ACAT inhibition and progression of carotid atherosclerosis in patients with familial hypercholesterolemia: the CAPTIVATE randomized trial.

CONTEXT: Inhibition of acyl coenzyme A:cholesterol acyltransferase (ACAT), an intracellular enzyme involved in cholesterol accumulation, with pactimibe was developed to assist in the prevention of cardiovascular disease. OBJECTIVE: To evaluate the efficacy and safety of pactimibe in inhibition of atherosclerosis. DESIGN, SETTING, AND PATIENTS: A prospective, randomized, stratified, double-blind, placebo-controlled study (Carotid Atherosclerosis Progression Trial Investigating Vascular ACAT Inhibition Treatment Effects [CAPTIVATE]) of 892 patients heterozygous for familial hypercholesterolemia conducted at 40 lipid clinics in the United States, Canada, Europe, South Africa, and Israel between February 1, 2004, and December 31, 2005. Study was terminated on October 26, 2005. INTERVENTION: Participants received either 100 mg/d of pactimibe (n = 443) or matching placebo (n = 438), in addition to standard lipid-lowering therapy. MAIN OUTCOME MEASURES: Carotid atherosclerosis, assessed by ultrasound carotid intima-media thickness (CIMT), at baseline, 12, 18, and 24 months. Maximum CIMT was the primary end point and mean CIMT the secondary end point. RESULTS: Because pactimibe failed to show efficacy in the intravascular coronary ultrasound ACTIVATE study, the CAPTIVATE study was terminated prematurely after a follow-up of 15 months. After 6 months of treatment with pactimibe, low-density lipoprotein cholesterol increased by 7.3% (SD, 23%) compared with 1.4% (SD, 28%) in the placebo group (P = .001). The carotid ultrasonographic scans of the 716 patients with at least 2 scans and obtained at least 40 weeks apart were analyzed. Maximum CIMT measurements did not show a pactimibe treatment effect (difference, 0.004 mm; 95% confidence interval [CI], -0.023 to 0.015 mm; P = .64); however, the less variable mean CIMT measurement revealed an increase of 0.014 mm (95% CI, -0.027 to 0.000 mm; P = .04) in patients administered pactimibe vs placebo. Major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) occurred more often in patients administered pactimibe vs placebo (10/443 [2.3%] vs 1/438 [0.2%]; P = .01). CONCLUSIONS: In patients with familial hypercholesterolemia, pactimibe had no effect on atherosclerosis as assessed by changes in maximum CIMT compared with placebo but was associated with an increase in mean CIMT as well as increased incidence of major cardiovascular events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00151788.

Clinical characteristics and initial management of patients with tuberculous pericarditis in the HIV era: the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry.

BACKGROUND: The incidence of tuberculous pericarditis has increased in Africa as a result of the human immunodeficiency virus (HIV) epidemic. However, the effect of HIV co-infection on clinical features and prognosis in tuberculous pericarditis is not well characterised. We have used baseline data of the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry to assess the impact of HIV co-infection on clinical presentation, diagnostic evaluation, and treatment of patients with suspected tuberculous pericarditis in sub-Saharan Africa. METHODS: Consecutive adult patients in 15 hospitals in three countries in sub-Saharan Africa were recruited on commencement of treatment for tuberculous pericarditis, following informed consent. We recorded demographic, clinical, diagnostic and therapeutic information at baseline, and have used the chi-square test and analysis of variance to assess probabilities of significant differences (in these variables) between groups defined by HIV status. RESULTS: A total of 185 patients were enrolled from 01 March 2004 to 31 October 2004, 147 (79.5%) of whom had effusive, 28 (15.1%) effusive-constrictive, and 10 (5.4%) constrictive or acute dry pericarditis. Seventy-four (40%) had clinical features of HIV infection. Patients with clinical HIV disease were more likely to present with dyspnoea (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.4 to 7.4, P = 0.005) and electrocardiographic features of myopericarditis (OR 2.8, 95% CI 1.1 to 6.9, P = 0.03). In addition to electrocardiographic features of myopericarditis, a positive HIV serological status was associated with greater cardiomegaly (OR 3.89, 95% CI 1.34 to 11.32, P = 0.01) and haemodynamic instability (OR 9.68, 95% CI 2.09 to 44.80, P = 0.0008). However, stage of pericardial disease at diagnosis and use of diagnostic tests were not related to clinical HIV status. Similar results were obtained for serological HIV status. Most patients were treated on clinical grounds, with microbiological evidence of tuberculosis obtained in only 13 (7.0%) patients. Adjunctive corticosteroids were used in 109 (58.9%) patients, with patients having clinical HIV disease less likely to be put on them (OR 0.37, 95% CI 0.20 to 0.68). Seven patients were on antiretroviral drugs. CONCLUSION: Patients with suspected tuberculous pericarditis and HIV infection in Africa have greater evidence of myopericarditis, dyspnoea, and haemodynamic instability. These findings, if confirmed in other studies, may suggest more intensive management of the cardiac disease is warranted in patients with HIV-associated pericardial disease.

