Effect of a balloon-expandable intracranial stent vs medical therapy on risk of stroke in patients with symptomatic intracranial stenosis: the VISSIT randomized clinical trial.

IMPORTANCE: Intracranial stenosis is one of the most common etiologies of stroke. To our knowledge, no randomized clinical trials have compared balloon-expandable stent treatment with medical therapy in symptomatic intracranial arterial stenosis. OBJECTIVE: To evaluate the efficacy and safety of the balloon-expandable stent plus medical therapy vs medical therapy alone in patients with symptomatic intracranial stenosis (≥70%). DESIGN, SETTING, AND PATIENTS: VISSIT (the Vitesse Intracranial Stent Study for Ischemic Stroke Therapy) trial is an international, multicenter, 1:1 randomized, parallel group trial that enrolled patients from 27 sites (January 2009-June 2012) with last follow-up in May 2013. INTERVENTIONS: Patients (N = 112) were randomized to receive balloon-expandable stent plus medical therapy (stent group; n = 59) or medical therapy alone (medical group; n = 53). PRIMARY OUTCOME MEASURE: a composite of stroke in the same territory within 12 months of randomization or hard transient ischemic attack (TIA) in the same territory day 2 through month 12 postrandomization. A hard TIA was defined as a transient episode of neurological dysfunction caused by focal brain or retinal ischemia lasting at least 10 minutes but resolving within 24 hours. Primary safety measure: a composite of any stroke, death, or intracranial hemorrhage within 30 days of randomization and any hard TIA between days 2 and 30 of randomization. Disability was measured with the modified Rankin Scale and general health status with the EuroQol-5D, both through month 12. RESULTS: Enrollment was halted by the sponsor after negative results from another trial prompted an early analysis of outcomes, which suggested futility after 112 patients of a planned sample size of 250 were enrolled. The 30-day primary safety end point occurred in more patients in the stent group (14/58; 24.1% [95% CI, 13.9%-37.2%]) vs the medical group (5/53; 9.4% [95% CI, 3.1%-20.7%]) (P = .05). Intracranial hemorrhage within 30 days occurred in more patients in the stent group (5/58; 8.6% [95% CI, 2.9%-19.0%]) vs none in the medical group (95% CI, 0%-5.5%) (P = .06). The 1-year primary outcome of stroke or hard TIA occurred in more patients in the stent group (21/58; 36.2% [95% CI, 24.0-49.9]) vs the medical group (8/53; 15.1% [95% CI, 6.7-27.6]) (P = .02). Worsening of baseline disability score (modified Rankin Scale) occurred in more patients in the stent group (14/58; 24.1% [95% CI, 13.9%-37.2%]) vs the medical group (6/53; 11.3% [95% CI, 4.3%-23.0%]) (P = .09).The EuroQol-5D showed no difference in any of the 5 dimensions between groups at 12-month follow-up. CONCLUSIONS AND RELEVANCE: Among patients with symptomatic intracranial arterial stenosis, the use of a balloon-expandable stent compared with medical therapy resulted in an increased 12-month risk of added stroke or TIA in the same territory, and increased 30-day risk of any stroke or TIA. These findings do not support the use of a balloon-expandable stent for patients with symptomatic intracranial arterial stenosis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00816166.

Design of the Vitesse Intracranial Stent Study for Ischemic Therapy (VISSIT) trial in symptomatic intracranial stenosis.

BACKGROUND: Patients with high-grade symptomatic intracranial stenosis (≥ 70%) have an increased risk of recurrent stroke despite medical treatment with antiplatelet or anticoagulant therapy. Intracranial stenting has been proposed as a viable treatment option for this high-risk patient population; however, evaluation of this therapy in randomized multicenter trials is needed. In this article, we present the design and methods of the Vitesse Intracranial Stent Study for Ischemic Therapy (VISSIT) trial for symptomatic intracranial stenosis. METHODS: The VISSIT trial is a randomized control study designed to evaluate the safety, probable benefit, and effectiveness of the PHAROS Vitesse neurovascular balloon-expandable stent system plus medical therapy versus medical therapy alone in patients with cerebral or retinal ischemia due to neurovascular stenosis (≥ 70%) for preventing the primary composite end point: stroke in the same territory (distal to the target lesion) as the presenting event within 12 months of randomization or hard transient ischemic attack in the same territory (distal to the target lesion) as the presenting event from day 2 through month 12 postrandomization. RESULTS: Enrollment began in February 2009 and was halted in January 2012 with 112 subjects enrolled into the study. Clinical follow-up will continue for the planned period of 12 months postrandomization. CONCLUSIONS: The VISSIT trial may provide valuable insight into the use of balloon-expandable intracranial stent as a treatment option for high-risk patients. Lessons learned from this trial may better guide future clinical trial design on best patient selection, stenting techniques, and periprocedural management.

