Safety profile of statins alone or combined with ezetimibe: a pooled analysis of 27 studies including over 22,000 patients treated for 6-24 weeks.

Aims: The aim of this analysis was to assess the overall safety and tolerability profiles of various statins + ezetimibe vs. statin monotherapy and to explore tolerability in sub-populations grouped by age, race, and sex. Methods: Study-level data were combined from 27 double-blind, placebo-controlled or active-comparator trials that randomized adult hypercholesterolemic patients to statin or statin + ezetimibe for 6-24 weeks. In the full cohort, % patients with AEs within treatment groups (statin: N = 10,517; statin + ezetimibe: N = 11,714) was assessed by logistic regression with terms for first-/second-line therapy (first line = drug-naïve or rendered drug-naïve by washout at study entry; second line = ongoing statin at study entry or statin run-in), trial within first-/second-line therapy, and treatment. The same model was fitted for age (< 65, ≥ 65 years), sex, race (white, black, other) and first-/second-line subgroups with additional terms for subgroup and subgroup-by-treatment interaction. Results: In the full cohort, the only significant difference between treatments was consecutive AST or ALT elevations ≥ 3 × upper limit of normal (ULN) (statin: 0.35%, statin + ezetimibe: 0.56%; p = 0.017). Significantly more subjects reported ≥ 1 AE; drug-related, hepatitis-related and gastrointestinal-related AEs; and CK elevations ≥ 10 × ULN (all p ≤ 0.008) in first-line vs. second-line therapy studies with both treatments. AEs were generally similar between treatments in subgroups, and similar rates of AEs were reported within age and race subgroups; however, women reported generally higher AE rates. Conclusions: In conclusion, in second-line studies, ongoing statin treatment at study entry likely screened out participants for previous statin-related AEs and tolerability issues. These results describe the safety profiles of widely used lipid-lowering therapies and encourage their appropriate and judicious use in certain subpopulations.

Cutting through the statistical fog: understanding and evaluating non-inferiority trials.

Every year, results from many important randomised, controlled trials are published. Knowing the elements of trial design and having the skills to critically read and incorporate results are important to medical practitioners. The goal of this article is to help physicians determine the validity of trial conclusions to improve patient care through more informed medical decision making. This article includes a review of 162 randomised, controlled non-inferiority (n = 116) and equivalence (n = 46) hypothesis studies as well as the larger Stroke Prevention using Oral Thrombin Inhibitor in atrial Fibrillation V study and the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial. Evaluation of data from small and large trials uncovers significant flaws in design and models employed and uncertainty about calculations of statistical measures. As one example of questionable study design, discussion includes a large (n = 3922), double-blind, randomised, multicentre trial comparing the efficacy of ximelagatran with warfarin for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and additional stroke risk factors. Investigators concluded that ximelagatran was effective compared with well-controlled warfarin for prevention of thromboembolism. However, deficiencies in design, as well as concerns about liver toxicity, resulted in the rejection of the drug by the US Food and Drug Administration. Many trials fail to follow good design principles, resulting in conclusions of questionable validity. Well-designed non-inferiority trials can provide valuable data and demonstrate efficacy for beneficial new therapies. Objectives and primary end-points must be clearly stated and rigorous standards met for sample size, establishing the margin, patient characteristics and adherence to protocol.

Glucose challenge test screening for prediabetes and undiagnosed diabetes.

AIMS/HYPOTHESIS: Diabetes prevention and care are limited by lack of screening. We hypothesised that screening could be done with a strategy similar to that used near-universally for gestational diabetes, i.e. a 50 g oral glucose challenge test (GCT) performed at any time of day, regardless of meal status, with one 1 h sample. METHODS: At a first visit, participants had random plasma and capillary glucose measured, followed by the GCT with plasma and capillary glucose (GCTplasma and GCTcap, respectively). At a second visit, participants had HbA(1c) measured and a diagnostic 75 g OGTT. RESULTS: The 1,573 participants had mean age of 48 years, BMI 30.3 kg/m(2) and 58% were women and 58% were black. Diabetes (defined by WHO) was present in 4.6% and prediabetes (defined as impaired glucose tolerance [2 h glucose 7.8-11.1 (140-199 mg/dl) with fasting glucose

Unrecognized glucose intolerance is not associated with depression. Screening for Impaired Glucose Tolerance study 3 (SIGT 3).

