Choice of estimand and analysis methods in diabetes trials with rescue medication.

The analysis of clinical trials aiming to show symptomatic benefits is often complicated by the ethical requirement for rescue medication when the disease state of patients worsens. In type 2 diabetes trials, patients receive glucose-lowering rescue medications continuously for the remaining trial duration, if one of several markers of glycemic control exceeds pre-specified thresholds. This may mask differences in glycemic values between treatment groups, because it will occur more frequently in less effective treatment groups. Traditionally, the last pre-rescue medication value was carried forward and analyzed as the end-of-trial value. The deficits of such simplistic single imputation approaches are increasingly recognized by regulatory authorities and trialists. We discuss alternative approaches and evaluate them through a simulation study. When the estimand of interest is the effect attributable to the treatments initially assigned at randomization, then our recommendation for estimation and hypothesis testing is to treat data after meeting rescue criteria as deterministically 'missing' at random, because initiation of rescue medication is determined by observed in-trial values. An appropriate imputation of values after meeting rescue criteria is then possible either directly through multiple imputation or implicitly with a repeated measures model. Crucially, one needs to jointly impute or model all markers of glycemic control that can lead to the initiation of rescue medication. An alternative for hypothesis testing only are rank tests with outcomes from patients 'requiring rescue medication' ranked worst, and non-rescued patients ranked according to final visit values. However, an appropriate ranking of not observed values may be controversial.

Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial.

BACKGROUND: LCI699, a novel inhibitor of aldosterone synthase, reduces serum aldosterone, and may have benefit in the treatment of hypertension. METHODS AND RESULTS: We performed the first double-blind, randomized trial with LCI699 in patients with primary hypertension. We randomized 524 patients to LCI699 0.25 mg once daily (n=92), 0.5 mg once daily (n=88), 1.0 mg once daily (n=86), and 0.5 mg twice daily (n=97); eplerenone 50 mg twice daily (n=84); or placebo (n=77) for 8 weeks. Adrenocorticotropic hormone (250 µg IV) stimulation testing was performed in a subset of patients to quantify the selectivity of LCI699 for aldosterone synthase compared with 11-ß-hydroxylase. Reductions in clinic diastolic blood pressure were significant for LCI699 1.0 mg (-7.1 mm Hg; P=0.0012) and eplerenone 50 mg twice daily (-7.9 mm Hg; P<0.0001) compared with placebo (-2.6 mm Hg) but not other doses of LCI699. Significant reductions in clinic systolic blood pressure were observed with all doses of LCI699 (P<0.005 or better) and eplerenone (P<0.0001). All doses of LCI699 significantly reduced 24-hour ambulatory blood pressure compared with placebo (P<0.01). Adrenocorticotropic hormone stimulation of cortisol was suppressed in ≈20% of subjects receiving LCI699 at a total daily dose of 1.0 mg. Safety and tolerability were similar among LCI699, placebo, and eplerenone. CONCLUSIONS: Aldosterone synthase inhibition with LCI699 significantly lowered clinic and ambulatory blood pressure. A minority of subjects developed blunted adrenocorticotropic hormone-stimulated release of cortisol. These results support additional research to evaluate use of aldosterone synthase inhibition in primary hypertension and/or patients characterized by aldosterone excess. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00758524.

What resting heart rate should one aim for when treating patients with heart failure with a beta-blocker? Experiences from the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF).

OBJECTIVES: The goal of this study was to explore the question: what resting heart rate (HR) should one aim for when treating patients with heart failure with a beta-blocker? BACKGROUND: The interaction of pretreatment and achieved resting HR with the risk-reducing effect of beta-blocker treatment needs further evaluation. METHODS: Cardiovascular risk and risk reduction were analyzed in five subgroups defined by quintiles (Q) of pretreatment resting HR in the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF). RESULTS: Mean baseline HR in the 5 Qs were 71, 76, 81, 87, and 98 beats/min; achieved HR 63, 66, 68, 72, and 75 beats/min; and net change -8, -10, -11, -13, and -14 beats/min, respectively. Baseline HR was related to a number of baseline characteristics. Cardiovascular risk was no different in Q1 to Q4 (placebo groups) but increased in Q5 (HR above 90 beats/min). No relationship was observed between the risk-reducing effect of metoprolol controlled release/extended release (CR/XL) and baseline HR in the five Qs of baseline HR, or achieved HR, or change in HR during follow-up, respectively. CONCLUSIONS: Metoprolol CR/XL significantly reduced mortality and hospitalizations independent of resting baseline HR, achieved HR, and change in HR. Achieved HR and change in HR during follow-up were closely related to baseline HR; therefore, it was not possible to answer the question posed. Instead, one has to apply a very simple rule: aim for the target beta-blocker dose used in clinical trials, and strive for the highest tolerated dose in all patients with heart failure, regardless of baseline and achieved HR.