A new technology for detecting cerebral blood flow: a comparative study of ultrasound tagged NIRS and 133Xe-SPECT.

There is a need for real-time non-invasive, continuous monitoring of cerebral blood flow (CBF) during surgery, in intensive care units and clinical research. We investigated a new non-invasive hybrid technology employing ultrasound tagged near infrared spectroscopy (UT-NIRS) that may estimate changes in CBF using a cerebral blood flow index (CFI). Changes over time for UT-NIRS CFI and 133Xenon single photon emission computer tomography (133Xe-SPECT) CBF data were assessed in 10 healthy volunteers after an intravenous bolus of acetazolamide. UT-NIRS CFI was measured continuously and SPECT CBF was measured at baseline, 15 and 60 min after acetazolamide. We found significant changes over time in CFI by UT-NIRS and CBF by SPECT after acetazolamide (P ≤ 0.001). Post hoc tests showed a significant increase in CFI (P = 0.011) and SPECT CBF (P < 0.001) at 15 min after acetazolamide injection. There was a significant correlation between CFI and SPECT CBF values (r = 0.67 and P ≤ 0.033) at 15 min, but not at 60 min (P ≥ 0.777). UT-NIRS detected an increase in CFI following an acetazolamide bolus, which correlated with CBF measured with 133Xe-SPECT. This study demonstrates that UT-NIRS technology may be a promising new technique for non-invasive and real-time bedside CBF monitoring.

Monitoring of volume status after subarachnoid hemorrhage.

Hypovolemia is common after subarachnoid hemorrhage, and fluid imbalance negatively affects clinical outcome. Standard bedside volume measures fail to adequately assess fluid status after subarachnoid hemorrhage. An electronic literature search of original research studies evaluating fluid status after subarachnoid hemorrhage was conducted for English language articles published through October 2010. Sixteen articles were included in this review, with seven articles produced by two research groups. These studies highlight that fluid status is often affected and difficult to assess after subarachnoid hemorrhage. Both non-invasive and invasive monitors may be used to more accurately define volume status.

Ondine's curse with accompanying trigeminal and glossopharyngeal neuralgia secondary to medullary telangiectasia.

BACKGROUND: Central hypoventilation syndrome ("Ondine's Curse") is an infrequent disorder that can lead to serious acute or chronic health consequences. This syndrome, especially in adults, is rare, and even less frequent in the absence of clear pathogenic lesions on MRI. In addition, we are not aware of any previously reported cases with associated cranial nerve neuralgias. METHODS: We describe a patient with baseline trigeminal and glossopharyngeal neuralgia, admitted with episodes of severe hypoventilatory failure of central origin, consistent with "Ondine's Curse". After evaluation, she was found to have a medullary capillary telangiectasia, thought to be the causative lesion, and which could explain her complete neurologic and hypoventilatory syndrome. The patient was treated with placement of a diaphragmatic pacing system, which has been effective thus far. RESULTS: This case illustrates the need for investigation of centrally mediated apnea, especially when co-occurring cranial nerve neuralgia is present and cardiopulmonary evaluation is negative. It provides an example of capillary telangiectasia as the causative lesion, one that to our knowledge has not been reported before. CONCLUSIONS: Placement of a diaphragmatic pacing system was warranted and became lifesaving as the patient was deemed to be severely incapacitated by chronic ventilatory insufficiency.

Predictors of rehemorrhage after treatment of ruptured intracranial aneurysms: the Cerebral Aneurysm Rerupture After Treatment (CARAT) study.