AIMS: To understand the metabolic and temporal links in the relationship between diabetes and depression, we determined the association between depressive symptoms and unrecognized glucose intolerance. METHODS: In a cross-sectional study, 1047 subjects without known diabetes were screened for diabetes or pre-diabetes using the oral glucose tolerance test and for depressive symptoms using the Patient Health Questionnaire (PHQ). RESULTS: Mean age was 48 years, body mass index 30 kg/m(2); 63% were female, 54% black, 11% previously treated for depression and 10% currently treated; 5% had diabetes and 34% pre-diabetes. Median PHQ score was 2 (interquartile range 0-5). Depressive symptoms did not increase with worsening glucose tolerance, after adjusting for age, sex, ethnicity, body mass index, family history, exercise, education and depression treatment. CONCLUSIONS: There is no association between depressive symptoms and unrecognized glucose intolerance. However, it remains possible that diagnosed diabetes, with its attendant health concerns, management issues, and/or biological changes, may be a risk for subsequent development of depression. Thus, patients with newly diagnosed diabetes should be counselled appropriately and monitored for the development of depression.

Cost-effectiveness of eplerenone plus standard treatment compared with standard treatment in patients with myocardial infarction complicated by left ventricular systolic dysfunction and heart failure in the Netherlands.

AIMS: Following the results of the EPHESUS study in patients with heart failure after myocardial infarction, a cost-effectiveness analysis was undertaken from a Dutch societal perspective to evaluate the lifetime benefits and costs of eplerenone as add-on to standard treatment. METHODS: Life-years gained in the eplerenone arm during the trial period were extrapolated to lifetime life-years gained using three sources of life expectancy data (Framingham Heart Study, Saskatchewan Health Database and Worcester Heart Attack Registry). Resource use measured included direct medical costs of hospitalisation, medications including eplerenone, outpatient diagnostic tests and procedures, and emergency room visits. Incremental cost-effectiveness ratios were calculated for life-years gained and quality-adjusted life-years gained. RESULTS: Eplerenone prolonged lifetime survival by five weeks at an additional cost of €803. The incremental cost-effectiveness ratio was about €8000 per life-year gained, well below the only published Dutch benchmark for cost-effectiveness of €18,000. Probabilistic sensitivity analyses showed the results to be robust when varying the discount rate applied to benefits and costs, the hospitalisation costs, and the source of life expectancy data used. CONCLUSION: Treatment with adjunctive eplerenone is effective in preventing deaths and prolonging life.

One year comparison of costs of coronary surgery versus percutaneous coronary intervention in the stent or surgery trial.

OBJECTIVES: To compare initial and one year costs of coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) in the stent or surgery trial. DESIGN: Prospective, unblinded, randomised trial. SETTING: Multicentre study. PATIENTS: 988 patients with multivessel disease. INTERVENTIONS: CABG and stent assisted PCI. MAIN OUTCOME MEASURES: Initial hospitalisation and one year follow up costs. RESULTS: At one year mortality was 2.5% in the PCI arm and 0.8% in the CABG arm (p = 0.05). There was no difference in the composite of death or Q wave myocardial infarction (6.9% for PCI v 8.1% for CABG, p = 0.49). There were more repeat revascularisations with PCI (17.2% v 4.2% for CABG). There was no significant difference in utility between arms at six months or at one year. Quality adjusted life years were similar 0.6938 for PCI v 0.6954 for PCI, Delta = 0.00154, 95% confidence interval (CI) -0.0242 to 0.0273). Initial length of stay was longer with CABG (12.2 v 5.4 days with PCI, p < 0.0001) and initial hospitalisation costs were higher (7321 pounds sterling v 3884 pounds sterling for PCI, Delta = 3437 pounds sterling, 95% CI 3040 pounds sterling to 3848 pounds sterling). At one year the cost difference narrowed but costs remained higher for CABG (8905 pounds sterling v 6296 pounds sterling for PCI, Delta = 2609 pounds sterling, 95% CI 1769 pounds sterling to 3314 pounds sterling). CONCLUSIONS: Over one year, CABG was more expensive and offered greater survival than PCI but little added benefit in terms of quality adjusted life years. The additional cost of CABG can be justified only if it offers continuing benefit at no further increase in cost relative to PCI over several years.

Off-pump coronary artery bypass grafting provides complete revascularization with reduced myocardial injury, transfusion requirements, and length of stay: a prospective randomized comparison of two hundred unselected patients undergoing off-pump versus conventional coronary artery bypass grafting.

