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BACKGROUND- Simultaneous contribution of hundreds of electrocardiographic (ECG) biomarkers to prediction of long-term mortality in postmenopausal women with clinically normal resting ECGs is unknown. METHODS AND RESULTS- We analyzed ECGs and all-cause mortality in 33 144 women enrolled in the Women's Health Initiative trials who were without baseline cardiovascular disease or cancer and had normal ECGs by Minnesota and Novacode criteria. Four hundred and seventy-seven ECG biomarkers, encompassing global and individual ECG findings, were measured with computer algorithms. During a median follow-up of 8.1 years (range for survivors, 0.5 to 11.2 years), 1229 women died. For analyses, the cohort was randomly split into derivation (n=22 096; deaths, 819) and validation (n=11 048; deaths, 410) subsets. ECG biomarkers and demographic and clinical characteristics were simultaneously analyzed using both traditional Cox regression and random survival forest, a novel algorithmic machine-learning approach. Regression modeling failed to converge. Random survival forest variable selection yielded 20 variables that were independently predictive of long-term mortality, 14 of which were ECG biomarkers related to autonomic tone, atrial conduction, and ventricular depolarization and repolarization. CONCLUSIONS- We identified 14 ECG biomarkers from among hundreds that were associated with long-term prognosis using a novel random forest variable selection methodology. These biomarkers were related to autonomic tone, atrial conduction, ventricular depolarization, and ventricular repolarization. Quantitative ECG biomarkers have prognostic importance and may be markers of subclinical disease in apparently healthy postmenopausal women. [ABSTRACT FROM AUTHOR]

Context: Immunosuppressive therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis have greatly advanced patient survival but have turned ANCA-associated vasculitis (AAV) into chronic, relapsing disorders. Long-term treatment and disease-related morbidity are major threats. The last decade has seen a collaborative international effort to determine effective treatment.Objective: To analyze the reported evidence on AAV therapy in order to provide physicians with a rational approach for dealing with various clinical scenarios.Data Sources: We searched English-language articles on the medical treatment of AAV published between 1966 and March 2007 using MEDLINE. Articles from the reference lists of the most relevant articles retrieved were also analyzed.Study Selection: Studies of current available drug treatments or medical interventions for patients with AAV were included. Duplicate publications, case reports, and uncontrolled trials and series including fewer than 10 patients were excluded.Data Synthesis: We included 2 meta-analyses, 20 randomized controlled prospective trials, and 62 uncontrolled trials with more than 10 patients or observational studies. Outcome measures and treatment protocols were heterogeneous across trials. Cotrimoxazole can be used alone or in combination with corticosteroids to induce and maintain remission in cases of isolated upper respiratory tract involvement. To induce remission, methotrexate plus corticosteroids can be used instead of cyclophosphamide for patients with generalized, non-organ-threatening disease. When methotrexate is used as maintenance therapy, the likelihood of relapse is high and rigorous monitoring is mandatory. Pulse cyclophosphamide with corticosteroids can be used to induce remission in patients with generalized organ-threatening disease. The combination of azathioprine and daily prednisone is effective in maintaining remission. Plasma exchange is at present the best complement to immunosuppressants in advanced renal disease. In Churg-Strauss syndrome, treatment can be started with high doses of corticosteroids, tapering them when the clinical situation improves. In patients with a high risk of death, cyclophosphamide should be introduced.Conclusions: Although AAV therapies should be tailored to the patient's specific clinical situation, evidence for treatment of several disease states is lacking. There is a need for safer and more effective drugs. [ABSTRACT FROM AUTHOR]

