Background Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. Methods In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1•5 mL/kg per min or greater increase in peak oxygen consumption (pVO 2) and at least one NYHA class reduction or a 3•0 mL/kg per min or greater pVO 2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO 2 , NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545.

People with type 2 diabetes mellitus have an excess risk of macrovascular disease and a poorer prognosis. PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) was a landmark study of secondary cardiovascular disease (CVD) prevention in type 2 diabetes that suggested a beneficial effect of pioglitazone therapy on macrovascular outcomes. Previous studies have already shown that pioglitazone has a good safety and tolerability profile in people with type 2 diabetes, but PROactive provided an opportunity to assess tolerability and safety associated with long-term exposure in a vulnerable subpopulation at very high cardiovascular risk. This review discusses all the key safety and tolerability characteristics associated with pioglitazone therapy in PROactive. As in previous studies, pioglitazone was associated with typical, but manageable, increases in oedema (26.4% vs 15.1% for placebo) and weight gain (mean change of +3.8 kg vs -0.6 kg for placebo). Increased hypoglycaemia with pioglitazone was consistent with improved glycaemic control. Despite more reports of serious heart failure in the pioglitazone group (5.7% vs 4.1% for placebo), there was a proportional improvement in macrovascular outcomes among patients developing heart failure, and absolute rates of macrovascular events and mortality were similar to those in the placebo group. Liver function tests confirmed the hepatic safety of pioglitazone with long-term use and revealed a tendency to improved hepatic function, which may reflect reductions in liver fat. The comparative incidence of malignancies was similar; however, more cases of bladder neoplasm (14 vs 5) and fewer cases of breast cancer (3 vs 11) were observed in the pioglitazone versus placebo arms of the study. A higher rate of bone fractures observed among pioglitazone-treated female patients (5.1% vs 2.5%) warrants further investigation. Overall, safety and tolerability was predictable, and adverse events were not treatment limiting. These results suggest that any beneficial effects of pioglitazone on macrovascular outcomes are accompanied by good long-term tolerability in this population of very high-risk patients with type 2 diabetes and established CVD.

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Background Recent studies have raised concerns about potential increased cardiovascular (CV) risk in type 2 diabetes patients treated with some peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists. Objective To ascertain the risk of hospitalization for acute myocardial infarction (AMI) in type 2 diabetes patients treated with pioglitazone relative to rosiglitazone. Methodology Using data covering 2003-2006 from a large health care insurer in the US, a retrospective cohort study was conducted in patients who initiated treatment with pioglitazone or rosiglitazone. The hazard ratio (HR) of incident hospitalization for AMI after initiation of treatment with these drugs was estimated from multivariate Cox's proportional hazards survival analysis; similarly, the HR was ascertained for hospitalization for the composite endpoint of AMI or coronary revascularization (CR). Results A total of 29 911 eligible patients were identified in the database; 14 807 in the pioglitazone and 15 104 in the rosiglitazone group. Baseline demographics, medical history, and dispensed medications were generally well balanced between groups. The unadjusted HR for hospitalization for AMI was 0.82, 95%CI: 0.67-1.01. After adjustment for baseline covariates the HR was 0.78, 95%CI: 0.63-0.96. The adjusted HR for the composite of AMI or CR was 0.85, 95%CI: 0.75-0.98. Conclusion This retrospective cohort study showed that pioglitazone, in comparison with rosiglitazone, is associated with a 22% relative risk reduction of hospitalization for AMI in patients with type 2 diabetes. KEY POINTS pioglitazone, in comparison to rosiglitazone, is associated with a 22% relative risk reduction of myocardial infarction. pioglitazone, in comparison to rosiglitazone, is associated with a 15% relative risk reduction of the composite endpoint of myocardial infarction or coronary revascularization.

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Detection of acid-fast bacilli (AFB) by sputum smear supports treatment decisions with pulmonary tuberculosis (TB), but smear sensitivity for Mycobacterium tuberculosis is only approximately 45 to 75%. In an effort to increase sensitivity, smears were prepared using a minimum sputum volume of 5.0 ml. Sensitivity of smears during a 39-mo period (n = 1,849) using >/= 5.0 ml of sputum was 92. 0%, significantly greater (p < 0.001) than a sensitivity of 72.5% in a previous 24-mo period (n = 3,486) when all specimens were processed regardless of volume. All new cases of TB (n = 18) were smear-positive with >/= 5.0 ml of sputum before treatment, and all were receiving antituberculosis drugs at hospital discharge. In contrast, significantly fewer new cases of TB (14 of 26, p = 0.002) were positive before treatment when smears were prepared using sputum of any volume, and significantly fewer of these new TB cases (18 of 26, p = 0.03) were receiving treatment at hospital discharge. The eight cases without treatment were smear-negative. These results indicate that acid-fast smear using >/= 5.0 ml of sputum increases sensitivity for M. tuberculosis and accelerates treatment of TB.