OBJECTIVE: Retrospective comparisons of selected patients undergoing off-pump versus conventional on-pump coronary artery bypass grafting have yielded inconsistent results and raised concerns about completeness of revascularization in off-pump coronary artery bypass grafting. METHODS: Two hundred unselected patients referred for elective primary coronary artery bypass grafting were randomly assigned to undergo off-pump coronary artery bypass grafting with an Octopus tissue stabilizer (Medtronic, Inc, Minneapolis, Minn) or conventional coronary artery bypass grafting with cardiopulmonary bypass by a single surgeon. Revascularization intent determined before random assignment was compared with the revascularization performed. All management followed strict, unbiased, criteria-driven protocols. Patients and nonoperative care providers were blinded to surgical group. RESULTS: Baseline characteristics were similar. The number of grafts performed per patient (mean +/- SD 3.39 +/- 1.04 for off-pump coronary artery bypass grafting, 3.40 +/- 1.08 for conventional coronary artery bypass grafting) and the index of completeness of revascularization (number of grafts performed/number of grafts intended, 1.00 +/- 0.18 for off-pump coronary artery bypass grafting, 1.01 +/- 0.09 for conventional coronary artery bypass grafting) were similar. Likewise, the index of completeness of revascularization was similar between groups for the lateral wall. Combined hospital and 30-day mortalities and stroke rates were similar. Postoperative myocardial serum enzyme measures were significantly lower after off-pump coronary artery bypass grafting, suggesting less myocardial injury. Adjusted postoperative thromboelastogram indices, fibrinogen, international normalized ratio, and platelet levels all showed significantly less coagulopathy after off-pump coronary artery bypass grafting. Patients undergoing off-pump coronary artery bypass grafting received fewer units of blood, were more likely to avoid transfusion altogether, and had a higher hematocrit at discharge. Cardiopulmonary bypass was an independent predictor of transfusion (odds ratio 2.42, P =.0073) by multivariate analysis. More patients undergoing off-pump coronary artery bypass grafting were extubated in the operating room and within 4 hours. Postoperative length of stay (in days) was shorter for off-pump coronary artery bypass grafting (5.1 +/- 6.5 for off-pump coronary artery bypass grafting, 6.1 +/- 8.2 for conventional coronary artery bypass grafting, P =.005 by Wilcoxon test). One patient (in the conventional coronary artery bypass grafting group) required angioplasty for graft closure within 30 days. CONCLUSIONS: When compared with conventional coronary artery bypass grafting with cardiopulmonary bypass, off-pump coronary artery bypass grafting achieved similar completeness of revascularization, similar in-hospital and 30-day outcomes, shorter length of stay, reduced transfusion requirement, and less myocardial injury.

Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial.

CONTEXT: Cardiac troponins I (cTnI) and T (cTnT) are useful for assessing prognosis in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). However, the use of cardiac troponins for predicting benefit of an invasive vs conservative strategy in this patient population is not clear. OBJECTIVE: To prospectively test whether an early invasive strategy provides greater benefit than a conservative strategy in acute coronary syndrome patients with elevated baseline troponin levels. DESIGN: Prospective, randomized trial conducted from December 1997 to June 2000. SETTING: One hundred sixty-nine community and tertiary care hospitals in 9 countries. PARTICIPANTS: A total of 2220 patients with acute coronary syndrome were enrolled. Baseline troponin level data were available for analysis in 1821, and 1780 completed the 6-month follow-up. INTERVENTIONS: Patients were randomly assigned to receive (1) an early invasive strategy of coronary angiography between 4 and 48 hours after randomization and revascularization when feasible based on coronary anatomy (n = 1114) or (2) a conservative strategy of medical treatment and, if stable, predischarge exercise tolerance testing (n = 1106). Conservative strategy patients underwent coronary angiography and revascularization only if they manifested recurrent ischemia at rest or on provocative testing. MAIN OUTCOME MEASURE: Composite end point of death, MI, or rehospitalization for acute coronary syndrome at 6 months. RESULTS: Patients with a cTnI level of 0.1 ng/mL or more (n = 1087) experienced a significant reduction in the primary end point with the invasive vs conservative strategy (15.3% vs 25.0%; odds ratio [OR], 0.54; 95% confidence interval [CI], 0.40-0.73). Patients with cTnI levels of less than 0.1 ng/mL had no detectable benefit from early invasive management (16.0% vs 12.4%; OR, 1.4; 95% CI, 0.89-2.05; P<.001 for interaction). The benefit of invasive vs conservative management through 30 days was evident even among patients with low-level (0.1-0.4 ng/mL) cTnI elevation (4.4% vs 16.5%; OR, 0.24; 95% CI, 0.08-0.69). Directionally similar results were observed with cTnT. CONCLUSION: In patients with clinically documented acute coronary syndrome who are treated with glycoprotein IIb/IIIa inhibitors, even small elevations in cTnI and cTnT identify high-risk patients who derive a large clinical benefit from an early invasive strategy.