Context: Left ventricular (LV) systolic dysfunction causes substantial morbidity and mortality, even with optimal pharmacotherapy. Atrial-synchronized biventricular pacemakers (cardiac resynchronization therapy [CRT]) received US Food and Drug Administration (FDA) approval for use in selected patients with LV systolic dysfunction in 2001.Objective: To summarize the current evidence base for the efficacy, effectiveness, and safety of CRT in patients with LV systolic dysfunction.Evidence Acquisition: A search of multiple electronic databases until November 2006 was supplemented by hand searches of reference lists of included studies and review articles, proceedings booklets from meetings, FDA reports, and contact with primary study authors and device manufacturers. A total of 14 randomized trials (4420 patients) were included for the CRT efficacy review, 106 studies (9209 patients) for the CRT effectiveness review, and 89 studies (9677 patients) reported safety outcomes with implantation of a CRT device.Evidence Synthesis: All patients in the CRT studies had LV systolic dysfunction (mean LV ejection fraction [LVEF] range, 21%-30%), prolonged QRS duration (mean range, 155-209 milliseconds), and 91% had New York Heart Association (NYHA) class 3 or 4 heart failure symptoms despite optimal pharmacotherapy. CRT improved LVEF (weighted mean difference, 3.0%; 95% confidence interval [CI], 0.9%-5.1%), quality of life (weighted mean reduction in Minnesota Living With Heart Failure Questionnaire, 8.0 points; 95% CI, 5.6-10.4 points), and functional status (improvements of >/=1 NYHA class were observed in 59% of CRT recipients in the randomized trials). CRT decreased hospitalizations by 37% (95% CI, 7%-57%), and all-cause mortality decreased by 22% (95% CI, 9%-33%). Implant success rate was 93.0% (95% CI, 92.2%-93.7%) and 0.3% of patients died during implantation (95% CI, 0.1%-0.6%). During a median 11-month follow-up, 6.6% (95% CI, 5.6%-7.4%) of CRT devices exhibited lead problems and 5% (95% CI, 4%-7%) malfunctioned.Conclusions: CRT reduces morbidity and mortality in patients with LV systolic dysfunction, prolonged QRS duration, and NYHA class 3 or 4 symptoms when combined with optimal pharmacotherapy. The incremental benefits of combined CRT plus implantable cardioverter-defibrillator devices vs CRT-alone devices in patients with LV systolic dysfunction remain uncertain. [ABSTRACT FROM AUTHOR]

Context: Many US clinicians and laboratory personnel are unfamiliar with the diagnosis and treatment of malaria.Objectives: To examine the evidence base for management of uncomplicated and severe malaria and to provide clinicians with practical recommendations for the diagnosis and treatment of malaria in the United States.Evidence Acquisition: Systematic MEDLINE search from 1966 to 2006 using the search term malaria (with the subheadings congenital, diagnosis, drug therapy, epidemiology, and therapy). Additional references were obtained from searching the bibliographies of pertinent articles and by reviewing articles suggested by experts in the treatment of malaria in North America.Evidence Synthesis: Important measures to reduce morbidity and mortality from malaria in the United States include the following: obtaining a travel history, considering malaria in the differential diagnosis of fever based on the travel history, and prompt and accurate diagnosis and treatment. Chloroquine remains the treatment of choice for Plasmodium falciparum acquired in areas without chloroquine-resistant strains. In areas with chloroquine resistance, a combination of atovaquone and proguanil or quinine plus tetracycline or doxycycline or clindamycin are the best treatment options. Chloroquine remains the treatment of choice for all other malaria species, with the exception of P vivax acquired in Indonesia or Papua New Guinea, in which case atovaquone-proguanil is best, with mefloquine or quinine plus tetracycline or doxycycline as alternatives. Quinidine is currently the recommended treatment for severe malaria in the United States because the artemisinins are not yet available. Severe malaria occurs when a patient with asexual malaria parasitemia, and no other confirmed cause of symptoms, has 1 or more designated clinical or laboratory findings. The only adjunctive measure recommended in severe malaria is exchange transfusion.Conclusions: Malaria remains a diagnostic and treatment challenge for US clinicians as increasing numbers of persons travel to and emigrate from malarious areas. A strong evidence base exists to help clinicians rapidly initiate appropriate therapy and minimize the major mortality and morbidity burdens caused by this disease. [ABSTRACT FROM AUTHOR]

