C Michael White

Thiazolidinedione use and post-operative atrial fibrillation: a US nested case-control study.

ABSTRACT Background: Previous investigations suggested thiazolidinediones (TZDs) have the ability to suppress inflammation. Since the pathophysiology of atrial fibrillation (AF) after cardiothoracic surgery (CTS) likely involves an inflammatory mechanism, we sought to determine whether preoperative use of TZDs could further reduce the incidence of post-CTS AF in a population treated with beta-blockers and prophylactic amiodarone. Methods: All diabetic patients over the age of 50 years, not in atrial arrhythmia prior to surgery, who underwent CTS from the Atrial Fibrillation Suppression Trials I, II and III (AFIST I, II and III) were evaluated in this nested case-control study. Patient demographics, surgical characteristics, medication utilization and the incidence of post-CTS AF (AF > 5 minutes duration) were collected as part of AFIST I, II and III. Multivariate logistic regression was used to calculate adjusted odds ratios with 95% confidence intervals (CIs). Results: One hundred and eighty-four diabetic patients were enrolled in the three trials. Overall, the study population averaged 66.9 ± 7.3 years of age, 71.7% were male, 7.1% underwent valve surgery, 4.9% had prior AF, 17.9% had heart failure and 84.2% and 41.8% received postoperative beta-blockade and prophylactic amiodarone, respectively. Forty patients (21.7%) received a preoperative TZD and 144 (78.3%) did not. In total, 66 patients (35.9%) developed post-CTS AF. Upon multivariate logistic regression, the preoperative use of TZDs was found to be associated with a 20% non-statistically significant reduction in post-CTS AF (adjusted odds ratio; 0.80, 95% CI 0.32–1.99; p = 0.63). Limitations: Patients were not randomized to receive TZDs or not. We may not have had adequate power to evaluate our post-CTS AF endpoint. Conclusions: In a diabetic population treated perioperatively with beta-blocker and amiodarone, adjunctive TZD use was associated with a non-statistically significant reduction in a patients odds of developing post-CTS AF. Further research is needed to determine whether TZDs, in fact, do not have anti-fibrillatory effects or whether our study was underpowered to detect a statistically significant benefit with TZDs.

Biological variation for N-Terminal Pro- and B-type natriuretic peptides and implications for therapeutic monitoring of patients with congestive heart failure

Given the limitations of low enrollments, this study suggests that a change of 130% for B-type natiuretic peptide (BNP) and 90% for N-terminal (NT)-proBNP are necessary before results of serially collected data can be considered statistically different. This study also shows that there are important differences in the performance of BNP versus NT-proBNP in monitoring patients with congestive heart failure that need to be further explored.

Effect of Statins on Skeletal Muscle Function

Background— Many clinicians believe that statins cause muscle pain, but this has not been observed in clinical trials, and the effect of statins on muscle performance has not been carefully studied. Methods and Results— The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study assessed symptoms and measured creatine kinase, exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo was administered for 6 months to 420 healthy, statin-naive subjects. No individual creatine kinase value exceeded 10 times normal, but average creatine kinase increased 20.8±141.1 U/L (P<0.0001) with atorvastatin. There were no significant changes in several measures of muscle strength or exercise capacity with atorvastatin, but more atorvastatin than placebo subjects developed myalgia (19 versus 10; P=0.05). Myalgic subjects on atorvastatin or placebo had decreased muscle strength in 5 of 14 and 4 of 14 variables, respectively (P=0.69). Conclusions— These results indicate that high-dose atorvastatin for 6 months does not decrease average muscle strength or exercise performance in healthy, previously untreated subjects. Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins increase muscle complaints. Atorvastatin also increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects. This increase in creatine kinase should prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular performance. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00609063.

Oral amiodarone for prevention of atrial fibrillation after open heart surgery, the Atrial Fibrillation Suppression Trial (AFIST): a randomised placebo-controlled trial

BACKGROUND Beta-blockers and amiodarone reduce the frequency of atrial fibrillation after open-heart surgery but the effectiveness of oral amiodarone in older patients already receiving beta-blockers is unknown. We have assessed the efficacy of oral amiodarone in preventing atrial fibrillation in patients aged 60 years or older undergoing open-heart surgery. METHODS We did a randomised, double-blind placebo-controlled trial in which patients undergoing open-heart surgery (n=220, average age 73 years) received amiodarone (n=120) or placebo (n=100). Patients enrolled less than 5 days before surgery received 6 g of amiodarone or placebo over 6 days beginning on preoperative day 1. Patients enrolled at least 5 days before surgery received 7 g over 10 days beginning on preoperative day 5. FINDINGS Patients on amiodarone had a lower frequency of any atrial fibrillation (22.5% vs 38.0%; p=0.01; absolute difference 15.5% [95% CI 3.4-27.6%]), and there were significant differences in favour of the active drug for symptomatic atrial fibrillation (4.2% vs 18.0%, p=0.001), cerebrovascular accident (1.7% vs 7.0%, p=0.04), and postoperative ventricular tachycardia (1.7% vs 7.0%, p=0.04). Beta-blocker use (87.5% amiodarone vs 91.0% placebo), nausea (26.7% vs 16.0%), 30-day mortality (3.3% vs 4.0%), symptomatic bradycardia (7.5% vs 7.0%), and hypotension (14.2% vs 10.0%) were similar. INTERPRETATION Oral amiodarone prophylaxis in combination with beta-blockers prevents atrial fibrillation and symptomatic fibrillation and reduces the risk of cerebrovascular accidents and ventricular tachycardia.