Predictors and outcomes associated with early extubation in older adults undergoing coronary artery bypass surgery.

BACKGROUND: Older age has been associated with prolonged mechanical ventilation after coronary artery bypass surgery. Prolonged mechanical ventilation contributes to increased morbidity and mortality and to use of limited financial resources among older adults. OBJECTIVES: To examine selected physiological and pathophysiological variables ofpresurgicalpatients to predict duration of mechanical ventilation in older adults after coronary artery bypass surgery. METHODS: Nonrandomized study of a clinical database of 919 patients (> or =65 years old) who had coronary artery bypass surgery between October 1996 and December 1997. RESULTS: Median elapsed time after coronary artery bypass surgery until extubation was used to sort patients into 2 groups: group 1, 6 hours or fewer (n = 464); and group 2, more than 6 hours (n = 455). With stepwise logistic regression, the physiological model included age (odds ratio, 1.05; P<.001) and female sex (odds ratio, 1.48; P = .005) with weak discrimination by group (concordance statistic = 0.5880). The pathophysiological model, which included renal insufficiency (odds ratio, 3.28; P = .01), previous peripheral vascular surgery (odds ratio, 2.87; P = .03), nonelective preoperative clinical status (odds ratio, 2.8; P = .006), congestive heartfailure (odds ratio, 2.6; P<.001), and reoperation (odds ratio, 2.34; P = .007), showed moderate discrimination bygroup (concordance statistic =0.6755). CONCLUSION: Many older adults were easily extubated and had good outcomes. The variables comorbid conditions and severity of illness provided better discrimination between extubation groups than a physiological model provided. Both predictive models allowed limited discrimination between groups.

Impact of the Duett sealing device on quality of life and hospitalization costs for coronary diagnostic and interventional procedures: Results from the Study of Economic and Quality of Life substudy of the SEAL trial.

BACKGROUND: The Simple and Effective Arterial Closure (SEAL) trial examined the safety and effectiveness of the Duett vascular sealing device (Vascular Solutions, Minneapolis, Minn) versus manual compression after diagnostic and interventional coronary procedures. We compared quality of life and initial hospitalization costs among patients treated with the Duett device versus manual compression. METHODS: Functional status was assessed with the Duke Activity Status Index (DASI) at 7 and 30 days after intervention. General health status was assessed with the Short Form (SF-36) at 30 days after intervention. Hospitalization costs were derived from the UB92 formulation of the hospital bill. RESULTS: There was a strong trend toward higher functional status in patients receiving treatment with the Duett device at 7 days both before (P =.04) and after (P =.08) adjustment for significant covariates. This difference was significant in the diagnostic group but not in the interventional group. No significant differences in quality of life between the Duett device and manual compression at 30 days were found. There was no significant difference in total hospitalization costs between treatment arms (P =.91). For interventional patients, mean total in-hospital costs were $10,167 in the Duett group and $10,225 in the manual compression group (P =.82). For diagnostic patients, mean hospitalization costs were $7784 and $7996 for the Duett device and manual compression groups, respectively (P =.72). Trends toward reduced recovery/observation room costs with the Duett device (P =.06) were found; this difference was significant in the diagnostic group ($198 vs $279, P =.02). CONCLUSIONS: The Duett sealing device was associated with significantly higher functional status at 7 days after the procedure in addition to shortened time to hemostasis and ambulation, with no associated increase in cost.

Trends in outcome and costs of coronary intervention in the 1990s.

Our objective was to examine trends in outcome and cost of percutaneous coronary intervention (PCI) between 1990 and 1999. PCI has become the most common form of myocardial revascularization in recent years, rivaling the more established coronary artery bypass surgery. There has been increasing interest in improving outcome of PCI while also seeking to minimize cost. A total of 21,755 patients undergoing PCI were evaluated. Clinical data were gathered from the Emory Cardiovascular Database and financial data from the UB92 formulation of the hospital bill. Charges were reduced to cost using departmental cost-to-charge ratios. Costs were inflated to 1999 dollars using medical care inflation rates. Mortality varied without a significant trend from 0.63% to 0.44% (p = 0.64). The Q-wave myocardial infarction rate decreased from 0.68% to 0.40% (p = 0.0003). Emergent coronary surgery decreased from 3.50% to 1.25% (p <0.0001). Mean hospital inflation-adjusted cost decreased from $10,478 to $8,367 (p <0.0001). Length of stay after the procedure decreased from 2.8 to 1.8 days (p <0.0001). Outcome of PCI continues to improve, with a decrease in coronary surgery and Q-wave myocardial infarction but with no significant change in mortality. This was accomplished while also decreasing costs and length of stay. Whether these favorable trends will continue remains to be seen.

