke and controls had left ventricular ejection fractionsof at least 40 percent, making it difficult to determine whethervery low ejection fractions were associated with stroke (Table 2).
The INR was a powerful determinant of the risk of stroke (Figure 1A,Figure 1B, and Figure 1C). The risk rose very steeply asINR values fell below 2.0. As compared with patients with INRsof 2.0, those with INRs of 1.7 had nearly twice the risk ofstroke; those with INRs of 1.5 had nearly three times the riskof patients whose INRs were 2.0, and those with INRs of 1.3had a sevenfold greater risk (Figure 1A, Figure 1B, and Figure 1C).
Figure 1. Distribution of INR Values in Patients with Stroke (Panel A) and Controls (Panel B) and Odds Ratios for Stroke According to INR Value (Panel C).
In Panels A and B, the bars show the number of strokes among subjects with each INR value, and the lines show nonparametric estimates of the density of INR values. The unadjusted odds ratios shown in Panel C were calculated by dividing the estimated density of patients who had stroke at a given INR (Panel A) by the estimated density of controls with the same INR (Panel B) and dividing the resulting ratio by the ratio at an INR of 2.0. This represents the estimated odds of stroke at the given INR as compared with an INR of 2.0. Note that the scales on the x axes are logarithmic, and that the scales on the y axes in Panels A and B differ.
The effect of the INR on the risk of stroke changed little whenother correlates of stroke were also included in multiple logisticmodels (Table 3). Table 4 shows the adjusted odds ratios forstroke at INR values from 1.0 to 2.0, as estimated in the model.
Table 4. Adjusted Odds Ratios for Ischemic Stroke According to the INR.
Among other independent determinants of the risk of stroke,having had a previous stroke was particularly strong. Diabetesmellitus, hypertension, and current smoking were also significantrisk factors for stroke (Table 3). There were no statisticallysignificant interactions between any of these factors and theINR. In particular, there was no evidence that the relationbetween the INR and the relative risk of stroke differed betweenpatients who had had a prior stroke and those who had not hada stroke.
Patients with Stroke and Controls Who Were Treated at the Anticoagulant-Therapy Unit
Fifty-three patients with ischemic stroke had their warfarintherapy managed by the staff of the hospital's anticoagulant-therapyunit. The effects of previously identified independent riskfactors for ischemic stroke were largely unchanged in analysesrestricted to these patients and their controls. The odds ratiofor stroke among patients with a 50 percent lower INR was 15.8(95 percent confidence interval, 6.6 to 37.9); among patientswith a prior stroke as compared with those without a prior stroke,the odds ratio was 7.1 (95 percent confidence interval, 2.8to 17.7); for current smoking, it was 5.1 (95 percent confidenceinterval, 1.1 to 24.5); for diabetes mellitus, 2.5 (95 percentconfidence interval, 1.1 to 6.1); and for hypertension, 2.0(95 percent confidence interval, 0.8 to 4.8).
Discussion
The randomized trials that demonstrated that anticoagulant therapyis strikingly effective in preventing stroke in patients withatrial fibrillation used a range of target levels of anticoagulation.2,3,4,5,6,7,8Anticoagulant agents were as effective in trials that used thelowest target intensities as in those using higher target levels.2,6These results, along with reports of the efficacy of very lowdoses of anticoagulant agents in preventing thrombosis in patientswith other clinical conditions,20,21 encouraged the belief thatanticoagulation at a barely detectable intensity might be effectivein patients with atrial fibrillation. Anticoagulant therapywith a very low target INR (e.g., <1.5) is currently beingtested in at least two randomized trials.22,23 Our results arguestrongly against the efficacy of such very-low-intensity regimens.
We observed a steep increase in the risk of stroke as INR valuesfell below 2.0. The risk of stroke doubled as the INR decreasedfrom 2.0 to 1.7, and it more than doubled again when the INRwas reduced to 1.4. In contrast, INR values greater than 2.0conferred little additional efficacy — beyond that oftherapy at an INR of 2.0 — in preventing ischemic strokes.
The case–control design of our study gave it substantialstatistical power to assess an uncommon outcome — ischemicstroke among patients with atrial fibrillation who were actuallytaking anticoagulants. On the basis of the event rates observedin randomized trials,7,8 our case–control study had statisticalpower equivalent to that conferred by approximately 6000 person-yearsof prospective follow-up. We were able to determine the relationbetween the risk of stroke and a patient's INR at the time ofthe stroke. By contrast, randomized trials assess the efficacyof a target INR range; the results of such trials depend onwhether those targets are achieved consistently. Secondary analysesof data from randomized trials investigating the relation betweenactual INR values and the rate of occurrence of stroke are aform of nonrandomized, prospective cohort study within the randomizedtrial. Using such an analysis, the European Atrial FibrillationTrial Study Group concluded that an INR below 2.0 conferredless protection against stroke than an INR of 2.0 or higher.24This conclusion was based on only seven thromboembolic eventsin patients with INRs below 2.0 and was restricted to patientswho had had a previous stroke or transient ischemic attack.In our study there were 58 events in patients with INRs below2.0, allowing us to calculate specific odds ratios for strokefor the entire range of INR values from 1.0 to 2.0. We includedboth subjects who had had a prior stroke and those who had not.