BACKGROUND AND PURPOSE: The primary purpose of intracranial aneurysm treatment is to prevent rupture. Risk factors for rupture after aneurysm treatment have not been clearly established, and the need to completely occlude aneurysms is debated. METHODS: The Cerebral Aneurysm Rerupture After Treatment (CARAT) study is an ambidirectional cohort study of all patients with ruptured intracranial aneurysms treated with coil embolization or surgical clipping at 9 high-volume centers in the United States from 1996 to 1998. All subjects were followed through 2005, and all potential reruptures were adjudicated by a panel of 3 specialists without knowledge of the initial treatment or aneurysm characteristics. Degree of aneurysm occlusion post-treatment was evaluated as a predictor of nonprocedural rerupture in univariate Kaplan-Meier analysis (log-rank test) and in a Cox proportional-hazards model after adjustment for potential confounders and censoring at time of retreatment. RESULTS: Among 1001 patients during a mean of 4.0 years follow-up, there were 19 postprocedural reruptures; median time to rerupture was 3 days and 58% led to death. The degree of aneurysm occlusion after treatment was strongly associated with risk of rerupture (overall risk: 1.1% for complete occlusion, 2.9% for 91% to 99% occlusion, 5.9% for 70% to 90%, 17.6% for <70%; P<0.0001 in univariate and multivariable analysis). Overall risk of rerupture tended to be greater after coil embolization compared with surgical clipping (3.4% versus 1.3%; P=0.092), but the difference did not persist after adjustment (P=0.83). CONCLUSIONS: Degree of aneurysm occlusion after the initial treatment is a strong predictor of the risk of subsequent rupture in patients presenting with subarachnoid hemorrhage, which justifies attempts to completely occlude aneurysms.

Head computed tomography findings predict short-term stroke risk after transient ischemic attack.

BACKGROUND AND PURPOSE: Current guidelines recommend the use of head CT in the evaluation of patients with transient ischemic attack (TIA), but data supporting its value are sparse. METHODS: Patients who presented to 1 of 16 emergency departments of a large Northern California health maintenance organization and received a diagnosis of TIA from November 1997 through February 1998 were enrolled and followed up for 90 days. Clinical, demographic, and outcome data were obtained from computerized databases and medical records. Physicians blinded to patient characteristics and outcomes abstracted head CT findings from radiology reports. Abstracted findings included evidence of old or new infarct, periventricular white-matter disease, cerebral atrophy, cerebral vascular calcification, and nonischemic lesions. RESULTS: Head CT was performed in 67% of eligible patients (n=322) diagnosed with TIA. Evidence of a new infarct was seen on head CT in 13 patients (4%). A nonischemic cause of TIA symptoms was found in 4 patients (1.2%). During follow-up, 10.9% of TIA patients experienced subsequent stroke. After adjustment for confounders, risk for stroke during follow-up was significantly higher in those with a new infarct on head CT compared with others with TIA (odds ratio, 4.06; 95% confidence interval, 1.16 to 14.14; P=0.028). Old infarction, periventricular white-matter disease, cerebral atrophy, and cerebral vascular calcification were not predictors of subsequent risk of stroke. CONCLUSIONS: Evidence of a new infarct on head CT in patients presenting with TIA is associated with increased short-term risk for stroke. Head CT appears to have prognostic value in patients with TIA and, for this reason alone, may be justified in their evaluation.

Association between subarachnoid hemorrhage outcomes and number of cases treated at California hospitals.

BACKGROUND AND PURPOSE: Studies of several complex medical conditions have shown that outcomes are better at hospitals that treat more cases. We tested the hypothesis that patients with subarachnoid hemorrhage treated at high-volume hospitals have better outcomes. METHODS: Using a database of all admissions to nonfederal hospitals in California from 1990 to 1999, we obtained discharge abstracts for patients with a primary diagnosis of subarachnoid hemorrhage who were admitted through the emergency department. Hospital volume, defined as the average number of subarachnoid hemorrhage cases admitted each year, was divided into quartiles. Rates of mortality, adverse outcomes (death or discharge to long-term care), length of stay, and hospital charges were computed by univariate analysis and by multivariable general estimating equations, with adjustment for demographic and admission characteristics. RESULTS: A total of 12 804 patients were admitted for subarachnoid hemorrhage through the emergency departments of 390 hospitals. Hospital volumes varied from 0 to 8 cases per year in the first quartile to 19 to 70 cases per year in the fourth quartile. The mortality rate in the lowest volume quartile (49%) was larger than that in the highest volume quartile (32%, P<0.001). In multivariable analysis, the difference persisted (odds ratio comparing highest with lowest volume quartiles 0.57, 95% CI 0.48 to 0.67; P<0.001). At higher volume hospitals, lengths of stay were longer, and hospital charges were greater in univariate and multivariable models (all P<0.001). Only 4.8% of those admitted to hospitals in the lowest volume quartile were transferred to hospitals in the highest quartile. CONCLUSIONS: In this study of discharge abstracts in California, hospitals that treated more cases of subarachnoid hemorrhage had substantially lower rates of in-hospital mortality. Few patients with subarachnoid hemorrhage are being transferred to high-volume centers.