Intravascular radiation therapy after balloon angioplasty of narrowed femoropopliteal arteries to prevent restenosis: results of the PARIS feasibility clinical trial.

PURPOSE: To conduct a feasibility study to assess the feasibility, safety, and outcome of endoluminal gamma radiation therapy after balloon angioplasty of superficial femoral artery (SFA) lesions. MATERIALS AND METHODS: Forty patients with claudication were enrolled in the study and underwent percutaneous transluminal angioplasty (PTA) of SFA lesions with a mean lesion length of 9.8 cm +/- 3.0 and a mean reference vessel diameter of 5.2 mm +/- 3.1. After successful PTA, a segmented centering balloon catheter was positioned to cover the PTA site. The patients were then transported to the radiation oncology suite and treated with a microSelectron HDR afterloader with use of an Ir-192 source with a prescribed dose of 14 Gy, 2 mm into the vessel wall. Ankle-brachial index (ABI) and Rutherford score were evaluated at 1, 6, and 12 months after the procedure and angiographic follow-up was conducted at 6 months. RESULTS: Radiation was delivered successfully to 35 of 40 patients. There were no procedural complications. Exercise and rest ABI were higher at 1 year (0.72 +/- 0.26 and 0.89 +/- 0.18, respectively) compared to baseline (0.51 +/- 0.25 and 0.67 +/- 0.17, respectively). Maximum walking time on a treadmill increased from 3.41 min +/- 2.41 to 4.43 min +/- 2.49 at 30 days and was 4.04 min +/- 2.8 at 12 months. The angiographic binary restenosis rate at 6 months was 17.2% and the clinical restenosis rate at 12 months was 13.3%. There were no angiographic or clinical adverse events related to the radiation therapy. CONCLUSIONS: Intraarterial radiation after PTA of SFA lesions with use of high-dose rate gamma radiation is feasible and safe. The angiographic and clinical improvements are sustainable at 1 year and represent a potent antirestenotic therapy for the treatment of narrowed peripheral arteries.

A collaborative program for cardiovascular patient follow-up.

Transitions from one health care system to another are common, but they can affect coordination of care and measurement of patient outcomes. In this project, a community hospital and a tertiary center collaborated to obtain follow-up information on patients 30 days after they underwent cardiac catheterization and revascularization. Results show that patients experienced similar physical and emotional concerns regardless of diagnosis or procedure. Although the intent was to gather information, nurses also provided education and arranged services for patients. This project has implications for the development of collaborative interventions to improve care for patients after undergoing coronary procedures.

Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban.

BACKGROUND: There is continued debate as to whether a routine, early invasive strategy is superior to a conservative strategy for the management of unstable angina and myocardial infarction without ST-segment elevation. METHODS: We enrolled 2220 patients with unstable angina and myocardial infarction without ST-segment elevation who had electrocardiographic evidence of changes in the ST segment or T wave, elevated levels of cardiac markers, a history of coronary artery disease, or all three findings. All patients were treated with aspirin, heparin, and the glycoprotein IIb/IIIa inhibitor tirofiban. They were randomly assigned to an early invasive strategy, which included routine catheterization within 4 to 48 hours and revascularization as appropriate, or to a more conservative (selectively invasive) strategy, in which catheterization was performed only if the patient had objective evidence of recurrent ischemia or an abnormal stress test. The primary end point was a composite of death, nonfatal myocardial infarction, and rehospitalization for an acute coronary syndrome at six months. RESULTS: At six months, the rate of the primary end point was 15.9 percent with use of the early invasive strategy and 19.4 percent with use of the conservative strategy (odds ratio, 0.78; 95 percent confidence interval, 0.62 to 0.97; P=0.025). The rate of death or nonfatal myocardial infarction at six months was similarly reduced (7.3 percent vs. 9.5 percent; odds ratio, 0.74; 95 percent confidence interval, 0.54 to 1.00; P<0.05). CONCLUSIONS: In patients with unstable angina and myocardial infarction without ST-segment elevation who were treated with the glycoprotein IIb/IIIa inhibitor tirofiban, the use of an early invasive strategy significantly reduced the incidence of major cardiac events. These data support a policy involving broader use of the early inhibition of glycoprotein IIb/IIIa in combination with an early invasive strategy in such patients.