Context: More than 50 million US adults take aspirin regularly for long-term prevention of cardiovascular disease, typically either 81 mg/d or 325 mg/d. Controversy remains regarding the most appropriate long-term daily dose.Objective: To review the mechanism of action of aspirin and the clinical literature for relationships among aspirin dosage, efficacy, and safety.Evidence Acquisition: A systematic review of the English-language literature was undertaken using MEDLINE and EMBASE (searched through February 2007) and the search term aspirin or acetylsalicylic acid and dose. The search was limited to clinical trials and was extended by a review of bibliographies of pertinent reports of original data and review articles. Published prospective studies using different aspirin dosages in the setting of cardiovascular disease were included.Evidence Synthesis: Although pharmacodynamic data demonstrate that long-term aspirin dosages as low as 30 mg/d are adequate to fully inhibit platelet thromboxane production, dosages as high as 1300 mg/d are approved for use. In the United States, 81 mg/d of aspirin is prescribed most commonly (60%), followed by 325 mg/d (35%). The available evidence, predominantly from secondary-prevention observational studies, supports that dosages greater than 75 to 81 mg/d do not enhance efficacy, whereas larger dosages are associated with an increased incidence of bleeding events, primarily related to gastrointestinal tract toxicity.Conclusions: Currently available clinical data do not support the routine, long-term use of aspirin dosages greater than 75 to 81 mg/d in the setting of cardiovascular disease prevention. Higher dosages, which may be commonly prescribed, do not better prevent events but are associated with increased risks of gastrointestinal bleeding. [ABSTRACT FROM AUTHOR]

Objectives: We examined the safety and efficacy of nonculprit multivessel compared with culprit-only stenting in patients with multivessel disease presenting with unstable angina or non-ST-segment elevation myocardial infarction (non-ST-segment elevation acute coronary syndromes [NSTE-ACS]).Background: In patients presenting with NSTE-ACS, multivessel coronary artery disease (CAD) is associated with adverse outcome.Methods: Patients with multivessel CAD and NSTE-ACS that underwent percutaneous coronary intervention were included. The culprit lesion was defined by reviewing each patient's angiographic report, electrocardiogram, echocardiogram and, if available, nuclear stress test. All patients had at least 2 vessels with > or =50% stenosis, and the angiographic severity of CAD was assessed using the Duke Prognostic Angiographic Score. Patients with coronary bypass grafts, chronic total occlusions, and those with uncertain culprit lesions were excluded. Our end point was the composite of death, myocardial infarction, or any target vessel revascularization.Results: From January 1995 to June 2005, 1,240 patients with ACS and multivessel CAD underwent percutaneous coronary intervention with bare-metal stenting and met our study criteria. Of these, 479 underwent multivessel and 761 underwent culprit-only stenting. There were 442 events during a median follow-up of 2.3 years. Multivessel intervention was associated with lower death, myocardial infarction, or revascularization after both adjusting for baseline and angiographic characteristics (hazard ratio 0.80; 95% confidence interval 0.64 to 0.99; p = 0.04) and propensity matched analysis (hazard ratio 0.67; 95% confidence interval 0.51 to 0.88; p = 0.004).Conclusions: In patients with multivessel CAD presenting with NSTE-ACS, multivessel intervention was significantly associated with a lower revascularization rate, which translated to a lower incidence of the composite end point compared with culprit-only stenting. [ABSTRACT FROM AUTHOR]

Context: Fish (finfish or shellfish) may have health benefits and also contain contaminants, resulting in confusion over the role of fish consumption in a healthy diet.Evidence Acquisition: We searched MEDLINE, governmental reports, and meta-analyses, supplemented by hand reviews of references and direct investigator contacts, to identify reports published through April 2006 evaluating (1) intake of fish or fish oil and cardiovascular risk, (2) effects of methylmercury and fish oil on early neurodevelopment, (3) risks of methylmercury for cardiovascular and neurologic outcomes in adults, and (4) health risks of dioxins and polychlorinated biphenyls in fish. We concentrated on studies evaluating risk in humans, focusing on evidence, when available, from randomized trials and large prospective studies. When possible, meta-analyses were performed to characterize benefits and risks most precisely.Evidence Synthesis: Modest consumption of fish (eg, 1-2 servings/wk), especially species higher in the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduces risk of coronary death by 36% (95% confidence interval, 20%-50%; P<.001) and total mortality by 17% (95% confidence interval, 0%-32%; P = .046) and may favorably affect other clinical outcomes. Intake of 250 mg/d of EPA and DHA appears sufficient for primary prevention. DHA appears beneficial for, and low-level methylmercury may adversely affect, early neurodevelopment. Women of childbearing age and nursing mothers should consume 2 seafood servings/wk, limiting intake of selected species. Health effects of low-level methylmercury in adults are not clearly established; methylmercury may modestly decrease the cardiovascular benefits of fish intake. A variety of seafood should be consumed; individuals with very high consumption (> or =5 servings/wk) should limit intake of species highest in mercury levels. Levels of dioxins and polychlorinated biphenyls in fish are low, and potential carcinogenic and other effects are outweighed by potential benefits of fish intake and should have little impact on choices or consumption of seafood (women of childbearing age should consult regional advisories for locally caught freshwater fish).Conclusions: For major health outcomes among adults, based on both the strength of the evidence and the potential magnitudes of effect, the benefits of fish intake exceed the potential risks. For women of childbearing age, benefits of modest fish intake, excepting a few selected species, also outweigh risks. [ABSTRACT FROM AUTHOR]

