Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study

Context  Tissue-type plasminogen activator (tPA) is the only therapy for acute ischemic stroke approved by the Food and Drug Administration. Objective  To assess the safety profile and to document clinical outcomes and adverse events in patients treated with intravenous tPA for acute stroke in clinical practice. Design and Setting  Prospective, multicenter study of consecutive patients enrolled between February 1997 and December 1998 at 57 medical centers in the United States (24 academic and 33 community). Intervention  Intravenous tPA (recombinant alteplase). Patients  Three hundred eighty-nine patients with a mean age of 69 years (range, 28-100 years); 55% were men. Main Outcome Measures  Time intervals between stroke symptom onset, hospital arrival, and treatment with tPA; pretreatment computed tomographic scan results, intracerebral hemorrhage, and major systemic bleeding. The modified Rankin Scale score was used to assess clinical outcomes at 30 days. Results  Median time from stroke onset to treatment was 2 hours 44 minutes, and the median baseline National Institutes of Health Stroke Scale score was 13. The 30-day mortality rate was 13%. At 30 days after treatment, 35% of patients had very favorable outcomes (modified Rankin score, 0-1) and 43% were functionally independent (modified Rankin score, 0-2). Thirteen patients (3.3%) experienced symptomatic intracerebral hemorrhage, including 7 who died. Twenty-eight patients (8.2%) had asymptomatic intracerebral hemorrhage within 3 days of treatment with tPA. Protocol violations were reported for 127 patients (32.6%), and included treatment with tPA more than 3 hours after symptom onset in 13.4%, treatment with anticoagulants within 24 hours of tPA administration in 9.3%, and tPA administration despite systolic blood pressure exceeding 185 mm Hg in 6.7%. A multivariate analysis found predictors of favorable outcome to be a less severe baseline National Institutes of Health Stroke Scale score, absence of specific abnormalities (effacement or hypodensity of >33% of the middle cerebral artery territory or a hyperdense middle cerebral artery) on the baseline computed tomographic scan, an age of 85 years or younger, and a lower mean arterial pressure at baseline. Conclusions  This study, conducted at multiple institutions throughout the United States, suggests that favorable clinical outcomes and low rates of symptomatic intracerebral hemorrhage can be achieved using tPA for stroke treatment.      

Intravenous ancrod for treatment of acute ischemic stroke: the STAT study: a randomized controlled trial. Stroke Treatment with Ancrod Trial

Context  Approved treatment options for acute ischemic stroke in the United States and Canada are limited at present to intravenous tissue-type plasminogen activator, but bleeding complications, including intracranial hemorrhage, are a recognized complication. Objective  To evaluate the efficacy and safety of the defibrinogenating agent ancrod in patients with acute ischemic stroke. Design  The Stroke Treatment with Ancrod Trial (STAT), a randomized, parallel-group, double-blind, placebo-controlled trial conducted between August 1993 and January 1998. Setting  Forty-eight centers, primarily community hospitals, in the United States and Canada. Patients  A total of 500 patients with an acute or progressing ischemic neurological deficit were enrolled and included in the intent-to-treat analysis. Interventions  Patients were randomly assigned to receive ancrod (n=248) or placebo (n=252) as a continuous 72-hour intravenous infusion beginning within 3 hours of stroke onset, followed by infusions lasting approximately 1 hour at 96 and 120 hours. The ancrod regimen was designed to decrease plasma fibrinogen levels to 1.18 to 2.03 µmol/L. Main Outcome Measures  The primary efficacy end point was functional status, with favorable functional status defined as survival to day 90 with a Barthel Index of 95 or more or at least the prestroke value, compared by treatment group. Primary safety variables included symptomatic intracranial hemorrhage and mortality. Results  Favorable functional status was achieved by more patients in the ancrod group (42.2%) than in the placebo group (34.4%; P=.04) by the prespecified covariate-adjusted analysis. Mortality was not different between treatment groups (at 90 days, 25.4% for the ancrod group and 23% for the placebo group; P=.62), and the proportion of severely disabled patients was less in the ancrod group than in the placebo group (11.8% vs 19.8%; P=.01). The favorable functional status observed with ancrod vs placebo was consistent in all subgroups defined for age, stroke severity, sex, prestroke disability, and time to treatment (3 or >3 hours after stroke onset). There was a trend toward more symptomatic intracranial hemorrhages in the ancrod group vs placebo (5.2% vs 2.0%; P=.06), as well as a significant increase in asymptomatic intracranial hemorrhages (19.0% vs 10.7%; P=.01). Conclusion  In this study, ancrod had a favorable benefit-risk profile for patients with acute ischemic stroke.      

Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience

Context  Little is known regarding outcomes after intravenous tissue-type plasminogen activator (IV tPA) therapy for acute ischemic stroke outside a trial setting. Objective  To assess the rate of IV tPA use, the incidence of symptomatic intracerebral hemorrhage (ICH), and in-hospital patient outcomes throughout a large urban community. Design  Historical prospective cohort study conducted from July 1997 through June 1998. Setting  Twenty-nine hospitals in the Cleveland, Ohio, metropolitan area. Patients  A total of 3948 patients admitted to a study hospital with a primary diagnosis of ischemic stroke (International Classification of Diseases, Ninth Revision, Clinical Modification code 434 or 436). Main Outcome Measures  Rate of IV tPA use and occurrence of symptomatic ICH among patients treated with tPA; proportion of patients receiving tPA whose treatment deviated from national guidelines; in-hospital mortality among patients receiving tPA compared with that among ischemic stroke patients not receiving tPA and with mortality predicted by a model. Results  Seventy patients (1.8%) admitted with ischemic stroke received IV tPA. Of those, 11 patients (15.7%; 95% confidence interval [CI], 8.1%-26.4%) had a symptomatic ICH (of which 6 were fatal) and 50% (95% CI, 37.8%-62.2%) had deviations from national treatment guidelines. In-hospital mortality was significantly higher among patients treated with tPA (15.7%) compared with patients not receiving tPA (5.1%, P<.001) and compared with the model's prediction (7.9%; P<.006). Conclusions  A small proportion of patients admitted with acute ischemic stroke in Cleveland received tPA; they experienced a high rate of ICH. Cleveland community experience with tPA for acute ischemic stroke may differ from that reported in clinical trials.      

Cranial Computed Tomography Interpretation in Acute Stroke: Physician Accuracy in Determining Eligibility for Thrombolytic Therapy

Context.— Intracranial hemorrhage must be excluded prior to administration of thrombolytic agents in acute stroke. Objective.— To evaluate physician accuracy in cranial computed tomography scan interpretation for determining eligibility for thrombolytic therapy in acute stroke. Design.— Administration of randomly selected, randomly ordered series of 15 computed tomography scans from a pool of 54 scans that demonstrated intracerebral hemorrhage, acute infarction, intracerebral calcifications (impostor for hemorrhage), old cerebral infarction (impostor for acute infarction), and normal findings. Participants.— A convenience sample of 38 emergency physicians, 29 neurologists, and 36 general radiologists. Main Outcome Measures.— Physician determination of eligibility for thrombolytic therapy based on computed tomography scan interpretation. Results.— Average correct score by all physicians on all computed tomography scans was 77% (95% confidence interval, 74%-80%). Of 569 computed tomography readings by emergency physicians, 67% were correct; of 435 readings by neurologists, 83% were correct; and of 540 readings by radiologists, 83% were correct. Overall sensitivity for detecting hemorrhage was 82% (95% confidence interval, 78%-85%); 17% of emergency physicians, 40% of neurologists, and 52% of radiologists achieved 100% sensitivity for identification of hemorrhage. Conclusion.— Physicians in this study did not uniformly achieve a level of sensitivity for identification of intracerebral hemorrhage sufficient to permit safe selection of candidates for thrombolytic therapy.      

Causes and severity of ischemic stroke in patients with internal carotid artery stenosis

Context  Therapeutic trials generally have not distinguished outcomes of stroke according to cause. Objective  To determine whether stroke and subsequent disability was of large-artery, lacunar, or cardioembolic origin in patients with different degrees of symptomatic and asymptomatic carotid stenosis. Design  Observational study of prospective data collected from the North American Symptomatic Carotid Endarterectomy Trial between 1987 and 1997. Setting and Patients  A total of 2885 patients from 106 sites in the United States and abroad (median age, 67 years; 70% male) who had symptomatic internal carotid artery stenosis. Main Outcome Measure  Risk of stroke from each of the 3 causes at 5 years by territory and degree of stenosis. Results  During an average follow-up of 5 years, 749 patients had 1039 strokes, including 112 of cardioembolic, 211 of lacunar, 698 of large-artery, 17 of primary intracerebral hemorrhage, and 1 of subarachnoid hemorrhage origin. The 5-year risk of first stroke after entry into the trial in any territory was 2.6% of cardioembolic cause, 6.9% of lacunar cause, and 19.7% of large-artery cause. The proportion of cardioembolic strokes in the territory of the symptomatic artery was 12.0% and 6.9% in 60% to 69% and 70% to 99% arterial stenosis, respectively; large-artery strokes predominated (78.4%) at 70% to 99% arterial stenosis. With 70% to 99% arterial stenosis, the proportion of strokes of cardioembolic and lacunar origin was 43.5% and 21.6% in asymptomatic and symptomatic arteries, respectively. A total of 67.6% of cardioembolic, 16.7% of lacunar, and 33.0% of large-artery strokes in the territory of the asymptomatic artery were disabling or fatal. Conclusions  Our data suggest that approximately 20% and 45% of strokes in the territory of symptomatic and asymptomatic carotid arteries with 70% to 99% stenosis, respectively, are unrelated to carotid stenosis. The cause of subsequent strokes in similar types of patients should be considered when making treatment decisions involving carotid endarterectomy for patients with asymptomatic carotid stenosis, since lacunar and cardioembolic strokes cannot be prevented by endarterectomy.      

Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice?

Context  Warfarin has been shown to be highly efficacious for preventing thromboembolism in atrial fibrillation in randomized trials, but its effectiveness and safety in clinical practice is less clear. Objective  To evaluate the effect of warfarin on risk of thromboembolism, hemorrhage, and death in atrial fibrillation within a usual care setting. Design  Cohort study assembled between July 1, 1996, and December 31, 1997, and followed up through August 31, 1999. Setting  Large integrated health care system in Northern California. Patients  Of 13 559 adults with nonvalvular atrial fibrillation, 11 526 were studied, 43% of whom were women, mean age 71 years, with no known contraindications to anticoagulation at baseline. Main Outcomes  Ischemic stroke, peripheral embolism, hemorrhage, and death according to warfarin use and comorbidity status, as determined by automated databases, review of medical records, and state mortality files. Results  Among 11 526 patients, 397 incident thromboembolic events (372 ischemic strokes, 25 peripheral embolism) occurred during 25 341 person-years of follow-up, and warfarin therapy was associated with a 51% (95% confidence interval [CI], 39%-60%) lower risk of thromboembolism compared with no warfarin therapy (either no antithrombotic therapy or aspirin) after adjusting for potential confounders and likelihood of receiving warfarin. Warfarin was effective in reducing thromboembolic risk in the presence or absence of risk factors for stroke. A nested case-control analysis estimated a 64% reduction in odds of thromboembolism with warfarin compared with no antithrombotic therapy. Warfarin was also associated with a reduced risk of all-cause mortality (adjusted hazard ratio, 0.69; 95% CI, 0.61-0.77). Intracranial hemorrhage was uncommon, but the rate was moderately higher among those taking vs those not taking warfarin (0.46 vs 0.23 per 100 person-years, respectively; P = .003, adjusted hazard ratio, 1.97; 95% CI, 1.24-3.13). However, warfarin therapy was not associated with an increased adjusted risk of nonintracranial major hemorrhage. The effects of warfarin were similar when patients with contraindications at baseline were analyzed separately or combined with those without contraindications (total cohort of 13 559). Conclusions  Warfarin is very effective for preventing ischemic stroke in patients with atrial fibrillation in clinical practice while the absolute increase in the risk of intracranial hemorrhage is small. Results of randomized trials of anticoagulation translate well into clinical care for patients with atrial fibrillation.      

Costs and effectiveness of ximelagatran for stroke prophylaxis in chronic atrial fibrillation

Context  Recent trials have found that ximelagatran and warfarin are equally effective in stroke prevention for patients with atrial fibrillation. Because ximelagatran can be taken in a fixed, oral dose without international normalized ratio monitoring and may have a lower risk of hemorrhage, it might improve quality-adjusted survival compared with dose-adjusted warfarin. Objective  To compare quality-adjusted survival and cost among 3 alternative therapies for patients with chronic atrial fibrillation: ximelagatran, warfarin, and aspirin. Design  Semi-Markov decision model. Patients  Hypothetical cohort of 70-year-old patients with chronic atrial fibrillation, varying risk of stroke, and no contraindications to anticoagulation therapy. Main Outcome Measures  Quality-adjusted life-years (QALYs) and costs in US dollars. Results  For patients with atrial fibrillation but no additional risk factors for stroke, both ximelagatran and warfarin cost more than $50 000 per QALY compared with aspirin. For patients with additional stroke risk factors and low hemorrhage risk, ximelagatran modestly increased quality-adjusted survival (0.12 QALY) at a substantial cost ($116 000 per QALY) compared with warfarin. For ximelagatran to cost less than $50 000 per QALY it would have to cost less than $1100 per year or be prescribed to patients who have an elevated risk of intracranial hemorrhage (>1.0% per year of warfarin) or a low quality of life with warfarin therapy. Conclusion  Assuming equal effectiveness in stroke prevention and decreased hemorrhage risk, ximelagatran is not likely to be cost-effective in patients with atrial fibrillation unless they have a high risk of intracranial hemorrhage or a low quality of life with warfarin.      

Predictors of in-hospital mortality in patients with acute ischemic stroke treated with thrombolytic therapy

Context  Data are limited regarding the risks and benefits of thrombolytic therapy for acute ischemic stroke outside of clinical trials. Objective  To investigate predictors of in-hospital mortality in patients with ischemic stroke treated with intravenous tissue plasminogen activator (tPA) within a pooled analysis of large German stroke registers. Design and Setting  Prospective, observational cohort study conducted at 225 community and academic hospitals throughout Germany cooperating within the German Stroke Registers Study Group. Patients  A total of 1658 patients with acute ischemic stroke who were admitted to study hospitals between 2000 and 2002 and were treated with tPA. Main Outcome Measure  In-hospital mortality. Results  One hundred sixty-six patients (10%) who received tPA died during hospitalization, with 67.5% of these deaths occurring within 7 days. Factors predicting in-hospital death after tPA use were older age (for each 10-year increment in age, adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3-1.9) and altered level of consciousness (adjusted OR, 3.4; 95% CI, 2.4-4.7). The overall rate of symptomatic intracranial hemorrhage was 7.1% and increased with age. One or more serious complications was observed in 27.2% of all patients and in 83.9% of patients who died after tPA treatment. An inverse relation between the number of patients treated with tPA in the respective hospital and the risk of in-hospital death was observed (adjusted OR, 0.97; 95% CI, 0.96-0.99 for each additional patient treated with tPA per year). Conclusion  In patients with ischemic stroke who are treated with tPA, disturbances of consciousness and increasing age are associated with increased in-hospital mortality.      