Characteristics of brain arteriovenous malformations with coexisting aneurysms: a comparison of two referral centers.

BACKGROUND: Patients harboring a brain arteriovenous malformation (BAVM) often have coexisting arterial aneurysms. Experts have argued about the clinical significance of these aneurysms, which may be important for risk stratification in patient management and clinical trials. We studied the association between coexisting aneurysms and initial presentation with intracranial hemorrhage (ICH) in patients with BAVM evaluated at two tertiary-care centers. METHODS: Demographic and clinical data were collected from a prospective series of patients evaluated for BAVM at the University of California, San Francisco (UCSF; n=82), and Columbia-Presbyterian Medical Center, New York (CPMC; n=254). Using multivariate logistic regression, we examined the independent association between ICH presentation and the presence of a coexisting aneurysm, and compared the association at the two hospitals. RESULTS: Aneurysms were associated with 28 BAVMs at UCSF (34%) and 74 at CPMC (29%; P=0.39). Initial presentation with ICH was associated with the presence of a coexisting aneurysm at CPMC (odds ratio 1.8, 95% confidence interval 1.0 to 3.0, P=0.044). The opposite trend was observed at UCSF (odds ratio 0.4, 95% confidence interval 0.2 to 1.1, P=0.085). We observed an interaction by site involving the association between ICH presentation and aneurysm (P=0.016). CONCLUSION: Although many BAVM characteristics were similar at the referral centers studied, the association between initial presentation with ICH and coexisting aneurysms was not. This heterogeneity between populations undermines the validity of inferences on the role of aneurysms from any single referral series, and emphasizes the complexity in creating BAVM risk-stratification models that incorporate aneurysms.

Electrocardiographic findings predict short-term cardiac morbidity after transient ischemic attack.

BACKGROUND: Current guidelines recommend the use of electrocardiography (ECG) in the evaluation of transient ischemic attack (TIA), but the data supporting its value in acute management are sparse. OBJECTIVE: To determine whether ECG findings are useful as independent predictors of short-term cardiac or neurologic complications after TIA. METHODS: We included patients who presented to 1 of 16 emergency departments of a health maintenance organization in northern California and received a diagnosis of TIA from March 1, 1997, through February 28, 1998, for a 90-day follow-up. A cardiac event was defined as a hospitalization or a death due to myocardial infarction, ventricular arrhythmia, heart failure, or unstable angina. RESULTS: Among the 1327 patients with TIA for whom ECG findings were available for diagnostic coding, cardiac events occurred in 2.9%, strokes in 10.9%, recurrent TIAs in 13.7%, and deaths in 2.6% during 90-day follow-up. The ECG findings disclosed a new diagnosis of atrial fibrillation in 28 (2.3%) of the 1200 patients with no history of this condition. The 90-day risk for a cardiac event was greater in those who had any abnormal ECG findings (4.2% vs 0.6%; P<.001). This association remained significant after adjustment for medical history and examination findings (odds ratio, 6.9; 95% confidence interval, 1.6-29.5; P =.009). Left ventricular hypertrophy, atrial fibrillation, and atrioventricular conduction abnormalities were each independently associated with more than doubling of the risk. The ECG abnormalities were not associated with risk for stroke or death. CONCLUSIONS: Short-term cardiac morbidity is substantial after TIA. Electrocardiographic findings disclose new atrial fibrillation in a significant portion of patients with TIA and can identify a group of patients at a substantially higher risk for short-term cardiac events.

The learning curve for coil embolization of unruptured intracranial aneurysms.

BACKGROUND AND PURPOSE: Several studies have shown that procedural outcomes are better at high-volume institutions, possibly due to greater physician experience (learning) or practice (repetition). Our purpose was to determine whether outcomes for coil embolization improved with the experience of the practitioner, after adjusting for the perceived risk of treatment. METHODS: We identified all unruptured aneurysms treated with coil embolization at our institution from 1990 through 1997. A clinical nurse specialist abstracted the characteristics from cases that met the entry criteria. Two neurologists independently determined the complications by using definitions established a priori. The influence of experience of the treating-physician on complications was evaluated with univariate and multivariable logistic regression analyses. RESULTS: Sixteen complications occurred in 94 patients (17%) treated with coil embolization. Complications occurred in 53% of the first five cases that each of three physicians treated, and in 10% of later cases (P <.001). After an adjustment for all other predictors, including physician assessment of the risk of the procedure, the odds of a complication decreased with increasing physician experience (odds ratio, 0.69 for every five cases treated; 95% confidence interval: 0.50, 0.96; P=.03). CONCLUSION: The risk of complications with coil embolization of unruptured aneurysms appears to decrease dramatically with physician experience. Because the physicians in this study were highly experienced in other endovascular techniques at study onset, the rate of learning may not be generalizable to other centers.