Context: While current practice guidelines provide an evidence-based approach to management of acute coronary syndromes (ACS), application of the evidence by individual physicians has been suboptimal.Objective: To assess and synthesize the evidence regarding optimal management of non-ST-segment elevation ACS (NSTE-ACS).Data Sources: Systematic searches of peer-reviewed publications were performed in MEDLINE and the Cochrane Database from January 1990 through November 2004, with consultation by content experts. Search terms included antiplatelet therapy, antithrombotic therapy, angiotensin-converting enzyme inhibition, angiotensin receptor blockade, beta-blockade, hypertension, hyperlipidemia, cigarette smoking, diet, diabetes mellitus, exercise, myocardial ischemia, and coronary artery disease.Study Selection and Data Extraction: Criteria for selection of studies included controlled study design, English language, and clinical pertinence. Data quality was based on the publishing journal and relevance to clinical management of NSTE-ACS.Data Synthesis: While outcomes of controlled studies support a comprehensive approach in the management of patients with NSTE-ACS, many physicians perceive existing guidelines as lengthy and complex. After risk stratification to identify those patients most likely to benefit from an early invasive vs early conservative strategy, a comprehensive management plan can be assembled through an "ABCDE" approach. The elements of this include "A" for antiplatelet therapy, anticoagulation, angiotensin-converting enzyme inhibition, and angiotensin receptor blockade; "B" for beta-blockade and blood pressure control; "C" for cholesterol treatment and cigarette smoking cessation; "D" for diabetes management and diet; and "E" for exercise.Conclusion: An "ABCDE" approach for the management of NSTE-ACS provides a practical and systematic means to implement evidence-based medicine into clinical practice. [ABSTRACT FROM AUTHOR]

Context: Coronary heart disease (CHD) remains the leading cause of mortality in industrialized countries and is rapidly becoming a primary cause of death worldwide. Thus, identification of the dietary changes that most effectively prevent CHD is critical.Objective: To review metabolic, epidemiologic, and clinical trial evidence regarding diet and CHD prevention.Data Sources and Study Selection: We searched MEDLINE through May 2002 for epidemiologic and clinical investigations of major dietary factors (fat, cholesterol, omega-3 fatty acids, trans-fatty acids, carbohydrates, glycemic index, fiber, folate, specific foods, and dietary patterns) and CHD. We selected 147 original investigations and reviews of metabolic studies, epidemiologic studies, and dietary intervention trials of diet and CHD.Data Extraction: Data were examined for relevance and quality and extracted by 1 of the authors.Data Synthesis: Compelling evidence from metabolic studies, prospective cohort studies, and clinical trials in the past several decades indicates that at least 3 dietary strategies are effective in preventing CHD: substitute nonhydrogenated unsaturated fats for saturated and trans-fats; increase consumption of omega-3 fatty acids from fish, fish oil supplements, or plant sources; and consume a diet high in fruits, vegetables, nuts, and whole grains and low in refined grain products. However, simply lowering the percentage of energy from total fat in the diet is unlikely to improve lipid profile or reduce CHD incidence. Many issues remain unsettled, including the optimal amounts of monounsaturated and polyunsaturated fats, the optimal balance between omega-3 and omega-6 polyunsaturated fats, the amount and sources of protein, and the effects of individual phytochemicals, antioxidant vitamins, and minerals.Conclusions: Substantial evidence indicates that diets using nonhydrogenated unsaturated fats as the predominant form of dietary fat, whole grains as the main form of carbohydrates, an abundance of fruits and vegetables, and adequate omega-3 fatty acids can offer significant protection against CHD. Such diets, together with regular physical activity, avoidance of smoking, and maintenance of a healthy body weight, may prevent the majority of cardiovascular disease in Western populations. [ABSTRACT FROM AUTHOR]

