Atorvastatin for high-risk statin-naïve patients undergoing noncardiac surgery: The Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose (LOAD) randomized trial.

Preliminary evidence suggests that statins may prevent major perioperative vascular complications. METHODS: We randomized 648 statin-naïve patients who were scheduled for noncardiac surgery and were at risk for a major vascular complication. Patients were randomized to a loading dose of atorvastatin or placebo (80 mg anytime within 18hours before surgery), followed by a maintenance dose of 40 mg (or placebo), started at least 12hours after the surgery, and then 40 mg/d (or placebo) for 7days. The primary outcome was a composite of all-cause mortality, nonfatal myocardial injury after noncardiac surgery, and stroke at 30days. RESULTS: The primary outcome was observed in 54 (16.6%) of 326 patients in the atorvastatin group and 59 (18.7%) of 316 patients in the placebo group (hazard ratio [HR] 0.87, 95% CI 0.60-1.26, P=.46). No significant effect was observed on the 30-day secondary outcomes of all-cause mortality (4.3% vs 4.1%, respectively; HR 1.14, 95% CI 0.53-2.47, P=.74), nonfatal myocardial infarction (3.4% vs 4.4%, respectively; HR 0.76, 95% CI 0.35-1.68, P=.50), myocardial injury after noncardiac surgery (13.2% vs 16.5%; HR 0.79, 95% CI 0.53-1.19, P=.26), and stroke (0.9% vs 0%, P=.25). CONCLUSION: In contrast to the prior observational and trial data, the LOAD trial has neutral results and did not demonstrate a reduction in major cardiovascular complications after a short-term perioperative course of statin in statin-naïve patients undergoing noncardiac surgery. We demonstrated, however, that a large multicenter blinded perioperative statin trial for high-risk statin-naïve patients is feasible and should be done to definitely establish the efficacy and safety of statin in this patient population.

Prevalence, characteristics, and predictors of early termination of cardiovascular clinical trials due to low recruitment: insights from the ClinicalTrials.gov registry.

BACKGROUND: Early termination of clinical trials due to low recruitment represents an understudied challenge for clinical research. We aimed to describe characteristics of cardiovascular trials terminated because of low recruitment and identify the major predictors of such early termination. METHODS: We reviewed all cardiovascular clinical trials (7,042 studies) registered in ClinicalTrials.gov from February 29, 2000, to January 17, 2013, and assessed information about trials that were completed and those that were terminated early. Logistic regression models were developed to identify independent predictors of early termination due to low recruitment. RESULTS: Our search strategy identified 6,279 cardiovascular clinical trials, of which 684 (10.9%) were terminated prematurely. Of these halted trials, the main reason for termination was lower than expected recruitment (278 trials; 53.6%). When comparing trials that terminated early because of low recruitment with those that were completed, we found that studies funded by the National Institutes of Health or other US federal agencies (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.14-0.89), studies of behavior/diet intervention (OR 0.35, 95% CI 0.19-0.65), and single-arm design studies (OR 0.57, 95% CI 0.42-0.78) were associated with a lower risk of early termination. University/hospital-funded (OR 1.52, 95% CI 1.10-2.10) and mixed-source-funded studies (OR 2.14, 95% CI 1.52-3.01) were associated with a higher likelihood of early termination due to lower than expected recruitment rates. CONCLUSIONS: Low recruitment represents the main cause of early termination of cardiovascular clinical trials. Funding source, type of intervention, and study design are factors associated with early termination due to low recruitment and might be good targets for improving enrollment into cardiovascular clinical trials.

Lipid-heparin infusion suppresses the IL-10 response to trauma in subcutaneous adipose tissue in humans.