Fish consumption and risk of stroke in men

Context  The effect of fish consumption or long-chain omega-3 polyunsaturated fatty acid (PUFA) intake on risk of stroke remains uncertain. Objective  To examine the relation of fish consumption and long-chain omega-3 PUFA intake and risk of stroke in men. Design and Setting  The Health Professional Follow-up Study, a US prospective cohort study with 12 years of follow-up. Participants  A total of 43 671 men aged 40 to 75 years who completed a detailed and validated semiquantitative food frequency questionnaire and who were free of cardiovascular disease at baseline in 1986. Main Outcome Measure  Relative risk (RR) of stroke by subtype based on cumulative average fish consumption or long-chain omega-3 PUFA intake, ascertained in 1986, 1990, and 1994. Results  We documented 608 strokes during the 12-year follow-up period, including 377 ischemic, 106 hemorrhagic, and 125 unclassified strokes. Compared with men who consumed fish less than once per month, the multivariate RR of ischemic stroke was significantly lower among those who ate fish 1 to 3 times per month (RR, 0.57; 95% confidence interval [CI], 0.35-0.95). However, a higher frequency of fish intake was not associated with further risk reduction; the RR was 0.54 (95% CI, 0.31-0.94) for men who consumed fish 5 or more times per week. This lack of linearity was confirmed by spline analyses. By dichotomized fish intake, the multivariate RR for men who consumed fish at least once per month compared with those who ate fish less than once per month was 0.56 (95% CI, 0.38-0.83) for ischemic stroke and 1.36 (95% CI, 0.48-3.82) for hemorrhagic stroke. The inverse association between fish intake and risk of ischemic stroke was not materially modified by use of aspirin. No significant associations were found between fish or long-chain omega-3 PUFA intake and risk of hemorrhagic stroke. Conclusion  Our findings suggest that eating fish once per month or more can reduce the risk of ischemic stroke in men.      

Mechanical reperfusion in patients with acute myocardial infarction presenting more than 12 hours from symptom onset: a randomized controlled trial

Context  No specifically designed studies have addressed the role of primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction (STEMI) presenting more than 12 hours after symptom onset. Current guidelines do not recommend reperfusion treatment in these patients. Objective  To assess whether an immediate invasive treatment strategy is associated with a reduction of infarct size in patients with acute STEMI, presenting between 12 and 48 hours after symptom onset, vs a conventional conservative strategy. Design, Setting, and Patients  International, multicenter, open-label, randomized controlled trial conducted from May 23, 2001, to December 15, 2004, of 365 patients aged 18 to 80 years without persistent symptoms admitted with the diagnosis of acute STEMI between 12 and 48 hours after symptom onset. Interventions  Random assignment to either an invasive strategy (n=182) based predominantly on coronary stenting with abciximab or a conventional conservative treatment strategy (n=183). Main Outcome Measures  The primary end point was final left ventricular infarct size according to single-photon emission computed tomography study with technetium Tc 99m sestamibi performed between 5 and 10 days after randomization in 347 patients (95.1%). Secondary end points included composite of death, recurrent MI, or stroke at 30 days. Results  The final left ventricular infarct size was significantly smaller in patients assigned to the invasive group (median, 8.0%; interquartile range [IQR], 2.0%-15.8%) vs those assigned to the conservative group (median, 13.0%; IQR, 3.0%-27.0%; P<.001). The mean difference in final left ventricular infarct size between the invasive and conservative groups was –6.8% (95% confidence interval [CI], –10.2% to –3.5%). The secondary end points of death, recurrent MI, or stroke at 30 days occurred in 8 patients in the invasive group (4.4%) and 12 patients in the conservative group (6.6%) (relative risk, 0.67; 95% CI, 0.27-1.62; P = .37). Conclusion  An invasive strategy based on coronary stenting with adjunctive use of abciximab reduces infarct size in patients with acute STEMI without persistent symptoms presenting 12 to 48 hours after symptom onset.      

