Bleeding complications associated with warfarin treatment in ischemic stroke patients with atrial fibrillation: a population-based cohort study.

BACKGROUND: Bleeding events are the major obstacle to the widespread use of warfarin for secondary stroke prevention. Previous studies have not examined the use of risk stratification scores to estimate lifetime bleeding risk associated with warfarin treatment in a population-based setting. The purpose of this study is to determine the lifetime risk of bleeding events in ischemic stroke patients with atrial fibrillation (AF) undergoing warfarin treatment in a population-based cohort and to evaluate the use of bleeding risk scores to identify patients at high risk for lifetime bleeding events. METHODS: The resources of the Rochester Epidemiology Project Medical Linkage System were used to identify acute ischemic stroke patients with AF undergoing warfarin treatment for secondary stroke prevention from 1980 to 1994. Medical information for patients seen at Mayo Clinic and at Olmsted Medical Center was used to retrospectively risk-stratify stroke patients according to bleeding risk scores (including the HAS-BLED and HEMORR2HAGES scores) before warfarin initiation. These scores were reassessed 1 and 5 years later and compared with lifetime bleeding events. RESULTS: One hundred patients (mean age, 79.3 years; 68% women) were studied. Ninety-nine patients were observed until death. Major bleeding events occurred in 41 patients at a median of 19 months after warfarin initiation. Patients with a history of hemorrhage before warfarin treatment were more likely to develop major hemorrhage (15% versus 3%, P = .04). Patients with baseline HAS-BLED scores of 2 or more had a higher lifetime risk of major bleeding events compared with those with scores of 1 or less (53% versus 7%, P < .01), whereas those with HEMORR2HAGES scores of 2 or more had a higher lifetime risk of major bleeding events compared with those with scores of 1 or less (52% versus 16%, P = .03). Patients with an increase in the HAS-BLED and HEMORR2HAGES scores during follow-up had a higher remaining lifetime risk of major bleeding events compared with those with no change. CONCLUSIONS: Our findings indicate high lifetime bleeding risk associated with warfarin treatment for patients with ischemic stroke. Risk stratification scores are useful to identify patients at high risk of developing bleeding complications and should be recalculated at regular intervals to evaluate the bleeding risk in anticoagulated patients with ischemic stroke.

Percutaneous device closure of patent foramen ovale in patients with presumed cryptogenic stroke or transient ischemic attack: the Mayo Clinic experience.

OBJECTIVES: We sought to determine safety, recurrence rates, and novel risk factors for recurrence in patients with cryptogenic stroke/transient ischemic attack (TIA) after patent foramen ovale closure. BACKGROUND: Patent foramen ovale closure in patients with cryptogenic stroke/TIA remains highly controversial. There are limited data on long-term recurrence rates and their predictors in these patients. METHODS: The records of all patients who underwent patent foramen ovale device closure between December 2001 and June 2006 were reviewed. Patients were seen for clinical follow-up at 3 months then followed annually via telephone. Primary end points were recurrent stroke/TIA. Kaplan-Meier methods were used to estimate recurrent event rates. Cox regression analysis was used to identify risk factors for recurrences. RESULTS: There were 352 patients with cryptogenic stroke (n = 225) or TIA (n = 118) with a mean age of 53.4 years. The procedural complication rate was 3.4%. Recurrent events occurred in 8 patients: 7 strokes and 2 TIA, 1 patient had 2 recurrent strokes. The recurrence rate was 0.6% and 2.1% for stroke and 0.3% and 0.7% for TIA at 1 and 4 years, respectively. The combined end point of recurrent stroke/TIA occurred at a rate of 0.9% and 2.8% at 1 and 4 years, respectively. Risk factors for recurrences were elevated pulmonary artery pressure (hazard ratio [HR]: 1.12, p = 0.009), elevated right ventricular pressure (HR: 1.09, p = 0.04), factor V Leiden mutation (HR: 7.42, p = 0.014), and protein S deficiency (HR: 12.2, p = 0.002). Residual shunt and atrial septal aneurysm were not associated with recurrences. CONCLUSIONS: Patent foramen ovale device closure is safe and is associated with a low recurrence of stroke/TIA. Factors associated with recurrence are thrombophilia and elevated intracardiac pressures.

Increased left atrial volume index: potent biomarker for first-ever ischemic stroke.