A Review of the Pharmacologic and Pharmacokinetic Aspects of Rosuvastatin

Rosuvastatin is a new HMG‐CoA reductase inhibitor with unique pharmacologic and pharmacokinetic properties. It has additional HMG‐CoA reductase enzyme‐binding interactions that cause tighter binding, has substantial active transport into hepatocytes, and has the lowest (LDL) for sterol synthesis in hepatocytes. Rosuvastatin 10 mg and 80 mg dosages have superior low‐density lipoprotein (LDL) cholesterol‐lowering efficacy as compared to atorvastatin 10 mg and 80 mg. Rosuvastatin 10 mg has also been shown to have superior LDL reductions to 20 mg of both simvastatin and pravastatin. This agent can raise high‐density lipoprotein (HDL) 8% to 12% and lower triglycerides by 10% to 35%. Rosuvastatin is a hydrophilic agent with poor penetration in extrahepatic tissue such as human umbilical vein endothelial cells and fibroblasts. It also has a low potential for cytochrome P450 drug interactions and can be dosed in the morning or night. In conclusion, rosuvastatin is an agent with molecular alterations that provide it with unique pharmacologic and pharmacokinetic effects. As such, it is a novel and unique HMG‐CoA reductase inhibitor for the treatment of hyperlipidemia.

Understanding heterogeneity in meta‐analysis: the role of meta‐regression

Background:  Meta‐regression has grown in popularity in recent years, paralleling the increasing numbers of systematic reviews and meta‐analysis published in the biomedical literature. However, many clinicians and decision‐makers may be unfamiliar with the underlying principles and assumptions made within meta‐regression leading to incorrect interpretation of their results.

Effects of Garlic on Blood Pressure in Patients with and Without Systolic Hypertension: A Meta-Analysis

Background: Garlic has been suggested to lower blood pressure; however, studios evaluating this parameter have provided conflicting results. Objective: To examine the effect of garlic on blood pressure in patients with and without elevated systolic blood pressure (SPB) through meta-analyses of randomized controlled trials. Methods: A systematic search of MEDLINE, CINAHL, and the Cochrane Central Register of Controlled Trials was conducted to identify randomized controlled trials in humans evaluating garlics effect on blood pressure. All databases were searched from their inception through June 26, 2008, using the key words garlic, Allium sativum, and allicin. A manual search of published literature was used to identify additional relevant studies. To be included in the analysis, studies must have been written in English or German and reported endpoints of SBP or diastolic blood pressure (DBP). Studies whose population had a mean baseline SBP greater than 140 mm Hg were evaluated separately from those whose population had lower baseline blood pressures. Garlics effect on SBP and DBP was treated as a continuous variable and weighted mean differences were calculated using a random-effects model. Results: Ten trials were included in the analysis; 3 of these had patients with elevated SBP. Garlic reduced SBP by 16.3 mm Hg (95% CI 6.2 to 26.5) and DBP by 9.3 mmHg (95% CI 5.3 to 13.3) compared with placebo in patients with elevated SBP. However, the use of garlic did not reduce SBP or DBP in patients without elevated SBP. There was only a minor degree of heterogeneity in the analyses and publication bias did not appear to influence the results. Conclusions: This meta-analysis suggests that garlic is associated with blood pressure reductions in patients with an elevated SBP although not in those without elevated SBP. Future research should focus on the impact of garlic on clinical events and the assessment of the long-term risk of harm.

Intravenous plus oral amiodarone, atrial septal pacing, or both strategies to prevent post-cardiothoracic surgery atrial fibrillation: The atrial fibrillation suppression trial II (AFIST II)

Background—The effect of a hybrid intravenous and oral prophylactic amiodarone regimen on postcardiothoracic surgery (CTS) atrial fibrillation (AF) is unknown. The impact of active atrial septal pacing on post-CTS AF has not been well characterized. In addition, the effect of using both amiodarone and atrial septal pacing together to prevent atrial fibrillation is unknown. Methods and Results—Patients (n=160) were randomized to amiodarone or placebo and then to pacing or no pacing using a 2×2 factorial design. All therapies began within 6 hours post-CTS. Amiodarone was given by intravenous infusion for the first 24 hours (1050 mg total) followed by oral therapy for 4 postoperative days (4800 mg total). Atrial septal pacing was given for 96 hours. Amiodarone reduced the risk of AF by 43% and the risk of symptomatic AF by 68% (P =0.037 and P =0.019) versus placebo. Atrial septal pacing did not reduce AF or symptomatic AF incidence versus no pacing. The risk of post-CTS AF in the patients receiving amiodarone+pacing was lower than the placebo+no pacing and the placebo+pacing groups (57.9% and 60.5% reductions, P =0.047 and P =0.040, respectively). Conclusions—Amiodarone given as both an intravenous and oral regimen is effective at reducing post-CTS AF but atrial septal pacing is ineffective. Combining amiodarone and pacing is better than placebo with or without pacing but not amiodarone alone.