Alcohol consumption and risk of stroke: a meta-analysis

Context  Observational studies suggest that heavy alcohol consumption may increase the risk of stroke while moderate consumption may decrease the risk. Objective  To examine the association between alcohol consumption and relative risk of stroke. Data Sources  Studies published in English-language journals were retrieved by searching MEDLINE (1966–April 2002) using Medical Subject Headings alcohol drinking, ethanol, cerebrovascular accident, cerebrovascular disorders, and intracranial embolism and thrombosis and the key word stroke; Dissertation Abstracts Online using the keywords stroke and alcohol; and bibliographies of retrieved articles. Study Selection  From 122 relevant retrieved reports, 35 observational studies (cohort or case control) in which total stroke, ischemic stroke, or hemorrhagic (intracerebral or total) stroke was an end point; the relative risk or relative odds and their variance (or data to calculate them) of stroke associated with alcohol consumption were reported; alcohol consumption was quantified; and abstainers served as the reference group. Data Extraction  Information on study design, participant characteristics, level of alcohol consumption, stroke outcome, control for potential confounding factors, and risk estimates was abstracted independently by 3 investigators using a standardized protocol. Data Synthesis  A random-effects model and meta-regression analysis were used to pool data from individual studies. Compared with abstainers, consumption of more than 60 g of alcohol per day was associated with an increased relative risk of total stroke, 1.64 (95% confidence interval [CI], 1.39-1.93); ischemic stroke, 1.69 (95% CI, 1.34-2.15); and hemorrhagic stroke, 2.18 (95% CI, 1.48-3.20), while consumption of less than 12 g/d was associated with a reduced relative risk of total stroke, 0.83 (95%, CI, 0.75-0.91) and ischemic stroke, 0.80 (95% CI, 0.67-0.96), and consumption of 12 to 24 g/d was associated with a reduced relative risk of ischemic stroke, 0.72 (95%, CI, 0.57-0.91). The meta-regression analysis revealed a significant nonlinear relationship between alcohol consumption and total and ischemic stroke and a linear relationship between alcohol consumption and hemorrhagic stroke. Conclusions  These results indicate that heavy alcohol consumption increases the relative risk of stroke while light or moderate alcohol consumption may be protective against total and ischemic stroke.      

Myocardial perfusion imaging for evaluation and triage of patients with suspected acute cardiac ischemia: a randomized controlled trial

Context  Observational studies of acute myocardial perfusion imaging in emergency department (ED) patients with chest pain have suggested high sensitivity and negative predictive value for acute cardiac ischemia, but use of this method has not been prospectively tested. Objective  To assess whether incorporating acute resting perfusion imaging into an ED evaluation strategy for patients with suspected acute ischemia but no initial electrocardiogram (ECG) changes diagnostic of acute ischemia improves clinical decision making for initial ED triage. Design, Setting, and Patients  Prospective, randomized controlled trial conducted at 7 academic medical centers and community hospitals between July 1997 and May 1999 among 2475 adult ED patients with chest pain or other symptoms suggestive of acute cardiac ischemia and with normal or nondiagnostic initial ECG results. Intervention  Patients were randomly assigned to receive either the usual ED evaluation strategy (n = 1260) or the usual strategy supplemented with results from acute resting myocardial perfusion imaging using single-photon emission computed tomography with injection of 20 to 30 mCi of Tc-99m sestamibi (n = 1215), interpreted in real time by local staff physicians and with results provided to the ED physician for incorporation into clinical decision making. Main Outcome Measure  Appropriateness of triage decision either to admit to hospital/observation or to discharge directly home from the ED. Results  Among patients with acute cardiac ischemia (ie, acute myocardial infarction [MI] or unstable angina; n = 329), there were no differences in ED triage decisions between those receiving standard evaluation and those whose evaluation was supplemented by a sestamibi scan. Among patients with acute MI (n = 56), 97% vs 96% were hospitalized (relative risk [RR], 1.00; 95% confidence interval [CI], 0.89-1.12), and among those with unstable angina (n = 273), 83% vs 81% were hospitalized (RR, 0.98; 95% CI, 0.87-1.10). However, among patients without acute cardiac ischemia (n = 2146), hospitalization was 52% with usual care vs 42% with sestamibi imaging (RR, 0.84; 95% CI, 0.77-0.92). Conclusions  Sestamibi perfusion imaging improves ED triage decision making for patients with symptoms suggestive of acute cardiac ischemia without obvious abnormalities on initial ECG. In this study, unnecessary hospitalizations were reduced among patients without acute ischemia, without reducing appropriate admission for patients with acute ischemia.      

Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome

Context  Severe acute respiratory syndrome (SARS) is an emerging infectious disease with a 25% incidence of progression to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and mortality exceeding 10%. Objective  To describe the clinical spectrum and outcomes of ALI/ARDS in patients with SARS-related critical illness. Design, Setting, and Patients  Retrospective case series of adult patients with probable SARS admitted to the intensive care unit (ICU) of a hospital in Singapore between March 6 and June 6, 2003. Main Outcome Measures  The primary outcome measure was 28-day mortality after symptom onset. Results  Of 199 patients hospitalized with SARS, 46 (23%) were admitted to the ICU, including 45 who fulfilled criteria for ALI/ARDS. Mortality at 28 days for the entire cohort was 20 (10.1%) of 199 and for ICU patients was 17 (37%) of 46. Intensive care unit mortality at 13 weeks was 24 (52.2%) of 46. Nineteen of 24 ICU deaths occurred late (=" BORDER="0">7 days after ICU admission) and were attributed to complications related to severe ARDS, multiorgan failure, thromboembolic complications, or septicemic shock. ARDS was characterized by ease of derecruitment of alveoli and paucity of airway secretion, bronchospasm, or dynamic hyperinflation. Lower Acute Physiology and Chronic Health Evaluation II scores and higher baseline ratios of PaO₂ to fraction of inspired oxygen were associated with earlier recovery. Conclusions  Critically ill patients with SARS and ALI/ARDS had characteristic clinical findings, high rates of complications; and high mortality. These findings may provide useful information for optimizing supportive care for SARS-related critical illness.      

Cerebral white matter lesions,retinopathy, and incident clinical stroke

Context  White matter lesions (WMLs) detected on cerebral imaging scans havebeen hypothesized to have a microvascular etiology and to precede the developmentof clinical stroke. However, few clinical data are available to support thesehypotheses. Objective  To examine the relationship of WMLs, retinal microvascular abnormalities,and incident clinical stroke in healthy, middle-aged men and women. Design and Setting  The Atherosclerosis Risk in Communities Study (ARIC), a prospective,population-based cohort study conducted in 4 US communities and initiatedin 1987-1989. Participants  A total of 1684 persons aged 51 to 72 years who had cerebral magneticresonance imaging (MRI) and retinal photography at the third examination (1993-1995). Main Outcome Measures  Odds of WMLs, defined by standardized methods from MRI, by presenceor absence of specific retinal microvascular abnormality (eg, microaneurysm,retinal hemorrhage) on retinal photograph; incident clinical stroke, ascertainedafter a median follow-up of 4.7 years, according to presence or absence ofWMLs and retinopathy. Results  Persons with retinopathy were more likely to have WMLs than those withoutretinopathy (22.9% vs 9.9%; odds ratio, 2.5; 95% confidence interval [CI],1.5-4.0, adjusted for age, sex, race, and vascular risk factors). The 5-yearcumulative incidence of clinical stroke was higher in persons with vs withoutWMLs (6.8% vs 1.4%; adjusted relative risk [RR], 3.4; 95% CI, 1.5-7.7) andin persons with vs without retinopathy (8.0% vs 1.4%; adjusted RR, 4.9; 95%CI, 2.0-11.9). Persons with both WMLs and retinopathy had a significantlyhigher 5-year cumulative incidence of stroke than those without either WMLsor retinopathy (20.0% vs 1.4%; adjusted RR, 18.1; 95% CI, 5.9-55.4). Conclusions  In this cohort, middle-aged persons with cerebral WMLs detected on MRIwere more likely to have retinal microvascular abnormalities and to have anincreased risk of clinical stroke than people without WMLs. The risk of strokewas higher when retinopathy was simultaneously present in persons with WMLs.      

Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis

Sonal Singh, MD, MPH; Yoon K. Loke, MBBS, MD; Curt D. Furberg, MD, PhD

JAMA. 2008;300(12):1439-1450.

Context  Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with chronic obstructive pulmonary disease (COPD) but their effect on the risk of cardiovascular outcomes is unknown.

Objective  To ascertain the cardiovascular risks of inhaled anticholinergics,including cardiovascular death, myocardial infarction (MI), and stroke.

Data Sources  Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews,regulatory authority Web sites in the United States and the United Kingdom, and manufacturers' trial registries with no date restrictions.

Study Selection  Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events.

Data Extraction  The primary outcome was a composite of cardiovascular death,MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I² statistic.

Data Synthesis  After a detailed screening of 103 articles, 17 trials enrolling 14 783 patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 135 of 7472 patients (1.8%) receiving inhaled anticholinergics and 86 of 7311 patients (1.2%) receiving control therapy (RR, 1.58 [95%confidence interval {CI}, 1.21-2.06]; P < .001,I² = 0%). Among individual components of the primary end point, inhaled anticholinergics significantly increased the risk of MI (RR, 1.53 [95% CI 1.05-2.23]; P = .03, I² = 0%) and cardiovascular death (RR, 1.80 [95% CI, 1.17-2.77]; P = .008,I² = 0%) without a statistically significant increase in the risk of stroke (RR, 1.46 [95% CI, 0.81-2.62]; P = .20, I² = 0%).All-cause mortality was reported in 149 of the patients treated with inhaled anticholinergics (2.0%) and 115 of the control patients (1.6%)(RR, 1.26 [95% CI, 0.99-1.61]; P = .06,I² = 2%). A sensitivity analysis restricted to 5 long-term trials (>6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95%CI, 1.27-2.36]; P < .001, I² = 0%).