Prospective evaluation of clinical outcomes after acute ST-elevation myocardial infarction in patients who are ineligible for reperfusion therapy: preliminary results from the TETAMI registry and randomized trial.

BACKGROUND: Treatment with lytics or primary percutaneous coronary interventions (PCI) reduces the mortality rate of patients with ST-elevation myocardial infarction (STEMI) presenting within 12 hours. Patients presenting >12 hours are generally considered to be ineligible for reperfusion therapy, and there are currently no specific treatment recommendations for this subgroup.Methods- All patients with STEMI <24 hours were included in the Treatment with Enoxaparin and Tirofiban in Acute Myocardial Infarction (TETAMI) randomized trial or registry. Those patients who were ineligible for acute reperfusion, had no cardiogenic shock, and were not planned for revascularization within 48 hours were randomized to 1 of 4 antithrombotic regimens involving enoxaparin or unfractionated heparin (UFH), in combination with tirofiban or placebo for 2 to 8 days. A concurrent registry tracked STEMI patients coming in within <12 hours, and who underwent reperfusion. This registry also tracked the remaining STEMI patients who neither received reperfusion nor were enrolled in the TETAMI randomized trial. The demographics and clinical outcomes of all three groups (received reperfusion therapy, too late for reperfusion and enrolled in the randomized trial, neither received reperfusion therapy nor were enrolled in the randomized trial) were prospectively tracked. RESULTS AND CONCLUSIONS: There were 2,737 patients who presented with STEMI or a new left branch bundle block (LBBB), of which 1,654 (60%) presented < or =12 hours. There were 1,196 (72%) of 1,654 patients who received reperfusion therapy. There were 458 (28%) of the 1,654 patients deemed "ineligible" for reperfusion, mostly because of a contraindication to lytics or for being "too old." In contrast, 1,083 (40%) of 2,737 patients presented >12 hours. Apart from 34 of these patients who had a stuttering infarction and were referred for reperfusion, the remaining patients did not receive reperfusion therapy. Registry patients who received reperfusion therapy, compared with TETAMI randomized patients (all of whom received antithrombotic therapy) and registry patients who did not receive reperfusion, were younger (61 years versus 63 years and 67 years), were more likely to be male (78% versus 73% and 63%), and had persistent ST-segment elevation as opposed to LBBB or Q waves. Registry patients who received reperfusion therapy had better clinical outcomes, even after adjusting for admission Killip class, compared with TETAMI randomized patients and registry patients who did not receive reperfusion therapy. TETAMI randomized patients had better outcomes than registry patients who did not receive reperfusion therapy. The major obstacle to expanding the delivery of reperfusion therapy to patients with STEMI is the large fraction of patients who present too late for reperfusion therapy. Examination of prospectively gathered data on STEMI patients who are ineligible for reperfusion may help optimize their treatment.

The safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and tirofiban versus placebo in the treatment of acute ST-segment elevation myocardial infarction patients ineligible for reperfusion (TETAMI): a randomized trial.