OBJECTIVE: To establish the incidence and correlation of increased left atrial volume index (LAVI) in patients with first-ever ischemic stroke. PARTICIPANTS AND METHODS: Using our institution's epidemiological database, we defined a cohort of 432 patients (cases) who underwent transthoracic echocardiography within 60 days of first ischemic stroke between January 1, 1985, and December 31, 1994. Left atrial volume was measured with the biplane area-length method, indexed to body surface area (LAVI, expressed as mL/m(2)). The control group consisted of 416 community residents who underwent transthoracic echocardiography as participants in a stroke risk factor study. Increased LAVI was defined as 28 mL/m(2) or higher. Survival in patients was compared with expected survival among white Minnesotans and was further modeled as a function of age, sex, LAVI, and clinical risk factors. RESULTS: Among the included 306 patients, 230 (75%) had increased LAVI (mean+/-SD, 49+/-21 mL/m(2)). Patients with increased LAVI were older than those with normal LAVI (mean+/-SD age, 76+/-11 vs 71+/-13 years; P=.003) and had more cardiovascular risk factors (mean+/-SD number, 1.8+/-0.07 vs 1.3+/-0.89; P<.001). Mean LAVI was higher in cases than in age- and sex-matched controls (P<.001). At 5-year follow-up, cases showed excess mortality compared with age-matched controls (P=.001). After variables were adjusted for age, sex, and clinical risk factors, LAVI was independently associated with mortality. CONCLUSION: A useful index for prediction of adverse cardiovascular events, LAVI might also predict first ischemic stroke and subsequent mortality.

Population-based study of the relationship between patent foramen ovale and cerebrovascular ischemic events.

OBJECTIVE: To determine whether patent foramen ovale (PFO) is a risk factor for a cryptogenic cerebrovascular ischemic event (CIE). METHODS: This case-control study of 1072 residents of Olmsted County, Minnesota, who underwent contrast transesophageal echocardiography between 1993 and 1997 included 519 controls without CIE randomly selected from the population, 262 controls without CIE referred for transesophageal echocardiography because of cardiac disease, 158 cases with incident CIE of obvious cause (noncryptogenic), and 133 cases with incident CIE of uncertain cause (cryptogenic). RESULTS: Large PFOs were detected in 108 randomly selected controls (20.8%), 22 referred controls (8.4%), 17 noncryptogenic CIE cases (10.8%), and 22 cryptogenic CIE cases (16.5%). After adjustment for age, sex, hypertension, smoking, atrial fibrillation, ischemic heart disease, and number of contrast injections, the presence of a large PFO was not significantly associated with group status (P=.07). Using the odds of the presence of large PFO in the randomly selected controls as the reference, the odds ratio (95% confidence interval) of the presence of large PFO was 0.47 (0.26-0.87) for referred controls, 0.69 (0.37-1.29) for noncryptogenic CIE cases, and 1.10 (0.63-1.90) for cryptogenic CIE cases. CONCLUSIONS: Patent foramen ovale is not a risk factor for cryptogenic ischemic stroke or transient ischemic attack in the general population. The PFO's importance in the genesis of cryptogenic CIE may have been overestimated in previous studies because of selective referral of cases and underascertainment of PFO among comparison groups of patients referred for echocardiography for clinical indications other than cryptogenic CIE.

Population-based study of the relationship between atherosclerotic aortic debris and cerebrovascular ischemic events.

OBJECTIVE: To assess the validity of the suggestion that protruding atheromatous material in the thoracic aorta is an important cause of cerebrovascular ischemic events (CIEs) (ie, transient ischemic attack or ischemic stroke). METHODS: This case-control study of Olmsted County, Minnesota, residents who underwent transesophageal echocardiography (TEE) from 1993 to 1997 included controls without CIE randomly selected from the population, controls without CIE referred for TEE because of cardiac disease, cases with incident CIE of obvious cause (noncryptogenic), and cases with incident CIE of uncertain cause (cryptogenic). RESULTS: Of the 1135 subjects, 520 were randomly selected controls without CIE, 329 were controls without CIE referred for TEE, 159 were noncryptogenic CIE cases, and 127 were cryptogenic CIE cases. Complex atherosclerotic aortic debris in ascending and transverse segments of the arch was detected in 8 randomly selected controls (1.5%), 13 referred controls (4.0%), and 15 noncryptogenic (9.4%) and 4 cryptogenic (3.1%) CIE cases. After adjusting for age, sex, hypertension, smoking, atrial fibrillation, valvular heart disease, congestive heart failure, and atherosclerosis other than in the thoracic aorta, complex atherosclerotic aortic debris was not significantly associated with group status. With randomly selected controls as the referent group, odds ratios (95% confidence intervals) were 1.72 (0.61-4.87) for referred controls, 3.16 (1.18-8.51) for noncryptogenic CIE cases, and 1.39 (0.39-4.88) for cryptogenic CIE cases. CONCLUSIONS: Complex atherosclerotic aortic debris is not a risk factor for cryptogenic ischemic stroke or transient ischemic attack but is a marker for generalized atherosclerosis and well-established atherosclerotic and cardioembolic mechanisms of cerebral ischemia. Embolization from the aorta is not a common mechanism of ischemic stroke or transient ischemic attack.