Conclusion  Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

     

Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial

Context  The Women's Health Initiative (WHI) trial of estrogen plus progestin was stopped early because of adverse effects, including an increased risk of stroke in the estrogen plus progestin group. Objective  To assess the effect of estrogen plus progestin on ischemic and hemorrhagic stroke and in subgroups, and to determine whether the effect of estrogen plus progestin was modified by baseline levels of blood biomarkers. Design  Multicenter double-blind, placebo-controlled, randomized clinical trial involving 16 608 women aged 50 through 79 years with an average follow-up of 5.6 years. Baseline levels of blood-based markers of inflammation, thrombosis, and lipid levels were measured in the first 140 centrally confirmed stroke cases and 513 controls. Interventions  Participants received 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102). Main Outcome Measures  Overall strokes and stroke subtype and severity were centrally adjudicated by stroke neurologists. Results  One hundred fifty-one patients (1.8%) in the estrogen plus progestin and 107 (1.3%) in the placebo groups had strokes. Overall 79.8% of strokes were ischemic. For combined ischemic and hemorrhagic strokes, the intention-to-treat hazard ratio (HR) for estrogen plus progestin vs placebo was 1.31 (95% confidence interval [CI], 1.02-1.68); with adjustment for adherence, the HR was 1.50 (95% CI, 1.08-2.08). The HR for ischemic stroke was 1.44 (95% CI, 1.09-1.90) and for hemorrhagic stroke, 0.82 (95% CI, 0.43-1.56). Point estimates of the HRs indicate that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin. Other risk factors for stroke, including smoking, blood pressure, diabetes, lower use of vitamin C supplements, blood-based biomarkers of inflammation, higher white blood cell count, and higher hematocrit levels did not modify the effect of estrogen plus progestin on stroke risk. Conclusions  Estrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin appeared to be present in all subgroups of women examined.      

Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage

Context  Delayed cerebral vasospasm causes permanent neurological deficits or death in at least 15% of patients following otherwise successful treatment for ruptured intracranial aneurysm. Decreased bioavailability of nitric oxide has been associated with the development of cerebral vasospasm. Objective  To determine whether infusions of nitrite will prevent delayed cerebral vasospasm. Design, Setting, and Subjects  A total of 14 anesthetized cynomolgus monkeys had an autologous blood clot placed around the right middle cerebral artery. Cerebral arteriography was performed before clot placement and on days 7 and 14 to assess vasospasm. The study was conducted from August 2003 to February 2004. Interventions  A 90-mg sodium nitrite intravenous solution infused over 24 hours plus a 45-mg sodium nitrite bolus daily (n = 3); a 180-mg sodium nitrite intravenous solution infused over 24 hours (n = 3); or a control saline solution infusion (n = 8). Each was infused continuously for 14 days. Main Outcome Measures  Nitrite, S-nitrosothiol, and methemoglobin levels in blood and cerebrospinal fluid and degree of arteriographic vasospasm. Results  In control monkeys, mean (SD) cerebrospinal fluid nitrite levels decreased from 3.1 (1.5) µmol/L to 0.4 (0.1) µmol/L at day 7 and to 0.4 (0.4) µmol/L at day 14 (P = .03). All 8 control monkeys developed significant vasospasm of the right middle cerebral artery, which was complicated by stroke and death in 1 animal. Sodium nitrite infusions increased the nitrite and methemoglobin levels (<2.1% of total hemoglobin) in the blood and cerebrospinal fluid without evoking systemic hypotension. Nitrite infusion prevented development of vasospasm (no animals developed significant vasospasm; mean [SD] reduction in right middle cerebral artery area on day 7 after subarachnoid hemorrhage of 8% [9%] in nitrite-treated monkeys vs 47% [5%] in saline-treated controls; P<.001). There was a negative correlation between the concentration of nitrite in cerebrospinal fluid and the degree of cerebral vasospasm (P<.001). Pharmacological effects of nitrite infusion were also associated with the formation of S-nitrosothiol in cerebrospinal fluid. There was no clinical or pathological evidence of nitrite toxicity. Conclusion  Subacute sodium nitrite infusions prevented delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage.      

Effect of daily vitamin E and multivitamin-mineral supplementation on acute respiratory tract infections in elderly persons: a randomized controlled trial