Angioplasty for intracranial symptomatic vertebrobasilar ischemia.

OBJECTIVE: Although anterior circulation disease has both medical and surgical treatment options, management of vertebrobasilar disease has predominantly had only medical options. Some patients remain symptomatic despite medical treatment, and angioplasty has been demonstrated to relieve critical stenoses. However, the elative safety and effectiveness of medical and surgical treatments is not clearly known. This report reviews the clinical characteristics, indications, and procedural risks of intracranial angioplasty in a series of patients with symptomatic posterior circulation ischemia. METHODS: All patients undergoing angioplasty for critical intracranial vertebral or basilar artery stenosis at the University of California at San Francisco Medical Center between June 1986 and July 1999 were included in a retrospective record review. Clinical features and procedural complications were recorded. RESULTS: Angioplasty was performed on 25 vessel lesions in 25 patients in whom medical therapy had failed. The patients ranged in age from 50 to 87 years. Of the 25 stenoses, 10 were intracranial vertebral, 9 vertebrobasilar junction, and 6 basilar in location. Angioplasty was effective in reducing the degree of stenosis by more than 40% in all 25 vessels. The overall risk of stroke or death was 28%, and the risk of disabling stroke or death was 16%. CONCLUSION: Intracranial posterior circulation angioplasty is effective in the reduction of stenosis and can be performed with relative safety. Angioplasty can be considered as a treatment option in patients with recurrent ischemic symptoms despite medical therapy.

Surgery for unruptured aneurysms.

OBJECT: Repair of unruptured aneurysms is a reasonable course of action if their expected natural history is worse than the predicted risks of treatment. The purpose of this study was to examine the presenting symptoms of unruptured aneurysms and to test the hypothesis that unruptured intracranial aneurysms can be repaired without significant functional worsening. A second hypothesis was also examined-that is, that the experience of the surgeon, the aneurysm size, and the patient age can be used to predict functional outcome. METHODS: Consecutive patients who underwent repair of an onruptured intracranial aneurysm at a single institution between 1980 and 1998 were studied. Clinical and radiographic data were collected in all patients. Their modified Rankin Scale (mRS) score was determined before treatment (baseline), at 6 weeks, and at 6 months. The primary endpoint for analysis was the mRS score. Four hundred forty-nine aneurysms were repaired in 366 patients by 10 surgeons. The mean size of the primary lesion repaired was 14.6 +/- 10.4 mm and 27% were judged to be symptomatic. Aneurysm treatment involved either microsurgical clipping (78%), wrapping (4%), trapping with or without bypass (5%), hunterian ligation with or without bypass (9%), or other methods (4%). The mRS scores at 6 weeks were worse than at baseline (p < 0.0001), but there was no significant difference between the baseline and 6-month mRS score. At 6 months, 94% of patients showed no significant functional worsening as a result of treatment. The number of aneurysms treated by a specific surgeon was a strong predictor of better functional outcome (r = 0.99, p = 0.05). Increasing patient age (r = 0.16, p = 0.003) and increasing aneurysm size (r = 0.15, p = 0.004) were predictors of worsened functional outcome. CONCLUSIONS: Many unruptured aneurysms produce symptoms. Unruptured intracranial aneurysms can be treated without significant permanent functional worsening. The surgeon's experience, aneurysm size, and patient age are predictors of functional outcome.

Safety and pharmacokinetics of sodium nitrite in patients with subarachnoid hemorrhage: a phase IIa study.

