A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer.

BACKGROUND: Masitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. RESULTS: Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. CONCLUSIONS: The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00789633.

A scoring system for ascertainment of incident stroke; the Risk Index Score (RISc).

OBJECTIVES: The main objective of this study was to develop and validate a computer-based statistical algorithm that could be translated into a simple scoring system in order to ascertain incident stroke cases using hospital admission medical records data. METHODS: The Risk Index Score (RISc) algorithm was developed using data collected prospectively by the Brain Attack Surveillance in Corpus Christi (BASIC) project, 2000. The validity of RISc was evaluated by estimating the concordance of scoring system stroke ascertainment to stroke ascertainment by physician and/or abstractor review of hospital admission records. RESULTS: RISc was developed on 1718 randomly selected patients (training set) and then statistically validated on an independent sample of 858 patients (validation set). A multivariable logistic model was used to develop RISc and subsequently evaluated by goodness-of-fit and receiver operating characteristic (ROC) analyses. The higher the value of RISc, the higher the patient's risk of potential stroke. The study showed RISc was well calibrated and discriminated those who had potential stroke from those that did not on initial screening. CONCLUSION: In this study we developed and validated a rapid, easy, efficient, and accurate method to ascertain incident stroke cases from routine hospital admission records for epidemiologic investigations. Validation of this scoring system was achieved statistically; however, clinical validation in a community hospital setting is warranted.

Random research.

Advances in computing have combined with the rapid dissemination of treatment discoveries for diseases of public health importance to create pressure for accelerated promulgation of promising research results to the medical community. The 2 recent examples of the US Carvedilol Heart Failure program and the Evaluation of Losartan In the Elderly (ELITE) study demonstrate the importance of the prospective nature of research design, as well as the consequences of its abandonment. This article explains in nonmathematical terms the rationale for the tenet "first say what you will do, then do what you said" in sample-based research.

VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial.

BACKGROUND: Plasma triglyceride concentration has been an inconsistent independent risk factor for coronary heart disease, perhaps because of the metabolic heterogeneity among VLDL particles, the main carriers of triglycerides in plasma. METHODS AND RESULTS: We conducted a prospective, nested case-control study in the Cholesterol and Recurrent Events (CARE) trial, a randomized placebo-controlled trial of pravastatin in 4159 patients with myocardial infarction and average LDL concentrations at baseline (115 to 174 mg/dL, mean 139 mg/dL). Baseline concentrations of VLDL-apolipoprotein (apo) B (the VLDL particle concentration), VLDL lipids, and apoCIII and apoE in VLDL+LDL and in HDL were compared in patients who had either a myocardial infarction or coronary death (cases, n=418) with those in patients who did not have a cardiovascular event (control subjects, n=370) in 5 years of follow-up. VLDL-cholesterol, VLDL-triglyceride, VLDL-apoB, apoCIII and apoE in VLDL+LDL and apoE in HDL were all interrelated, and each was a univariate predictor of subsequent coronary events. The significant independent predictors were VLDL-apoB (relative risk [RR] 3.2 for highest to lowest quintiles, P:=0.04), apoCIII in VLDL+LDL (RR 2.3, P:=0.04), and apoE in HDL (RR 1.8, P:=0.02). Plasma triglycerides, a univariate predictor of coronary events (RR 1.6, P:=0.03), was not related to coronary events (RR 1.3, P:=0.6) when apoCIII in VLDL+LDL was included in the model, whereas apoCIII remained significant. Adjustment for LDL- and HDL-cholesterol did not affect these results. CONCLUSIONS: The plasma concentrations of VLDL particles and apoCIII in VLDL and LDL are more specific measures of coronary heart disease risk than plasma triglycerides perhaps because their known metabolic properties link them more closely to atherosclerosis.

Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. The Care Investigators.