An imbalance between pro- and anti-inflammatory cytokine productions in adipose tissue is thought to contribute to chronic, systemic, low-grade inflammation and consequently to an increased risk of cardiovascular complications in obese and type 2 diabetic patients. Nonesterified fatty acids (NEFA), whose serum levels are elevated in such patients, have been shown to interfere with cytokine production in vitro. In order to evaluate the effects of elevated NEFA levels on cytokine production in adipose tissue in vivo we used an 18-gauge open-flow microperfusion (OFM) catheter to induce local inflammation in the subcutaneous adipose tissue (SAT) of healthy volunteers and to sample interstitial fluid (IF) specifically from the inflamed tissue. In two crossover studies, nine subjects received either an intravenous lipid-heparin infusion to elevate circulating NEFA levels or saline over a period of 28 h. The former increased the circulating levels of triglycerides (TGs), NEFA, glucose, and insulin over the study period. NEFA effects on locally induced inflammation were estimated by measuring the levels of a panel adipokines in the OFM probe effluent. Interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) levels increased during the study period but were not affected by lipid-heparin infusion. In contrast, the level of IL-10, an anti-inflammatory cytokine, was significantly reduced during the final hour of lipid-heparin infusion (saline: 449.2 ± 105.9 vs. lipid-heparin: 65.4 ± 15.4 pg/ml; P = 0.02). These data provide the first in vivo evidence that elevated NEFA can modulate cytokine production by adipose tissue.

Azithromycin does not prevent six-month myointimal proliferation but attenuates the transient systemic inflammation occurring after coronary stenting.

OBJECTIVES: Stent implantation produces a systemic increase of inflammatory markers that correlates with Chlamydophila pneumoniae infection in atherosclerotic plaque. We performed a clinical intervention study to investigate the effect of antibiotic treatment on 6-month follow-up angiographic minimal luminal diameter after stenting. METHODS: Ninety patients were randomly assigned to oral azithromycin or placebo in a double-blinded and randomized fashion. Medication was initiated 2 weeks before a pre-scheduled stenting procedure and maintained 12 weeks thereafter. Angiographic outcomes were evaluated by a six-month follow-up angiography and laboratorial parameters were accessed by blood sampling 2 weeks before stenting, within the first 24 h after procedure and additional samples after four weeks and 6 months. RESULTS: Minimal luminal diameter (1.76 +/- 0.56 mm Vs. 1.70 +/- 0.86 mm; P = 0.7), restenosis rate, diameter stenosis, late loss, and binary restenosis rates were comparable in placebo and azithromycin group in the 6 months follow-up. Serum levels of C-reactive protein presented a three fold significant increase in the control group one day after stenting but did not change in the azithromycin group (8.5 [3.0;16.4] Vs. 2.9 [1.7;6.6]-median [25;75 percentile] P < 0.01). CONCLUSIONS: Azithromycin does not improve late angiographic outcomes but attenuates the elevation of C-reactive protein levels after stenting, indicating an anti-inflammatory effect.

Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial.

OBJECTIVES: This prospective, randomized, placebo-controlled, double-blind clinical trial was performed to analyze the effect of atorvastatin compared with placebo on the occurrence of a 6-month composite of cardiovascular events after vascular surgery. Cardiovascular complications are the most important cause of perioperative morbidity and mortality among patients undergoing vascular surgery. Statin therapy may reduce perioperative cardiac events through stabilization of coronary plaques. METHODS: One hundred patients were randomly assigned to receive 20 mg atorvastatin or placebo once a day for 45 days, irrespective of their serum cholesterol concentration. Vascular surgery was performed on average 30 days after randomization, and patients were prospectively followed up over 6 months. The cardiovascular events studied were death from cardiac cause, nonfatal myocardial infarction, unstable angina, and stroke. RESULTS: Fifty patients received atorvastatin, and 50 received placebo. During the 6-month follow-up primary end points occurred in 17 patients, 4 in the atorvastatin group and 13 in the placebo group. The incidence of cardiac events was more than three times higher with placebo (26.0%) compared with atorvastatin (8.0%; P =.031). The risk for an event was compared between the groups with the Kaplan-Meier method, as event-free survival after vascular surgery. Patients given atorvastatin exhibited a significant decrease in the rate of cardiac events, compared with the placebo group, within 6 months after vascular surgery (P =.018). CONCLUSION: Short-term treatment with atorvastatin significantly reduces the incidence of major adverse cardiovascular events after vascular surgery.

Ainda há lugar para o uso de antibióticos na prevenção da placa aterosclerótica vulnerável? / Is there a place for the use of antibiotics on prevention of unstable atheroscleotic plaque?

Processos infecciosos têm sido considerados como possíveis agentes na instabilização da placa aterosclerótica e no desencadeamento de eventos cardiovasculares. Numerosos indícios experimentais, histopatológicos e clínicos levaram à elaboração de ensaios clínicos testando a eficácia de antibióticos na prevenção de eventos cardiovasculares. Até o momento, não há evidências que suportem de forma conclusiva a utilização de antibióticos nesse contexto...