OBJECTIVES: The aims of the Safety and Efficacy of Subcutaneous Enoxaparin Versus Intravenous Unfractionated Heparin and Tirofiban Versus Placebo in the Treatment of Acute ST-Segment Elevation Myocardial Infarction Patients Ineligible for Reperfusion (TETAMI) study were to demonstrate that enoxaparin was superior to unfractionated heparin (UFH) and that tirofiban was better than placebo in patients with acute ST-segment elevation myocardial infarction (STEMI) who do not receive timely reperfusion. BACKGROUND: An optimal treatment strategy has not been identified for the many STEMI patients ineligible for acute reperfusion. METHODS: A total of 1224 patients were enrolled in 91 centers in 14 countries between July 1999 and July 2002. Patients with STEMI ineligible for reperfusion were randomized to enoxaparin, enoxaparin plus tirofiban, UFH, or UFH plus tirofiban. All patients received oral aspirin. The primary efficacy end point was the 30-day combined incidence of death, reinfarction, or recurrent angina; the primary analysis was the comparison of the pooled enoxaparin and UFH groups. RESULTS: The incidence of the primary efficacy end point was 15.7% enoxaparin versus 17.3% for UFH (odds ratio 0.89 [95% confidence interval CI = 0.66 to 1.21]) and 16.6% for tirofiban versus 16.4% for placebo (odds ratio 1.02 [95% CI 0.75 to 1.38]). The Thrombolysis In Myocardial Infarction (TIMI) major hemorrhage rate was 1.5% for enoxaparin versus 1.3% for UFH (odds ratio 1.16 [95% CI 0.44 to 3.02]) and 1.8% versus 1% for tirofiban versus placebo (odds ratio 1.82 [95% CI 0.67 to 4.95]). CONCLUSIONS: This study did not show that enoxaparin significantly reduced the 30-day incidence of death, reinfarction, and recurrent angina compared with UFH in non-reperfused STEMI patients. However, enoxaparin appears to have a similar safety and efficacy profile to UFH and may be an alternative treatment. Additional therapy with tirofiban did not appear beneficial.

Mortality in patients treated for tuberculous pericarditis in sub-Saharan Africa.

OBJECTIVE: To determine the mortality rate and its predictors in patients with a presumptive diagnosis of tuberculous pericarditis in sub-Saharan Africa. DESIGN: Between 1 March 2004 and 31 October 2004, we enrolled 185 consecutive patients with presumed tuberculous pericarditis from 15 referral hospitals in Cameroon, Nigeria and South Africa, and observed them during the 6-month course of antituberculosis treatment for the major outcome of mortality. This was an observational study, with the diagnosis and management of each patient left at the discretion of the attending physician. Using Cox regression, we have assessed the effect of clinical and therapeutic characteristics (recorded at baseline) on mortality during follow-up. RESULTS: We obtained the vital status of 174 (94%) patients (median age 33; range 14 - 87 years). The overall mortality rate was 26%. Mortality was higher in patients who had clinical features of HIV infection than in those who did not (40% v. 17%, p=0.001). Independent predictors of death during followup were: (i) a proven non-tuberculosis final diagnosis (hazard ratio (HR) 5.35, 95% confidence interval (CI) 1.76 - 16.25), (ii) the presence of clinical signs of HIV infection (HR 2.28, CI 1.14 - 4.56), (iii) coexistent pulmonary tuberculosis (HR 2.33, CI 1.20 - 4.54), and (iv) older age (HR 1.02, CI 1.01 - 1.05). There was also a trend towards an increase in death rate in patients with haemodynamic instability (HR 1.80, CI 0.90 - 3.58) and a decrease in those who underwent pericardiocentesis (HR 0.34, CI 0.10 - 1.19). CONCLUSION: A presumptive diagnosis of tuberculous pericarditis is associated with a high mortality in sub-Saharan Africa. Attention to rapid aetiological diagnosis of pericardial effusion and treatment of concomitant HIV infection may reduce the high mortality associated with the disease.

The role of gender and other factors as predictors of not receiving reperfusion therapy and of outcome in ST-segment elevation myocardial infarction.