Context  Immune response in elderly individuals has been reported to improve after micronutrient supplementation. However, efficacy trials evaluating infectious diseases as outcomes are scarce and inconclusive. Objective  To investigate the effect of daily multivitamin-mineral and vitamin E supplementation on incidence and severity of acute respiratory tract infections in elderly individuals. Design  A randomized, double blind, placebo-controlled, 2 x 2 factorial trial. Setting and Participants  A total of 652 noninstitutionalized individuals aged 60 years or older enrolled from 2 community-based sampling strategies in the Wageningen area of the Netherlands, conducted from 1998 to 2000. At baseline, 6% of participants had suboptimal ascorbic acid and 1.3% had suboptimal -tocopherol plasma concentration. Intervention  Physiological doses of multivitamin-minerals, 200 mg of vitamin E, both, or placebo. Main Outcome Measures  Incidence and severity of self-reported acute respiratory tract infections at 15 months, as assessed by a nurse (telephone contact), home visits, and microbiological and serological testing in subsets of patients. Results  During a median observation period of 441 days, 443 (68%) of 652 participants recorded 1024 respiratory tract infection episodes. The incidence rate ratio of acute respiratory tract infection for multivitamin-mineral supplementation was 0.95 (95% confidence interval, 0.75-1.15; P = .58) and for vitamin E supplementation, 1.12 (95% confidence interval, 0.88-1.25; P = .21). Severity of infections was not influenced by multivitamin-mineral supplementation. For vitamin E vs no vitamin E, severity was worse: median (interquartile range) for illness-duration was 19 (9-37) vs 14 (6-29) days, P = .02; number of symptoms, 6 (3-8) vs 4 (3-8), P = .03; presence of fever, 36.7% vs 25.2%, P = .009; and restriction of activity, 52.3% vs 41.1%, P = .02. Conclusions  Neither daily multivitamin-mineral supplementation at physiological dose nor 200 mg of vitamin E showed a favorable effect on incidence and severity of acute respiratory tract infections in well-nourished noninstitutionalized elderly individuals. Instead we observed adverse effects of vitamin E on illness severity.      

Extracranial thrombotically active carotid plaque as a risk factor for ischemic stroke

Context  Recent studies suggest that factors other than the degree of carotid stenosis are involved in ischemic stroke pathogenesis, especially modifications of plaque composition and related complications. Objective  To examine the role of carotid plaque rupture and thrombosis in ischemic stroke pathogenesis in patients undergoing carotid endarterectomy, excluding those with possible cardiac embolization or with severe stenosis of the circle of Willis. Design, Setting, and Patients  A total of 269 carotid plaques selected from an Interinstitutional Carotid Tissue Bank were studied by histology after surgical endarterectomy between January 1995 and December 2002. A total of 96 plaques were from patients with ipsilateral major stroke, 91 plaques from patients with transient ischemic attack (TIA), and 82 plaques from patients without symptoms. Main Outcome Measures  Differences in the frequency of thrombosis, cap rupture, cap erosion, inflammatory infiltrate, and major cardiovascular risk factors between study groups. Results  A thrombotically active carotid plaque associated with high inflammatory infiltrate was observed in 71 (74.0%) of 96 patients with ipsilateral major stroke (and in all 32 plaques from patients operated within 2 months of symptom onset) compared with 32 (35.2%) of 91 patients with TIA (P < .001) or 12 (14.6%) of 82 patients who were without symptoms (P < .001). In addition, a fresh thrombus was observed in 53.8% of patients with stroke operated 13 to 24 months after the cerebrovascular event. An acute thrombus was associated with cap rupture in 64 (90.1%) of 71 thrombosed plaques from patients with stroke and with cap erosion in the remaining 7 cases (9.9%). Ruptured plaques of patients affected by stroke were characterized by the presence of a more severe inflammatory infiltrate, constituted by monocytes, macrophages, and T lymphocyte cells compared with that observed in the TIA and asymptomatic groups (P = .001). There was no significant difference between groups in major cardiovascular risk factors. Conclusion  These results demonstrate a major role of carotid thrombosis and inflammation in ischemic stroke in patients affected by carotid atherosclerotic disease.      

Secular trends in nosocomial infections and mortality associated with noninvasive ventilation in patients with exacerbation of COPD and pulmonary edema

Context  Randomized controlled trials have shown that the use of noninvasive ventilation (NIV) reduces the need for endotracheal intubation and invasive mechanical ventilation and reduces complication rates and mortality in selected groups of patients. But whether these benefits translate to a clinical setting is unclear. Objective  To evaluate longitudinally the routine implementation of NIV and its effect on patients admitted to the intensive care unit (ICU) with acute exacerbation of chronic obstructive pulmonary disease (COPD) or severe cardiogenic pulmonary edema (CPE). Design  Retrospective, observational cohort study using prospectively collected data from January 1, 1994, through December 31, 2001. Setting  A 26-bed medical intensive care unit (ICU) of a French university referral hospital. Participants  A cohort of 479 consecutive patients ventilated for acute exacerbation of COPD or CPE. Main Outcome Measures  The ICU mortality and incidence rates of ICU-acquired infections. Results  A significant increase in NIV use and a concomitant decrease in mortality and ICU-acquired infection rates were observed over the study years. With adjustment for relevant covariates and propensity scores, NIV was identified as an independent factor linked with a reduced risk of death in the cohort (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.18-0.78), whereas a high severity score on admission (OR, 1.05; 95% CI, 1.01-1.10) and the occurrence of a nosocomial infection (OR, 3.08; 95% CI, 1.62-5.84) were independently associated with death. Rates of ICU-acquired pneumonia decreased from 20% in 1994 to 8% in 2001 (P = .04). Conclusion  Implementing routine use of NIV in critically ill patients with acute exacerbation of COPD or severe CPE was associated with improved survival and reduction of nosocomial infections.