Although our primary goal was to define the relation betweenthe INR and the risk of ischemic stroke, our study design allowedus to explore the role of other clinical factors. Like mostother studies of the risk of stroke in patients with atrialfibrillation, our study identified a history of stroke as amarker for substantially increased risk. Diabetes mellitus andhypertension were also independent risk factors for stroke,nearly tripling the risk. Our findings regarding these riskfactors were similar to the results of the pooled analysis ofthe initial studies of patients with atrial fibrillation.8 Ourfindings differed from those of the pooled analysis in two ways,however. First, we found no independent effect of age, althoughan age greater than 75 years was a significant risk factor inour univariate analysis. Second, we found current smoking tobe a strong risk factor for stroke, although the small numberof smokers made our estimates imprecise. Population-based studieshave repeatedly found current smoking to be a risk factor forstroke.25,26
The primary methodologic concern with respect to case–controlstudies is selection bias — that is, in this study, theconcern that patients with stroke may have been selected becausetheir INR was low or that controls may have been selected becausetheir INR was relatively high. The structure of our study reducedthe possibility of such bias. The case subjects were the entiregroup of eligible patients admitted to our hospital from 1989through 1994. The controls were randomly selected from the groupof all patients with atrial fibrillation whose treatment wasmanaged by our anticoagulant-therapy unit in 1994, the firstcalendar year when INR values were available for all patients.Furthermore, our findings were essentially unchanged when theanalysis was restricted to patients with stroke whose treatmenthad been managed by the anticoagulant-therapy unit, a fact thatargues against the existence of referral bias.
Our earlier work indicated that the risk of intracranial hemorrhagein patients receiving warfarin increased exponentially at INRvalues above 4.0.12 Cannegieter et al. observed a steep increasein the risk of intracranial hemorrhage at an INR of 5.0.15 Forpatients with atrial fibrillation, anticoagulant prophylaxisis effective at INRs above 2.0, and safety is preserved at INRslower than 4.0. The risk of either ischemic stroke or intracranialhemorrhage rises very steeply beyond these boundaries.
Surveys indicate that many physicians use low target INRs (suchas 1.5) for elderly patients with atrial fibrillation in orderto reduce what they perceive as a high risk of bleeding.27 Ourresults suggest that greater efforts at tight control of theINR would have a better effect on health than using anticoagulanttherapy at an ineffectively low intensity. Such efforts wouldinclude more widespread use of anticoagulant-therapy units anddosing algorithms that might require more frequent, rather thanless frequent, measurements of the INR. Innovations such ashaving patients test their own INR levels could reduce the burdenof frequent testing.28
Anticoagulant therapy in patients with atrial fibrillation isamong the most effective preventive interventions in older adults,from the perspective of both health and cost.29 To optimizethe use of anticoagulants, the target INR needs to be both highenough to prevent ischemic stroke and low enough to avert majorhemorrhage. The current standard target — an INR between2.0 and 3.0 — was established by consensus on the basisof the results of randomized trials.30 The empirical evidencefor this recommendation was limited, however, since severalof the trials did not even use an INR target. We are now accumulatingbetter evidence of the true therapeutic range of anticoagulationin patients with atrial fibrillation. This range appears toextend from an INR of 2.0 to nearly 4.0, and indeed it includesthe current INR standard of 2.0 to 3.0. The key to realizingthe great potential benefit of anticoagulant therapy in patientswith atrial fibrillation is to develop management strategiesthat keep the level of anticoagulation, as indicated by thepatients' INR values, consistently within the range of 2.0 to3.0.
Supported in part by the Eliot B. Shoolman Fund of MassachusettsGeneral Hospital.
We are indebted to Dr. Robert A. Hughes for facilitating ouruse of data from the Massachusetts General Hospital AnticoagulantTherapy Unit, to the nurses working in the unit for their dedicationto the care of patients and to the maintenance of a high-qualitydata base, and to Dr. Yu-Chiao Chang for help with the statisticalanalyses.
Source Information
From the General Internal Medicine Division, Clinical Epidemiology Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston.
Address reprint requests to Dr. Hylek at the Medical Practices Evaluation Center, S 50-9, Massachusetts General Hospital, Boston, MA 02114.
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