This study assessed the safety and efficacy of a single-daily dose antibiotic regimen potentially suited to outpatient administration, compared with a triple antibiotic regimen using traditional dosing in febrile neutropenic recipients of autologous peripheral blood progenitor cell transplants. This was a randomized, comparative trial performed in a bone marrow transplant inpatient unit at a 925-bed academic medical center. Eighty patients with breast cancer, Hodgkin's disease, non-Hodgkin's lymphoma, or other cancers receiving autologous peripheral blood progenitor cell transplants were enrolled in the trial. At the time of first episode of neutropenic fever, patients were randomized to receive either CipoTV (single-daily-dose vancomycin 1.5 g/d plus single-daily dose tobramycin 5 tng/kg/d plus oral ciprofloxacin 750 mg po BID) versus Cef/TV (vancomycin 1 g IV q 12h plus tobramycin 2 mg/kg IV load, then 1.4 mg/kg q 8h, plus ceftazidime 1 g IV q 8h). Positive blood cultures, serum creatinine, neutropenic days, total antibiotic days, documented infection, rash, diarrhea, and length of stay all were not significantly different between CipTV and CetTV. There were no deaths in either group. There was a trend toward more febrile days and more changes in regimen in the CipTV group. Changes in dosing were more frequent in the CipTV group (43% vs. 18%, p = 0.02, OR 3.32), largely reflecting change from single-daily to standard dosing. Comparison of CipTV and CefTV showed no significant differences in outcome, but both regimens were changed frequently. In particular, inability to continue oral ciprotloxacin in patients with mucositis, and clinician tendency to seek alternative gram-negative and expanded anaerobic coverage, may make such a regimen impractical for outpatient administration. [ABSTRACT FROM AUTHOR]

Context: Many studies indicate that women are less likely than men to undergo cardiac procedures after an acute myocardial infarction (AMI), raising concerns of sexual bias in clinical care. However, no data exist regarding the relationship between patient sex, physician sex, and use of cardiac procedures.Objective: To determine whether sex differences in cardiac catheterization after AMI were greater when patients were treated by male attending physicians compared with female attending physicians.Design, Setting, and Patients: Analysis of data from the Cooperative Cardiovascular Project, a retrospective medical record review. A total of 104 >231 Medicare fee-for-service beneficiaries who were hospitalized in US acute care hospitals for an AMI between January 1994 and February 1995.Main Outcome Measure: Use of cardiac catheterization within 60 days of admission, compared between the 4 groups of patient sex-physician sex combinations.Results: Women underwent fewer cardiac catheterizations than men when treated by either male physicians (38.6% vs 50.8%; P =.001) or female physicians (34.8% vs 45.8%; P =.001). Sex differences in procedure use were not greater when a patient and physician were of different sexes (P for interaction =.85). After potential confounders in multivariable analysis were accounted for, women were less likely to undergo cardiac catheterization (risk ratio, 0.90 [95% confidence interval (CI), 0.88-0.92]), regardless of the treating physician's sex. Patients treated by male physicians were more likely to undergo cardiac catheterization (risk ratio, 1.06 [95%CI, 1.02-1.10]) than those treated by female physicians, regardless of patient sex.Conclusions: Women who have had an AMI undergo a cardiac catheterization less often than men, whether treated by a male or female physician. These results suggest that factors other than sexual bias by male physicians toward women account for sex differences in cardiac procedure use. [ABSTRACT FROM AUTHOR]