Neurothrombectomy devices for the treatment of acute ischemic stroke: state of the evidence

BACKGROUND Acute ischemic strokes are associated with poor outcomes and high health care burden. Evidence exists evaluating the use of neurothrombectomy devices in patients receiving currently recommended treatments that may have limited efficacy. PURPOSE To describe the state of the evidence supporting use of neurothrombectomy devices in the treatment of acute ischemic stroke. DATA SOURCES MEDLINE, SCOPUS, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Web of Science were searched, without language restrictions, from their inception through May 2010. The MEDLINE and Cochrane Central Register of Controlled Trials searches were updated through November 2010. STUDY SELECTION Two independent investigators screened citations for human studies of any design or case series or case reports of patients with an acute ischemic stroke that evaluated a neurothrombectomy device and reported at least 1 clinical effectiveness outcome or harm. DATA EXTRACTION Using standardized protocols, 2 independent investigators extracted information about study characteristics and outcomes, and a third reviewer resolved disagreement. DATA SYNTHESIS 87 articles met eligibility criteria, including 18 prospective single-group studies, 7 noncomparative retrospective studies, and 62 case series or case reports. Two U.S. Food and Drug Administration (FDA)-cleared devices, the MERCI Retriever (Concentric Medical, Mountain View, California) (40%) and the Penumbra System (Penumbra, Alameda, California) (9%), represented a large portion of the available data. All prospective and retrospective studies provided data on successful recanalization with widely varying rates (43% to 78% with the MERCI Retriever and 83% to 100% with the Penumbra System). Rates of harms, including symptomatic (16 studies; 0% to 10% with the MERCI Retriever and 0% to 11% with the Penumbra System) or asymptomatic (13 studies; 28% to 43% and 1% to 30%, respectively) intracranial hemorrhage and vessel perforation or dissection (11 studies; 0% to 7% and 0% to 5%, respectively), also varied by device. Predictors of harm included older age, history of stroke, and higher baseline stroke severity scores, whereas successful recanalization was the sole predictor of good outcomes. LIMITATIONS Most available data are from single-group, noncomparative studies. In addition, the patient population most likely to benefit from these devices is undetermined. CONCLUSION Currently available neurothrombectomy devices offer intriguing treatment options in patients with acute ischemic stroke. Future trials should use a randomized design, with adequate power to show equivalency or noninferiority between competing strategies or devices, and strive to identify populations that are most likely to benefit from use of neurothrombectomy devices. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Acute beta-blockade reduces the extent and severity of myocardial perfusion defects with dipyridamole Tc-99m sestamibi SPECT imaging.

OBJECTIVES The goal of this study was to examine the effect of acute beta-blockade on dipyridamole Tc-99m sestamibi myocardial perfusion imaging (DMPI). BACKGROUND Studies suggest that antianginal drugs may reduce the presence and severity of myocardial perfusion defects with dipyridamole stress. However, there are no data regarding specific drugs. METHODS Patients with catheterization-proven coronary artery disease (CAD) were enrolled in this prospective, double-blind, placebo-controlled study and randomly assigned to DMPI after placebo, low-dose metoprolol (up to 10 mg), and high-dose metoprolol (up to 20 mg). Patients underwent one Tc-99m sestamibi study at rest on a separate day. The interval between DMPI studies was <or=14 days. Images were interpreted by three observers blinded to clinical data using a 17-segment, five-point model. For each image, a summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) were calculated (SDS = SSS - SRS). Images with an SSS <4 were considered normal. RESULTS Twenty-one patients completed all four Tc-99m sestamibi studies. The sensitivity of DMPI for detection of CAD was 85.7% with placebo versus 71.4% with low- and high-dose metoprolol. In comparison with placebo, the SSS was significantly lower (p < 0.05) with low- and high-dose metoprolol (12.0 +/- 10.1 vs. 8.7 +/- 9.0 and 9.3 +/- 10.6, respectively). The SDS also was significantly lower (8.4 +/- 8.8 with placebo vs. 5.0 +/- 6.7 [p < 0.001] and 5.4 +/- 7.9 [p < 0.01] with low- and high-dose metoprolol, respectively). CONCLUSIONS The presence and severity of CAD may be underestimated in patients receiving beta-blocker therapy undergoing dipyridamole stress myocardial perfusion imaging.