BACKGROUND: The role of lipid modification in stroke prevention is controversial, although increasing evidence suggests that HMG-CoA reductase inhibition may reduce cerebrovascular events in patients with prevalent coronary artery disease. METHODS AND RESULTS: To test the hypothesis that cholesterol reduction with pravastatin may reduce stroke incidence after myocardial infarction, we followed 4159 subjects with average total and LDL serum cholesterol levels (mean, 209 and 139 mg/dL, respectively) who had sustained an infarction an average of 10 months before study entry and who were randomized to pravastatin 40 mg/d or placebo in the Cholesterol and Recurrent Events (CARE) trial. Using prospectively defined criteria, we assessed the incidence of stroke, a prespecified secondary end point, and transient ischemic attack (TIA) over a median 5-year follow-up period. Patients were well matched for stroke risk factors and the use of antiplatelet agents (85% of subjects in each group). Compared with placebo, pravastatin lowered total serum cholesterol by 20%, LDL cholesterol by 32%, and triglycerides by 14% and raised HDL cholesterol by 5% over the course of the trial. A total of 128 strokes (52 on pravastatin, 76 on placebo) and 216 strokes or TIAs (92 on pravastatin, 124 on placebo) were observed, representing a 32% reduction (95% CI, 4% to 52%, P=0.03) in all-cause stroke and 27% reduction in stroke or TIA (95% CI, 4% to 44%, P=0.02). All categories of strokes were reduced, and treatment effect was similar when adjusted for age, sex, history of hypertension, cigarette smoking, diabetes, left ventricular ejection fraction, and baseline total, HDL, and LDL cholesterol and triglyceride levels. There was no increase in hemorrhagic stroke in patients on pravastatin compared with placebo (2 versus 6, respectively). CONCLUSIONS: Pravastatin significantly reduced stroke and stroke or TIA incidence after myocardial infarction in patients with average serum cholesterol levels despite the high concurrent use of antiplatelet therapy.

Criteria for the accurate interpretation of changes in left ventricular ejection fraction and cardiac volumes as assessed by rest and exercise gated radionuclide angiography.

Although serial left ventricular ejection fraction and volumetric measurements using gated radionuclide angiography are commonly used to evaluate clinical changes and therapeutic outcomes in individual patients, criteria are not available for accurately interpreting whether a change in any of these hemodynamic measurements is clinically meaningful. Accordingly, the magnitude of inherent variability among sequential measurements of hemodynamic variables assessed by gated radionuclide angiography was investigated in a double-blind placebo-controlled fashion in 39 patients during two placebo periods separated by 6 weeks. All patients analyzed had remained clinically stable during the study period. Although the mean values for all hemodynamic variables between the two placebo periods were minimally changed, the differences in individual patients were striking. Criteria were developed to allow meaningful interpretation of changes in hemodynamic variables by estimating the likelihood that an observed change is due to variability alone. On the basis of this analysis of placebo radionuclide angiographic data, variation due to chance alone is unlikely to account for all variability if a change observed between the two rest gated studies in a patient is greater than or equal to 7% units for left ventricular ejection fraction, greater than or equal to 45 ml/m2 for end-diastolic volume index, greater than or equal to 35 ml/m2 for end-systolic volume index, greater than or equal to 20 ml/m2 for stroke volume index and greater than or equal to 1.25 liters/min per m2 for cardiac index. An observed 4% unit change in left ventricular ejection fraction (increase or decrease) after a medical intervention in an individual patient occurs by random variation greater than 25% of the time.(ABSTRACT TRUNCATED AT 250 WORDS)

Nicotine patch therapy in smoking cessation reduces the extent of exercise-induced myocardial ischemia.

OBJECTIVES: We sought to determine the effects of nicotine patch therapy, when used to promote smoking cessation, on myocardial ischemia in patients with coronary artery disease. BACKGROUND: Nicotine patches substantially increase quit rates among cigarette smokers, but their safety in patients with myocardial ischemia who are attempting to quit smoking is unknown. METHODS: This is a prospective study using exercise thallium-201 single-photon emission computed tomography (SPECT) to assess serial changes in the total and ischemic myocardial perfusion defect size at baseline while patients were smoking and during treatment with 14- and 21-mg nicotine patches. Entry criteria required that patients 1) smoked > or = 1 pack of cigarettes per day; 2) had known coronary artery disease; and 3) had myocardial ischemia (i.e., > or = 5% reversible perfusion defect) on SPECT. All patients performed symptom-limited treadmill exercise, and the baseline SPECT study served as its own control. We interpreted and computer quantified the SPECT images with no knowledge of the testing sequence. RESULTS: Thirty-six of the 40 enrolled patients had exercise SPECT at baseline and during treatment with at least 14-mg nicotine patches. These patients had an initial perfusion defect size of 17.5 +/- 10.6% while smoking an average of 31 +/- 11 cigarettes per day for 40 +/- 12 years. A significant reduction in the total perfusion defect size (p < 0.001) was observed from baseline (17.5 +/- 10.6%) to treatment with 14-mg (12.6 +/- 10.1%) and 21-mg (11.8 +/- 9.9%) nicotine patches. This reduction occurred despite an increase in treadmill exercise duration (p < 0.05) and higher serum nicotine levels (p < 0.001). There was a significant correlation between the reduction in defect size and exhaled carbon monoxide levels (p < 0.001) because patients reduced their smoking by approximately 74% during the trial. CONCLUSIONS: Nicotine patches, when used to promote smoking cessation, significantly reduce the extent of exercise-induced myocardial ischemia as assessed by exercise thallium-201 SPECT.

Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators.

OBJECTIVES: This study assessed whether treatment with a beta-adrenergic blocking agent in addition to the use of the angiotensin-converting enzyme (ACE) inhibitor captopril decreases cardiovascular mortality and morbidity in patients with asymptomatic left ventricular dysfunction after myocardial infarction (MI) and whether the presence of neurohumoral activation at the time of hospital discharge predicts the effects of beta-blocker treatment in these patients. BACKGROUND: Both beta-blockers and ACE inhibitors have been shown to have beneficial effects in patients with left ventricular dysfunction but no overt heart failure after MI. These patients often have persistent neurohumoral activation at the time of hospital discharge, and one would expect that patients with activation of the sympathetic nervous system derive the most benefit from treatment with beta-blockers. However, beta-blockers are underutilized in this high risk group of patients, and it is unknown whether their beneficial effects are additive to those of ACE inhibitors. METHODS: We performed a retrospective analysis of data from the Survival and Ventricular Enlargement (SAVE) study and its neurohumoral substudy. The relations between beta-blocker use at the time of randomization and neurohumoral activation and the subsequent development of cardiovascular events were analyzed by use of Cox proportional hazards models controlling for covariates. RESULTS: After adjustment for baseline imbalances, beta-blocker use was associated with a significant reduction in risk of cardiovascular death (30%, 95% confidence interval [CI] 12% to 44%) and development of heart failure (21%, 95% CI 3% to 36%), but the reduction in recurrent MI (11%, 95% CI 13% to 31%) was not significant. These reductions were independent of the use of captopril. Beta-blockers were not found to have a greater effect in patients with neurohumoral activation at the time of hospital discharge. CONCLUSIONS: The beneficial effects of beta-blocker use at the time of hospital discharge in patients with asymptomatic left ventricular dysfunction after MI appear to be additive to those of captopril and other interventions known to improve prognosis. Neurohumoral activation at the time of hospital discharge fails to identify those patients who will derive the greatest benefit from treatment with beta-blockers.

Pravastatin prevents clinical events in revascularized patients with average cholesterol concentrations. Cholesterol and Recurrent Events CARE Investigators.

OBJECTIVES: This analysis was carried out to determine if revascularized patients derive benefit from the 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin. BACKGROUND: The HMG-CoA reductase inhibitors result in substantial reductions in serum cholesterol and stabilization of atherosclerotic plaques in patients with coronary artery disease. METHODS: Pravastatin was found to reduce clinical cardiovascular events in the Cholesterol and Recurrent Events (CARE) trial consisting of 4,159 patients with a documented myocardial infarction and an average cholesterol level (mean 209 mg/dl and all <240 mg/dl). A total of 2,245 patients underwent coronary revascularization before randomization including 1,154 patients with percutaneous transluminal coronary angioplasty (PTCA) alone, 876 patients with coronary artery bypass graft (CABG) alone, and 215 patients with both procedures. Clinical events in revascularized patients were compared between patients on placebo and on pravastatin. RESULTS: In the 2,245 patients who had undergone revascularization, the primary endpoint of coronary heart disease death or nonfatal myocardial infarction (MI) was reduced by 4.1% with pravastatin (relative risk [RR] reduction 36%, 95% confidence interval [CI] 17 to 51, p = 0.001). Fatal or nonfatal MI was reduced by 3.3% (RR reduction 39%, 95% CI 16 to 55, p = 0.002), postrandomization repeat revascularization was reduced by 2.6% (RR reduction 18%, 95% CI 1 to 33, p = 0.068) and stroke was reduced by 1.5% (RR reduction 39%, 95% CI 3 to 62, p = 0.037) with pravastatin. Pravastatin was beneficial in both the 1,154 PTCA patients and in the 1,091 CABG patients who had undergone revascularization before randomization. CONCLUSIONS: Pravastatin reduced clinical events in revascularized postinfarction patients with average cholesterol levels. This therapy was well tolerated and its use should be considered in most patients following coronary revascularization.