Patent foramen ovale: innocent or guilty? Evidence from a prospective population-based study.

OBJECTIVES: We sought to determine the association between patent foramen ovale (PFO), atrial septal aneurysm (ASA), and stroke prospectively in a unselected population sample. BACKGROUND: The disputed relationship between PFO and stroke reflects methodologic weaknesses in studies using invalid controls, unblinded transesophageal echocardiography examinations, and data that are unadjusted for age or comorbidity. METHODS: The use of transesophageal echocardiography to identify PFO was performed by a single echocardiographer using standardized definitions in 585 randomly sampled, Olmsted County (Minnesota) subjects age 45 years or older participating in the Stroke Prevention: Assessment of Risk in a Community (SPARC) study. RESULTS: A PFO was identified in 140 (24.3%) subjects and ASA in 11 (1.9%) subjects. Of the 140 subjects with PFO, 6 (4.3%) had an ASA; of the 437 subjects without PFO, 5 had an ASA (1.1%, two-sided Fisher exact test, p = 0.028). During a median follow-up of 5.1 years, cerebrovascular events (cerebrovascular disease-related death, ischemic stroke, transient ischemic attack) occurred in 41 subjects. After adjustment for age and comorbidity, PFO was not a significant independent predictor of stroke (hazard ratio 1.46, 95% confidence interval 0.74 to 2.88, p = 0.28). The risk of a cerebrovascular event among subjects with ASA was nearly four times higher than that in those without ASA (hazard ratio 3.72, 95% confidence interval 0.88 to 15.71, p = 0.074). CONCLUSIONS: These prospective population-based data suggest that, after correction for age and comorbidity, PFO is not an independent risk factor for future cerebrovascular events in the general population. A larger study is required to test the putative stroke risk associated with ASA.

Outcomes among valvular heart disease patients experiencing ischemic stroke or transient ischemic attack in Olmsted County, Minnesota.

OBJECTIVE: To estimate the rates and predictors of survival and recurrence among residents of Olmsted County, Minnesota, who received an Initial diagnosis based on 2-dimensional color Doppler echocardiography of moderate or severe mitral or aortic stenosis or regurgitation and who experienced a first ischemic stroke, transient ischemic attack (TIA), or amaurosis fugax. PATIENTS AND METHODS: At the Mayo Clinic in Rochester, Minn, we used the resources of the Rochester Epidemiology Project to identify Individuals who met the criteria for inclusion in the study and to verify exclusion criteria. The study included all residents of Olmsted County, Minnesota, who experienced a first Ischemic stroke, TIA, or amaurosis fugax within 30 days of or subsequent to receiving a first-time 2-dimensional color Doppler echocardlography-based diagnosis of moderate or severe mitral or aortic stenosis or regurgitation between January 1, 1985, and December 31, 1992. The Kaplan-Meier product-limit method was used to estimate the rates of subsequent stroke and death after the ischemic stroke, TIA, or amaurosis fugax. The Cox proportional hazards model was used to assess the effect of several potential risk factors on subsequent stroke occurrence and death. RESULTS: For the 125 patients in the study, the Kaplan-Meier estimates of the risk of death and the risk of stroke at 2-year follow-up were 38.6% (95% confidence interval [CI], 29.9%-47.5%) and 18.5% (95% CI, 10.0%-27.0%), respectively. Compared with the general population, death rates were significantly Increased (standardized mortality ratio = 1.75; 95% CI, 1.38-2.19; P < .001) but rates of subsequent stroke occurrence were not (standardized morbidity ratio = 1.20; 95% CI, 0.75-1.84; P = .40). After adjustment for age, sex, and cardiac comorbidity, neither the type nor severity of valvular heart disease was an independent determinant of survival or subsequent stroke occurrence. CONCLUSIONS: Patients with mitral or aortic valvular heart disease who experience Ischemic stroke, TIA, or amaurosis fugax have Increased rates of death, but not recurrent stroke, compared with expected rates. Other cardiovascular risk factors are more important determinants of survival In these patients than the type or echocardiographic severity of the valvular heart disease.

Left atrial volume in the prediction of first ischemic stroke in an elderly cohort without atrial fibrillation.