BACKGROUND: The standard of care for ST-segment elevation myocardial infarction (STEMI) is prompt coronary reperfusion with thrombolysis or percutaneous coronary intervention. Women have higher mortality rates than men following STEMI and fewer women are considered eligible for reperfusion therapy. We analyzed the impact of gender, and other factors, on the outcome and treatment of STEMI in the TETAMI trial and registry. METHODS: This exploratory analysis included 2741 patients from Treatment with Enoxaparin and Tirofiban in Acute Myocardial Infarction (TETAMI) presenting with STEMI within 24 hours of symptom onset. The primary composite end point was the combined incidence of all-cause death, recurrent myocardial infarction, and recurrent angina, at 30 days. Three multivariate analyses were performed to determine predictors of not receiving reperfusion therapy, the composite end point, or death. RESULTS: The triple end point occurred in 17.8% of women versus 13.3% of men. Reperfusion therapy was utilized in 38.2% of women versus 47.3% in men. However, age > 75 years, delayed presentation, high systolic blood pressure (> 100) and region (South Africa), were significant, independent predictors of not receiving reperfusion therapy. Significant predictors of the triple end point included not receiving reperfusion therapy, age > 60 years, and higher Killip class. Predictors of death included age > 60 years, low systolic blood pressure, higher Killip class, high heart rate, delayed presentation, and region (South Africa and South America). CONCLUSION: Female gender was not an independent predictor of outcome or underutilization of reperfusion therapy. Factors more common in female STEMI patients (advanced age and delayed presentation) were associated with not receiving reperfusion therapy and adverse outcome. Increased awareness is needed to reduce delayed presentation after symptom onset, especially among women. Abbreviated abstract. In this analysis of 2741 ST-segment elevation myocardial infarction patients in the TETAMI trial and registry, a trend was observed for women being less likely to receive reperfusion therapy and more likely to have an adverse outcome than men. This was related to factors more common in female patients (advanced age and delayed presentation), and showed that an increased awareness is needed to reduce delayed presentation after symptom onset, especially among women.

Safety and efficacy of tigecycline in treatment of skin and skin structure infections: results of a double-blind phase 3 comparison study with vancomycin-aztreonam.

In a randomized, double-blind, controlled trial, 546 patients with complicated skin and skin structure infections received tigecycline 100 mg/day (a 100-mg initial dose and then 50 mg intravenously twice daily) or the combination of vancomycin 2 g/day (1 g intravenously twice daily) and aztreonam 4 g/day (2 g intravenously twice daily) for up to 14 days. The primary end point was the clinical response in the clinical modified intent-to-treat (c-mITT) and clinically evaluable (CE) populations at the test-of-cure visit 12 to 92 days after the last dose. The microbiologic response at the test-of-cure visit was also assessed. Safety was assessed by physical examination, laboratory results, and adverse event reporting. Five hundred twenty patients were included in the c-mITT population (tigecycline group, n = 261; combination group, n = 259), and 436 were clinically evaluable (tigecycline group, n = 223; combination group, n = 213). The clinical responses in the tigecycline and the combination vancomycin and aztreonam groups were similar in the c-mITT population (84.3% versus 86.9%; difference, -2.6% [95% confidence interval, -9.0, 3.8]; P = 0.4755) and the CE population (89.7% versus 94.4%; difference, -4.7% [95% confidence interval, -10.2, 0.8]; P = 0.1015). Microbiologic eradication (documented or presumed) occurred in 84.8% of the patients receiving tigecycline and 93.2% of the patients receiving vancomycin and aztreonam (difference, -8.5 [95% confidence interval, -16.0, -1.0]; P = 0.0243). The numbers of patients reporting adverse events were similar in the two groups, with increased nausea and vomiting rates in the tigecycline group and an increased incidence of rash and increases in alanine aminotransferase and aspartate aminotransferase levels in the combination vancomycin and aztreonam group. Tigecycline was shown to be safe and effective for the treatment of complicated skin and skin structure infections.

Efficacy and dangers of statin therapy.

The statins are among the most widely used pharmaceutical drugs and have shown to be extremely effective in the treatment of dyslipidaemia. The statins are effective in the primary and secondary prevention of coronary artery disease, in peripheral and cerebral vascular disease and in a wide variety of patient groups. In addition they have a beneficial effect on the vascular wall and atherosclerotic process, which is not related to their cholesterol-lowering effect. Despite their potency they are relatively well tolerated, with adverse effects mostly as a result of muscle and liver involvement. Some of the issues relating to efficacy and detrimental effects are discussed briefly.