Incidence and Predictors of Hyperkalemia in Patients With Heart Failure: An Analysis of the CHARM Program Akshay S. Desai, Karl Swedberg, John J. V. McMurray, Christopher B. Granger, Salim Yusuf, ...James B. Young, Mark E. Dunlap, Scott D. Solomon, James W. Hainer, Bertil Olofsson, Eric L. Michelson, Marc A. Pfeffer We examined the incidence and predictors of hyperkalemia in a broad population of patients with symptomatic heart failure enrolled in the CHARM (Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity) Program. Independent of assignment to candesartan or placebo, the risk of hyperkalemia increased with advanced age, male gender, baseline hyperkalemia, renal failure, diabetes, and background use of angiotensin-converting enzyme inhibitors or spironolactone. Candesartan increased the observed rate of hyperkalemia in these subgroups but was associated with a consistent reduction in the risk of cardiovascular death or heart failure hospitalization. Although renin-angiotensin-aldosterone antagonists improve clinical outcomes in heart failure patients, careful surveillance of serum potassium and creatinine is essential.
Red Cell Distribution Width as a Novel Prognostic Marker in Heart Failure: Data From the CHARM Program and the Duke Databank G. Michael Felker, Larry A. Allen, Stuart J. Pocock, Linda K. Shaw, John ...J. V. McMurray, Marc A. Pfeffer, Karl Swedberg, Duolao Wang, Salim Yusuf, Eric L. Michelson, Christopher B. Granger, for the CHARM Investigators Among 36 routine laboratory measures in the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) program, higher red cell distribution width showed the greatest association with cardiovascular death and heart failure hospitalization (adjusted hazard ratio 1.17 per 1 SD increase, p < 0.001). Only age and cardiomegaly showed better independent association with outcome. This finding was replicated in the Duke Databank, in which red cell distribution width continued to be strongly associated with mortality (adjusted hazard ratio 1.29 per 1 SD, p < 0.001). Understanding how and why this marker is associated with outcome may provide novel insights into heart failure pathophysiology.
Thorough QT studies conducted according to the International Council on Harmonisation E14 guideline are required for new nonantiarrhythmic drugs to assess the potential to prolong ventricular ...repolarization. Special considerations may be needed for conducting such studies with antidiabetes drugs as changes in blood glucose and other physiologic parameters affected by antidiabetes drugs may prolong the QT interval and thus confound QT/corrected QT assessments. This review discusses potential mechanisms for QT/corrected QT interval prolongation with antidiabetes drugs and offers practical considerations for assessing antidiabetes drugs in thorough QT studies. This article represents collaborative discussions among key stakeholders from academia, industry, and regulatory agencies participating in the Cardiac Safety Research Consortium. It does not represent regulatory policy.
This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of blood pressure (BP) responses to drugs being developed ...for indications not of a direct cardiovascular (CV) nature. A wide range of drugs are associated with off-target BP increases, and both scientific attention and regulatory attention to this topic are increasing. The article provides a detailed summary of scientific discussions at a Cardiac Safety Research Consortium–sponsored Think Tank held on July 18, 2012, with the intention of moving toward consensus on how to most informatively collect and analyze BP data throughout clinical drug development to prospectively identify unacceptable CV risk and evaluate the benefit-risk relationship. The overall focus in on non-CV drugs, although many of the points also pertain to CV drugs. Brief consideration of how clinical assessment can be informed by nonclinical investigation is also outlined. These discussions present current thinking and suggestions for furthering our knowledge and understanding of off-target drug-induced BP increases and do not represent regulatory guidance.
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