OBJECTIVE: To determine the clinical importance of left atrial (LA) volume in the prediction of first ischemic stroke. PATIENTS AND METHODS: This retrospective cohort study included randomly selected residents of Olmsted County, Minnesota, aged 65 years or older, who had undergone transthoracic echocardiography at least once at the Mayo Clinic in Rochester, Minn, between January 1, 1990, and December 31, 1998, were in sinus rhythm, and had no history of stroke, transient ischemic attack, atrial fibrillation, or valvular heart disease. Patients were monitored through medical records for first ischemic stroke or death. RESULTS: Of 1554 residents (59% women) aged 75+/-7 years, 92 (6%) had experienced at least 1 ischemic stroke over 4.3+/-2.7 years (incident stroke rate, 1.4 per 100 person-years). Left atrial volume of 32 mL/m2 or greater (hazard ratio [HR], 1.63; confidence interval [CI], 1.08-2.46) was independent of age (HR, 1.04; CI, 1.02-1.07), diabetes (HR, 1.91; CI, 1.07-3.41), myocardial infarction (HR, 1.64; CI, 1.01-2.64), and hyperlipidemia (HR, 1.55; CI, 1.01-2.37) for the prediction of first ischemic stroke. When quartiles of LA dimension were plotted against quartiles of indexed LA volume, a stepwise increase in risk with each quartile increment was evident only for indexed LA volume. Also, an LA volume of 32 mL/m2 or greater was associated with an increased mortality risk (HR, 1.30; CI, 1.09-1.56), independent of age, sex, and stroke status. CONCLUSIONS: In our elderly cohort with no prior atrial fibrillation, LA volume was independently predictive of first ischemic stroke, incremental to age, diabetes, myocardial infarction, and hyperlipidemia. It was also an independent predictor of death.

Evaluation and management of transient ischemic attack and minor cerebral infarction.

After immediate intervention for cerebral infarction or transient ischemic attack (TIA), the primary goal is secondary prevention of future cerebral ischemia and prevention of complications related to the initial ischemic event. The goals of the diagnostic evaluation are to (1) determine potential contributing mechanisms (cardioembolic, large-vessel disease of the extracranial and intracranial vessels, small-vessel disease, coagulation defects, and cryptogenic), (2) identify contributing risk factors (hypertension, hyperlipidemia, tobacco use, diabetes), and (3) complete the evaluation in a cost-effective and safe manner. We provide a sequential approach to the diagnostic evaluation of cerebral infarction or TIA to optimize diagnostic yield of testing, minimize cost and potential harm to the patient, and provide information that will change management. This systematic approach focuses on 6 important questions: (1) Are the symptoms consistent with a cerebral infarction or TIA (versus nonischemic pathology)? (2) Where does the ischemic event localize? (3) What etiologies and mechanisms of cerebral infarction and TIA are possible? (4) What is the prevalence of each potential etiology? (5) What treatments are available for this etiology? (6) What tests and studies are useful to evaluate this etiology?

Patent foramen ovale in cryptogenic stroke: current understanding and management options.

There is increasing interest in the association between patent foramen ovale (PFO) and documented stroke of unknown cause, commonly referred to as cryptogenic stroke. We reviewed the literature and, on the basis of the available data, designed a diagnostic and treatment algorithm for patients with PFO and cryptogenic stroke. Patent foramen ovale is relatively common in the general population, but its prevalence is higher in patients with cryptogenic stroke. Importantly, paradoxical embolism through a PFO should be strongly considered in young patients with cryptogenic stroke. There is no consensus on the optimal management strategy, but treatment options include antiplatelet agents, warfarin sodium, percutaneous device closure, and surgical closure. High-risk features in the patient's history (ie, temporal association between Valsalva-inducing maneuvers and stroke, coexisting hypercoagulable state, recurrent strokes, and PFO with large opening, large right-to-left shunt, or right-to-left shunting at rest, and a coexisting atrial septal aneurysm) should prompt PFO closure.

The prevalence of atrial fibrillation in incident stroke cases and matched population controls in Rochester, Minnesota: changes over three decades.