OBJECT: Intravenous sodium nitrite has been shown to prevent and reverse cerebral vasospasm in a primate model of subarachnoid hemorrhage (SAH). The present Phase IIA dose-escalation study of sodium nitrite was conducted to determine the compound's safety in humans with aneurysmal SAH and to establish its pharmacokinetics during a 14-day infusion. Methods In 18 patients (3 cohorts of 6 patients each) with SAH from a ruptured cerebral aneurysm, nitrite (3 patients) or saline (3 patients) was infused. Sodium nitrite and saline were delivered intravenously for 14 days, and a dose-escalation scheme was used for the nitrite, with a maximum dose of 64 nmol/kg/min. Sodium nitrite blood levels were frequently sampled and measured using mass spectroscopy, and blood methemoglobin levels were continuously monitored using a pulse oximeter. RESULTS: In the 14-day infusions in critically ill patients with SAH, there was no toxicity or systemic hypotension, and blood methemoglobin levels remained at 3.3% or less in all patients. Nitrite levels increased rapidly during intravenous infusion and reached steady-state levels by 12 hours after the start of infusion on Day 1. The nitrite plasma half-life was less than 1 hour across all dose levels evaluated after stopping nitrite infusions on Day 14. CONCLUSIONS: Previous preclinical investigations of sodium nitrite for the prevention and reversal of vasospasm in a primate model of SAH were effective using doses similar to the highest dose examined in the current study (64 nmol/kg/min). Results of the current study suggest that safe and potentially therapeutic levels of nitrite can be achieved and sustained in critically ill patients after SAH from a ruptured cerebral aneurysm.

The problem with asymptomatic cerebral embolic complications in vascular procedures: what if they are not asymptomatic?

Cerebral embolic events related to carotid and cardiac disease have been known for decades. Recently, cerebral embolic events have become a focus of clinical importance as complications of vascular procedures. Further, the development of new technologies and procedures has increased the overall clinical significance. Although the relative safety of these procedures is usually defined by acute stroke risk, it is also becoming clear that far more subclinical events are occurring. Recent reports provided substantial evidence of memory loss, cognitive decline, and dementia related to these so-called silent infarcts. Literature reports of magnetic resonance imaging events lead to an estimate of as many as 600,000 patients with new brain injury each year in the United States alone. Given the magnitude of the numbers involved, the impact of accelerated cognitive loss and premature senescence in a vulnerable at-risk population could well be significant.

A comparison of risk factors for recurrent TIA and stroke in patients diagnosed with TIA.

BACKGROUND: Some spells consistent with TIA may be benign, such as those produced by migraine or migraine accompaniments in the elderly. Distinguishing these from embolic or thrombotic events may be difficult. METHODS: Emergency department physicians identified patients who presented with a presumed TIA at one of 16 hospitals in Northern California from March 1997 through February 1998. Recurrent TIAs and strokes were recorded for 90 days afterwards. RESULTS: Of 1,707 patients in whom TIA had been diagnosed in the emergency department, 191 (11.2%) had a recurrent TIA and 180 (10.5%) had a stroke during 90-day followup. Independent risk factors for recurrent TIA were age >60 years (odds ratio 1.9; 95% CI 1.2 to 2.9; p = 0.003), history of multiple TIAs (odds ratio 2.9; 2.1 to 4.0; p < 0.001), duration of spell 10 minutes, diabetes, weakness, and speech impairment. Among the 30 patients with isolated sensory symptoms lasting

The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation.

BACKGROUND: Nonrheumatic atrial fibrillation increases the risk of stroke, presumably from atrial thromboemboli. There is uncertainty about the efficacy and risks of long-term warfarin therapy to prevent stroke. METHODS: We conducted an unblinded, randomized, controlled trial of long-term, low-dose warfarin therapy (target prothrombin-time ratio, 1.2 to 1.5) in patients with nonrheumatic atrial fibrillation. The control group was not given warfarin but could choose to take aspirin. RESULTS: A total of 420 patients entered the trial (212 in the warfarin group and 208 in the control group) and were followed for an average of 2.2 years. Prothrombin times in the warfarin group were in the target range 83 percent of the time. Only 10 percent of the patients assigned to receive warfarin discontinued the drug permanently. There were 2 strokes in the warfarin group (incidence, 0.41 percent per year) as compared with 13 strokes in the control group (incidence, 2.98 percent per year), for a reduction of 86 percent in the risk of stroke (warfarin:control incidence ratio = 0.14; 95 percent confidence interval, 0.04 to 0.49; P = 0.0022). There were 37 deaths altogether. The death rate was markedly lower in the warfarin group than in the control group: 2.25 percent as compared with 5.97 percent per year, for an incidence ratio of 0.38 (95 percent confidence interval, 0.17 to 0.82; P = 0.005). There was one fatal hemorrhage in each group. The frequency of bleeding events that led to hospitalization or transfusion was essentially the same in both groups. The warfarin group had a higher rate of minor hemorrhage than the control group (38 vs. 21 patients). CONCLUSIONS: Long-term low-dose warfarin therapy is highly effective in preventing stroke in patients with non-rheumatic atrial fibrillation, and can be quite safe with careful monitoring.