Context: Although aspirin has been shown to reduce cardiovascular morbidity and short-term mortality following acute myocardial infarction, the association between its use and long-term all-cause mortality has not been well defined.Objectives: To determine whether aspirin is associated with a mortality benefit in stable patients with known or suspected coronary disease and to identify patient characteristics that predict the maximum absolute mortality benefit from aspirin.Design and Setting: Prospective, nonrandomized, observational cohort study conducted between 1990 and 1998 at an academic medical institution, with a median follow-up of 3.1 years.Patients: Of 6174 consecutive adults undergoing stress echocardiography for evaluation of known or suspected coronary disease, 2310 (37%) were taking aspirin. Patients with significant valvular disease or documented contraindication to aspirin use, including peptic ulcer disease, renal insufficiency, and use of nonsteroidal anti-inflammatory drugs, were excluded.Main Outcome Measure: All-cause mortality according to aspirin use.Results: During 3.1 years of follow-up, 276 patients (4.5%) died. In a simple univariable analysis, there was no association between aspirin use and mortality (4.5% vs 4.5%). However, after adjustment for age, sex, standard cardiovascular risk factors, use of other medications, coronary disease history, ejection fraction, exercise capacity, heart rate recovery, and echocardiographic ischemia, aspirin use was associated with reduced mortality (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.51-0.87; P =.002). In further analysis using matching by propensity score, 1351 patients who were taking aspirin were at lower risk for death than 1351 patients not using aspirin (4% vs 8%, respectively; HR, 0.53; 95% CI, 0.38-0.74; P =.002). After adjusting for the propensity for using aspirin, as well as other possible confounders and interactions, aspirin use remained associated with a lower risk for death (adjusted HR, 0.56; 95% CI, 0.40-0.78; P<.001). The patient characteristics associated with the most aspirin-related reductions in mortality were older age, known coronary artery disease, and impaired exercise capacity.Conclusion: Aspirin use among patients undergoing stress echocardiography was independently associated with reduced long-term all-cause mortality, particularly among older patients, those with known coronary artery disease, and those with impaired exercise capacity. [ABSTRACT FROM AUTHOR]

Background: Abnormal heart rate recovery after symptom-limited exercise predicts death. It is unknown whether this is also true among patients undergoing submaximal testing.Objective: To test the prognostic implications of heart rate recovery in cardiovascularly healthy adults undergoing submaximal exercise testing.Design: Population-based cohort study.Setting: 10 primary care sites.Participants: 5234 adults without evidence of cardiovascular disease who were enrolled in the Lipid Research Clinics Prevalence Study.Measurements: Heart rate recovery was defined as the change from peak heart rate to that measured 2 minutes later (heart rate recovery was defined as < or =42 beats/min).Results: During 12 years of follow-up, 312 participants died. Abnormal heart rate recovery predicted death (relative risk, 2.58 [CI, 2.06 to 3.20]). After adjustment for standard risk factors, fitness, and resting and exercise heart rates, abnormal heart rate recovery remained predictive (adjusted relative risk, 1.55 [CI, 1.22 to 1.98]) (P<0.001).Conclusion: Even after submaximal exercise, abnormal heart rate recovery predicts death. [ABSTRACT FROM AUTHOR]

Functional testing is recommended for risk stratification of medically treated patients with unstable angina. Exercise echocardiography is used in this situation, but its safety and prognostic value are not well defined. The objective of this study was to assess the incremental prognostic value of exercise echocardiography in 226 consecutive patients (128 men, age 59+/-13 years) with medically treated unstable angina, who underwent exercise echocardiography from 1991 to 1996. Clinical risk was designated as low in 108 patients, intermediate in 116, and high in 2 patients according to the unstable angina practice guidelines. There were no major complications from the stress tests. The exercise electrocardiogram was nondiagnostic in 57 patients (25%). Ischemia was identified by exercise electrocardiography in 33 patients and exercise echocardiography in 55 patients. Patients were followed for 29+/-18 months. After exclusion of 38 patients who underwent early revascularization, 28 patients had cardiac death, nonfatal infarction, and late (>3 months) revascularization. Ischemia at exercise echocardiography was associated with a 24-month event-free survival of 81%, compared to 95% with negative exercise echocardiography (p=0.02). A positive exercise electrocardiogram was associated with a 24-month event-free survival of 84%, compared to 93% with negative exercise electrocardiograms (p=0.08). In a Cox regression model, event-free survival was predicted by ischemia at exercise echocardiography (relative risk 2.8, confidence interval: 1.3 to 6.3, p=0.05), but not at exercise electrocardiography (relative risk 2.1, confidence interval 0.7 to 5.8, p=0.16). [ABSTRACT FROM AUTHOR]