International REgistry to assess medical Practice with lOngitudinal obseRvation for Treatment of Heart Failure (REPORT-HF): rationale for and design of a global registry.

AIMS: The clinical characteristics, initial presentation, management, and outcomes of patients hospitalized with new-onset (first diagnosis) heart failure (HF) or decompensation of chronic HF are poorly understood worldwide. REPORT-HF (International REgistry to assess medical Practice with lOngitudinal obseRvation for Treatment of Heart Failure) is a global, prospective, and observational study designed to characterize patient trajectories longitudinally during and following an index hospitalization for HF. METHODS: Data collection for the registry will be conducted at ∼300 sites located in ∼40 countries. Comprehensive data including demographics, clinical presentation, co-morbidities, treatment patterns, quality of life, in-hospital and post-discharge outcomes, and health utilization and costs will be collected. Enrolment of ∼20 000 adult patients hospitalized with new-onset (first diagnosis) HF or decompensation of chronic HF over a 3-year period is planned with subsequent 3 years follow-up. PERSPECTIVE: The REPORT-HF registry will explore the clinical characteristics, management, and outcomes of HF worldwide. This global research programme may have implications for the formulation of public health policy and the design and conduct of international clinical trials.

Genetic analysis of fluvastatin response and dyslipidemia in renal transplant recipients.

The Assessment of Lescol in Renal Transplantation clinical trial demonstrated the efficacy of fluvastatin in reducing cardiovascular (CV) disease in renal transplant recipients. The study included a voluntary pharmacogenetic component, enrolling 1,404 patients, which allowed association testing of baseline measures and longitudinal analysis of the 707 fluvastatin-treated and 697 placebo-treated individuals. A candidate gene approach, examining 42 polymorphisms in 18 genes, was used to test for association between selected polymorphisms and major adverse cardiac events, graft failure, change in LDL and HDL cholesterol, and baseline LDL and HDL cholesterol. Reported associations between cholesteryl ester transfer protein (CETP) and baseline HDL cholesterol were replicated, with four previously implicated single nucleotide polymorphisms significantly associated in males and one in females; tests of reported associations between CETP and CV disease yielded varying results. We found no evidence for genetic factors affecting fluvastatin response. Polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) previously reported to affect the efficacy of pravastatin did not show a similar effect on the reduction of LDL cholesterol by fluvastatin.

Effects of angiotensin type-1 receptor antagonism on small artery function in patients with type 2 diabetes mellitus.

Endothelial dysfunction has been demonstrated to occur in small arteries from patients with type 2 diabetes and hypertension. The effects of angiotensin II receptor blockade on vessel function were examined using pressure myography in a randomized 12-week double-blind placebo-controlled parallel group study using candesartan cilexitil. The maximal vascular response to acetylcholine (Ach) was impaired at baseline and improved with candesartan. This improvement was primarily caused by an effect in the nitric oxide component of Ach-mediated dilatation. The degree of endothelial dysfunction directly correlated with serum low-density lipoprotein cholesterol levels. Sodium nitroprusside-induced endothelium-independent dilatation was reduced in diabetic patients and intervention with candesartan lead to an improvement in EC50 with no change in maximal response. Vasoconstriction to norepinephrine was normal and did not change with intervention, but responses to angiotensin II were reduced after candesartan in diabetic patients. These results demonstrate that even brief treatment with angiotensin II receptor blockade is associated with a significant improvement in resistance vessel endothelial function.