Activation of neurohumoral systems in postinfarction left ventricular dysfunction.

OBJECTIVES: This study was conducted to evaluate the degree of neurohumoral activation around the time of hospital discharge after myocardial infarction. BACKGROUND: Because pharmacologic interventions that block the effects of neurohumoral activation improve the prognosis after infarction, we hypothesized that widespread neurohumoral activation persists in some patients until at least the time of hospital discharge and that the determinants of activation vary from one system to another. METHODS: Five hundred nineteen patients in the Survival and Ventricular Enlargement Study (SAVE) had plasma neurohormones measured before randomization at a mean of 12 days after infarction. All patients had left ventricular dysfunction (left ventricular ejection fraction < or = 40%) but no overt heart failure. RESULTS: Although all neurohormones except epinephrine were increased compared with values in age-matched control subjects, plasma norepinephrine (301 +/- 193 vs. 222 +/- 87 pg/ml, p < 0.001), renin activity (3.0 +/- 3.7 vs. 1.2 +/- 1.2 ng/ml per h, p < 0.001), arginine vasopressin (1.9 +/- 6.9 vs. 0.7 +/- 0.3 pg/ml, p < 0.001) and atrial natriuretic peptide (75 +/- 75 vs. 21 +/- 9 pg/ml, p < 0.001) values ranged from normal to very high, indicating a wide spectrum of neurohumoral activation. Activation of one system did not correlate with activation of another. The clinical and laboratory variables most closely associated with neurohumoral activation were Killip class, left ventricular ejection fraction, age and use of diuretic drugs. The association between neurohumoral activation and clinical and laboratory variables varied from one neurohormone to another. CONCLUSIONS: Neurohumoral activation occurs in a significant proportion of patients at the time of hospital discharge after infarction. Which neurohormone is activated and which clinical and laboratory variables determine this activation vary from one neurohormone to another.

Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: effect of captopril.

OBJECTIVES: This study attempted to evaluate whether neurohumoral activation at the time of hospital discharge in postinfarction patients helps to predict long-term prognosis and whether long-term therapy with the angiotensin-converting enzyme inhibitor captopril modifies this relation. BACKGROUND: Neurohumoral activation persists at the time of hospital discharge in a large number of postinfarction patients. The Survival and Ventricular Enlargement (SAVE) study demonstrated that the angiotensin-converting enzyme inhibitor captopril improves survival and decreases the development of severe heart failure in patients with left ventricular dysfunction (left ventricular ejection fraction < or = 40%) but no overt postinfarction heart failure. METHODS: In 534 patients in the SAVE study, plasma neurohormone levels were measured a mean of 12 days after infarction. Patients were then randomized to receive captopril or placebo and were followed up for a mean (+/- SD) of 38 +/- 6 months (range 24 to 55). The association between activation of plasma neurohormones at baseline and subsequent cardiovascular mortality or the development of heart failure was assessed with and without adjustment for other important prognostic factors. RESULTS: By univariate analysis, activation of plasma renin activity and aldosterone, norepinephrine, atrial natriuretic peptide and arginine vasopressin levels were related to subsequent cardiovascular events, whereas epinephrine and dopamine levels were not. By multivariate analysis, only plasma renin activity (relative risk 1.6, 95% confidence interval [CI] 1.0 to 2.5) and atrial natriuretic peptide (relative risk 2.2, 95% CI 1.3 to 3.8) were independently predictive of cardiovascular mortality, whereas the other neurohormones were not. Only plasma renin activity and aldosterone, atrial natriuretic peptide and arginine vasopressin were independent predictors of the combined end points of cardiovascular mortality, development of severe heart failure or recurrent myocardial infarction. Except for 1-year cardiovascular mortality, the use of captopril did not significantly modify these relations. CONCLUSIONS: Neurohumoral activation at the time of hospital discharge in postinfarction patients is an independent sign of poor prognosis. This is particularly true for plasma renin activity and atrial natriuretic peptide. Except for 1-year cardiovascular mortality, captopril does not significantly modify these relations.