OBJECTIVES: We sought evidence of a change in the prevalence of atrial fibrillation (AF) over a 30-year period among residents of Rochester, Minnesota. BACKGROUND: Atrial fibrillation is increasingly encountered in clinical practice, but there is limited data on secular trends of AF over time. METHODS: Within a longitudinal case-control study of ischemic stroke, the prevalence of AF and of selected comorbid conditions among incident stroke cases and age- and gender-matched controls between 1960 and 1989 was determined. RESULTS: The mean age +/- standard deviation for the 1,871 stroke cases (45% men) and matched controls was 75 +/- 11 years. For cases, age-adjusted estimates of AF prevalence for 1960 to 1969, 1970 to 1979, and 1980 to 1989 were 11%, 13%, and 16%, respectively, for men, and 13%, 16%, and 20% for women. For controls, the rates were 5%, 8%, and 12%, respectively, for men, and 4%, 6%, and 8% for women. Increasing AF prevalence was associated with increasing age (doubling of odds per decade of age in both cases and controls) and calendar time adjusted for age and gender (cases: odds ratio [OR] per 5 years 1.13, 95% confidence interval [CI], 1.05 to 1.22; controls: OR per 5 years 1.24, 95% CI 1.12 to 1.37). The rates of increase with calendar time were significant for cases (p = 0.001) and controls (p < 0.001) and comparable between the genders. CONCLUSIONS: The prevalence of AF increased significantly in ischemic stroke patients and their controls from 1960 to 1989 in Rochester, Minnesota, independent of age and gender. The rate of increase did not differ significantly between men and women.

Cause-specific mortality after first cerebral infarction: a population-based study.

BACKGROUND AND PURPOSE: Mortality after cerebral infarction (CI) has remained unchanged during the past 20 years, despite advances in neurologic care. Key factors affecting survival may be underrecognized. The purpose of this study was to determine the rate and cause of mortality after first CI. METHODS: In this case-control, population-based study, all available medical records were reviewed for Rochester (Minnesota) residents with a first CI between 1985 and 1989 to identify morbidities and cause of death. Predictors for mortality were analyzed. RESULTS: First CI was recorded for 444 patients. Survival was 83% at 1 month, 71% at 1 year, and 46% at 5 years. The most frequent causes of death were cardiovascular events (22%), respiratory infection (21%), and initial stroke complications (14%). Recurrent stroke and cancer accounted for 9% and 7.5% of deaths, respectively. In the first month after CI, 51% of deaths were attributed to the initial CI, 22% to respiratory infections, and 12% to cardiovascular events. During the first year, 26% of deaths resulted from respiratory infections and 28% from cardiovascular disease. Mortality was higher among patients than controls for at least 2 years after CI. Age, cardiac comorbid conditions, CI severity, stroke recurrence, seizures, and respiratory and cardiovascular morbidities were independent predictors of death. CONCLUSIONS: In the first month after CI, mortality resulted predominantly from neurologic complications. Later mortality remained high because of respiratory and cardiovascular causes. To improve long-term survival after CI, aggressive management of pulmonary and cardiac disease is as important as secondary stroke prevention.

Cerebral ischemic events after diagnosis of mitral valve prolapse: a community-based study of incidence and predictive factors.

BACKGROUND AND PURPOSE: Association of mitral valve prolapse (MVP) with ischemic neurological events (INEs) is uncertain. METHODS: In the community of Olmsted County (Minn), we identified all MVP diagnosed (1989 to 1998) in patients in sinus rhythm with no prior history of INE. We measured INE rates and compared them with expected rates in our community to define the excess risk of INE. RESULTS: Among 777 eligible subjects (age, 49+/-20 years; 66% female; follow-up, 5.5+/-3.0 years), 30 patients had at least 1 INE during follow-up (at 10 years, 7+/-1%). Compared with expected INEs in the same community, subjects with MVP showed excess risk of lifetime INE (relative risk [RR], 2.2; 95% CI, 1.5 to 3.2; P<0.001) and during follow-up under purely medical management (RR, 1.8; 95% CI, 1.1 to 2.8; P=0.009). Independent determinants of INE were older age (RR, 1.08 per year; 95% CI, 1.04 to 1.11; P<0.001), mitral thickening (RR, 3.2; 95% CI, 1.4 to 7.4; P=0.008), atrial fibrillation (AFib) during follow-up (RR, 4.3; 95% CI, 1.9 to 10.0; P<0.001), and need for cardiac surgery (RR, 2.5; 95% CI, 1.1 to 5.8; P=0.03). INE 10-year rates were low in patients <50 years of age (0.4+/-0.4%, P=0.60 versus expected) but were excessive in patients >50 years of age (16+/-3%, P<0.001 versus expected) or with thickened leaflets (7+/-2%, P<0.001 versus expected). Predictors of follow-up AFib were age, mitral regurgitation, and left atrium diameter (all P<0.01). CONCLUSIONS: In the community, subjects with MVP display a lifetime excess rate of INE compared with expected. Clinical (older age) and echocardiographic (leaflets thickening) characteristics define patients with MVP at high risk for INE, and subsequent AFib or need for cardiac surgery, both related to the degree of mitral regurgitation, increase the risk of INE.