Effect of pravastatin on cardiovascular events in women after myocardial infarction: the cholesterol and recurrent events (CARE) trial.

OBJECTIVES: We sought to determine the effect of pravastatin on recurrent cardiovascular events in women with average cholesterol levels after myocardial infarction (MI). BACKGROUND: Little information is available on the effectiveness of lipid lowering in secondary prevention of coronary heart disease (CHD) in women; in particular, those with CHD and average cholesterol levels. METHODS: In the Cholesterol and Recurrent Events (CARE) trial, 576 postmenopausal women, between 3 and 20 months after MI, with a total cholesterol level <240 mg/dl and a low density lipoprotein cholesterol level 115 to 174 mg/dl, were randomized to receive pravastatin 40 mg/day or matching placebo for a median follow-up period of 5 years. The main outcome measures were combined coronary events (coronary death, nonfatal MI, percutaneous transluminal coronary angioplasty [PTCA] or coronary artery bypass graft surgery [CABG]), the primary trial end point (coronary death or nonfatal MI) and stroke. RESULTS: Women treated with pravastatin had a risk reduction of 43% for the primary end point (p = 0.035), 46% for combined coronary events (p = 0.001), 48% for PTCA (p = 0.025), 40% for CABG (p = 0.14) and 56% for stroke (p = 0.07). The 3,583 men in the CARE trial also showed a reduction in risk, but the magnitude tended to be less. Pravastatin improved plasma lipids similarly in men and women. There were no differences in risk of coronary events in the placebo group between men and women. Minor differences between men and women were present in baseline characteristics and treatment for MI, in general, conferring a higher risk status and a lower incidence of CABG in the women. CONCLUSIONS: Pravastatin led to significant early reduction of a wide range of cardiovascular events in post-MI women with average cholesterol levels.

Influence of baseline lipids on effectiveness of pravastatin in the CARE Trial. Cholesterol And Recurrent Events.

OBJECTIVES: We sought to assess the influence of baseline lipid levels on coronary event rates and the effectiveness of pravastatin therapy in the Cholesterol And Recurrent Events (CARE) study. BACKGROUND: The CARE study cohort provided a relatively unique opportunity to examine the relation between lipid levels and clinical events in a post-myocardial infarction (MI) population with relatively low cholesterol and low density lipoprotein (LDL) cholesterol values. METHODS: There were 4,159 patients with a previous infarct and a total cholesterol level <240 mg/dl, LDL cholesterol level 115 to 174 mg/dl and triglyceride level <350 mg/dl randomly allocated to placebo (n=2,078) or pravastatin 40 mg/day (n=2,081). Time to either coronary death or nonfatal MI (primary end point) or to the secondary end point, which included undergoing a coronary revascularization procedure, was determined as a function of baseline lipids (total, LDL, high density lipoprotein [HDL] cholesterol and triglyceride levels). RESULTS: Quartile analysis indicated important effects for LDL cholesterol, in which a higher LDL was associated with greater cardiac event rates (in the placebo group, every 25-mg/dl increment in LDL was associated with a 28% increased risk [5% to 56%, p=0.015]) in the primary event. The differential event rates with respect to baseline LDL cholesterol for placebo and pravastatin groups reduced the difference in clinical outcomes at lower LDL cholesterol levels. In both the placebo and pravastatin groups, an inverse relation between baseline HDL cholesterol and cardiac events was observed (10 mg/dl lower baseline HDL cholesterol level was associated with a 10% [0% to 19%, p=0.046] increase in coronary death or nonfatal MI). CONCLUSIONS: Within the LDL cholesterol levels in CARE (115 to 174 mg/dl), baseline values influenced both the risk of events in the placebo group as well as the clinical effectiveness of pravastatin therapy.

Impact of the treatment of isolated systolic hypertension on behavioral variables. Results from the systolic hypertension in the elderly program.

BACKGROUND: Little information has been published on the impact of antihypertensive medications on quality of life in older persons. Particular concern has existed that lowering systolic blood pressure in older persons might have adverse consequences on cognition, mood, or leisure activities. METHODS: A multicenter double-blind randomized controlled trial was conducted over an average of 5 years' followup involving 16 academic clinical trial clinics. Participants consisted of 4736 persons (1.06%) selected from 447,921 screenees aged 60 years and older. Systolic blood pressure at baseline ranged from 160 to 219 mm Hg, while diastolic blood pressure was less than 90 mm Hg. Participants were randomized to active antihypertensive drug therapy or matching placebo. Active treatment consisted of 12.5 to 25 mg of chlorthalidone for step 1, while step 2 consisted of 25 to 50 mg of atenolol. If atenolol was contraindicated, 0.05 to 0.10 mg of reserpine could be used for the second-step drug. The impact of drug treatment on measures of cognitive, emotional, and physical function and leisure activities was assessed. RESULTS: Our analyses demonstrate that active treatment of isolated systolic hypertension in the Systolic Hypertension in the Elderly Program cohort had no measured negative effects and, for some measures, a slight positive effect on cognitive, physical, and leisure function. The positive findings in favor of the treatment group were small. There was no effect on measures related to emotional state. Measures of cognitive and emotional function were stable in both groups for the duration of the study. Both treatment groups showed a modest trend toward deterioration of some measures of physical and leisure function over the study period. CONCLUSIONS: The overall study cohort exhibited decline over time in activities of daily living, particularly the more strenuous ones, and some decline in certain leisure activities. However, mood, cognitive function, basic self-care, and moderate leisure activity were remarkably stable for both the active and the placebo groups throughout the entire study. Results of this study support the inference that medical treatment of isolated systolic hypertension does not cause deterioration in measures of cognition, emotional state, physical function, or leisure activities.

Barriers to acute stroke therapy and stroke prevention in Mexican Americans.

BACKGROUND AND PURPOSE: The purpose of this study was to identify specific targets to improve acute stroke treatment and stroke prevention in the Mexican American (MA) community. METHODS: A professional, academic survey research team provided structured questions and elicited responses from 719 subjects identified by random-digit dialing in the biethnic community of Corpus Christi, TEXAS: This community of approximately 300 000 is approximately half MA and half non-Hispanic white (NHW). The cooperation rate for the survey was 58%. RESULTS: MAs (n=357) were younger, less well educated, and had lower family income than NHWs (n=362, P=0.001). MAs had a higher prevalence of diabetes mellitus (P=0.001) but similar rates of hypertension, elevated cholesterol, and current tobacco use. MAs less commonly recognized that acute stroke therapy existed (P=0.029), were less likely to acknowledge a time window for acute stroke treatment (P=0.001), and were more reticent to say they would call 911 for stroke symptoms (P=0.01) than NHWS: MAs were significantly less able to recall stroke symptoms and risk factors than NHWS: Only approximately 20% of both groups identified stroke as the NO: 1 cause of disability. MAs expressed less confidence in their ability to prevent stroke (P<0.001), more distrust in the medical establishment (P=0.007), and more concern that money impedes their seeking medical care (P<0.001). CONCLUSIONS: There are significant barriers to both acute stroke treatment and stroke prevention in MAS: This study identifies specific targets amenable for testing in an intervention project following confirmation by a methodology other than telephone survey.

Comparison of stroke hospitalization rates among Mexican-Americans and non-Hispanic whites.

The authors performed a prospective, community-based pilot stroke surveillance project in Nueces County, TX. Mexican-Americans showed a trend toward higher completed ischemic stroke hospitalization rates compared with non-Hispanic whites. Mexican-Americans were more commonly uninsured (p = 0.007) and were less likely to receive neuroimaging (p = 0.001). Additional studies are needed to confirm this finding and to determine the role of stroke risk factors and access to care variables.

Should linen in newborn intensive care units be autoclaved?

The American Academy of Pediatrics' Standards and Recommendations for Hospital Care of Newborn Infants recommends that linen in newborn intensive care, intermediate care, continuing care and admission observation areas be autoclaved. Questionnaires sent to 269 directors of newborn intensive care units (69% returned) showed that 74% of the respondents do not autoclave linen used in their newborn intensive care unit. There were 284 linen cultures performed in our newborn intensive care unit where linen is not autoclaved; 68% of the cultures were positive, but only 2.5% had a colony count greater than 20 colonies per plate. The most common organisms obtained were Staphylococcus epidermidis, diphtheroids, and Micrococcus species. Two cultures grew Staphylococcus aureus, one colony and two colonies per plate. Three-factor analysis of variance showed that the location of the linen in the top of the pile exerted a statistically significant effect on the bacterial contamination rate. The fact that three fourths of neonatal intensive care centers in this country do not autoclave nursery linen, the lack of reports in the literature relating linen contamination to nosocomial infections, and the microbiologic results of this study suggest that the recommendations of the American Academy of Pediatrics merit further study and reevaluation.

The Cardiac Arrhythmia Suppression Trial: background, interim results and implications.

The Cardiac Arrhythmia Suppression Trial (CAST) was designed to test the hypothesis that suppression of ventricular premature complexes (VPCs) in survivors of acute myocardial infarction would reduce arrhythmic death risk. Instead, a preliminary finding from the CAST was that the encainide and flecainide groups had a 3.6-fold increase in arrhythmic death compared with their placebo group. These unfortunate results were especially surprising in that the CAST population represented patients in whom the risk of arrhythmic death was only moderate and the risk of proarrhythmia was thought to be low. In contrast, the arrhythmic death rate of the CAST placebo group was unusually low, to the extent that it paralleled the arrhythmic death rate in previous clinical trials of patients surviving myocardial infarction with no ventricular arrhythmia. The excessive arrhythmic death rate in patients taking encainide and flecainide occurred over the duration of the CAST, implying a proarrhythmic effect that may be due to mechanisms that are unique in this population, and thus challenging traditional concepts of proarrhythmia. The existing knowledge regarding the proarrhythmic and negative inotropic effects of encainide and flecainide are reviewed. The previous pharmaceutical database experience with these 2 antiarrhythmic drugs exceeded 3,000 patients; however, there was no indication of this serious proarrhythmic effect. In contrast, the CAST population taking encainide and flecainide totaled only 725 patients who were followed for 10 months and had an extremely high proarrhythmic event rate. The reasons for this discrepancy are discussed. The results of the CAST emphasize the power of a randomized, placebo-controlled clinical trial to uncover previously unsuspected benefits or liabilities of traditional therapies.

Rationale, design and baseline characteristics of the survival and ventricular enlargement trial. SAVE Investigators.

Heart failure, often associated with ventricular enlargement and recurrent myocardial infarction, is one of the major causes of postinfarction mortality. This observation suggests that measures used to prevent ventricular enlargement may improve postinfarction survival. The Survival and Ventricular Enlargement (SAVE) trial is a randomized, double-blind, placebo-controlled clinical trial with the purpose of evaluating the effect of angiotensin-converting enzyme (ACE) inhibition on postinfarction death and ventricular dilation. This multicenter trial had a sample size goal of 2,220 patients between 21 and 79 years of age who had recently sustained a myocardial infarction and who have an ejection fraction determined by radionuclide ventriculogram (RVG-EF) of less than or equal to 40%. In addition to conventional therapy, patients were randomly assigned to captopril or placebo therapy commencing within 3-16 days following their myocardial infarction. A second RVG-EF is performed on all surviving participants at the end of the average 3.5-year treatment and follow-up period. The study has 90% power to detect a 25% improvement in postinfarction mortality or prevention of greater than or equal to 9 unit absolute reduction in radionuclide ejection fraction. Additional end points, design features, and the administrative organization of the trial are described.

Design of a randomized, placebo-controlled multicenter trial on the long-term effects of intermittent transdermal nitroglycerin on left ventricular remodeling after acute myocardial infarction. Transdermal Nitroglycerin Investigators Group.

Nitrates are widely used in the treatment of patients with ischemic heart disease and in those with angina following acute myocardial infarction. Short-term studies indicate that the administration of nitrates may prevent left ventricular (LV) dilation and infarct expansion. Animal models suggest that prolonged nitroglycerin use after infarction may limit LV remodeling similar to that observed with angiotensin-converting enzyme inhibitors. However, to date there have been no trials evaluating the effects of nitrates on LV volumes in patients surviving acute myocardial infarction. We therefore performed a randomized double-blind, placebo-controlled trial designed to investigate the long-term (6 month) efficacy of intermittent transdermal nitroglycerin patches on LV remodeling in 291 survivors of acute myocardial infarction. Patients were randomized to receive either placebo or a nitroglycerin patch that delivered 0.4, 0.8, or 1.6 mg/hour. Gated radionuclide angiography was used to assess serial changes in LV ejection and cardiac volumes. The baseline characteristics of the study population were similar in all 4 treatment groups. The study protocol and the main design-related issues are described.