Rice, Madeline Murguia

Background: Patients with chronic kidney disease are at increased risk for cardiovascular morbidity and mortality. We assessed the association between albuminuria and death or cardiovascular events among patients with stable coronary disease. Methods: We studied patients enrolled in the Prevention of Events with an ACE Inhibitor (PEACE) trial, in which patients with chronic stable coronary disease and preserved systolic function were randomized to trandolapril or placebo and followed for a median of 4.8 years. The urinary albumin to creatinine ratio (ACR) assessed in a core laboratory in 2977 patients at baseline and in 1339 patients at follow-up (mean 34 months) was related to estimated glomerular filtration rate (eGFR) and outcomes. Results: The majority of patients (73%) had a baseline albumin/creatinine ratio within the normal range. Independent of the eGFR and other baseline covariates, a higher albumin/creatinine ratio even within the normal range was associated with increased risks for all-cause mortality (p < 0.001) and cardiovascular death (p = 0.01). The effect of trandolapril therapy on outcomes was not significantly modified by the level of albuminuria. Nevertheless, trandolapril therapy was associated with a significantly lower mean follow-up ACR (12.5 ug/mg vs 14.6 ug/mg, p = 0.0002), after adjusting for baseline ACR, time between collections and other covariates. An increase in ACR over time was associated with increased risk of cardiovascular death (HR per log ACR 1.74, 95% confidence intervals 1.08–2.82). Conclusions: Albuminuria, even in low levels within the normal range, is an independent predictor of cardiovascular and all-cause mortality.

Abstract Clinical trial Data and Safety Monitoring Boards (DSMBs) have a primary obligation of ensuring study participant safety, while maintaining trial integrity. The role of DSMBs is expanding, and ideally should include post-hoc reporting of deliberative processes related to clinically important safety issues or factors that could impact on future trial designs. We describe how the TOPCAT DSMB detected, investigated, and adjudicated an unexpectedly large renal adverse event signal midway through the trial, and offer general guidelines for dealing with similar unanticipated occurrences in future trials. The detection of a greater than expected incidence of deterioration in renal function, occurring in 6.1% of patients in the spironolactone arm compared with 3.9% in the placebo arm (P = 0.009), led to an in-depth DSMB review of associated study medication withdrawals and adverse events. The trial continued uninterrupted throughout the review, which reached the conclusions that spironolactone-associated renal dysfunction did not compromise overall patient safety or interfere with a perceived efficacy signal. Although no discrete mechanism for the spironolactone-associated renal adverse event signal was identified, likely possibilities are discussed. In clinical trials, DSMBs and co-ordinating centres should have the resources to detect, investigate, and adjudicate unexpected safety issues, with goals of ensuring patient safety and preserving the potential for detection of therapeutic effectiveness. In TOPCAT, spironolactone-associated renal dysfunction emerged as a potentially trial-threatening adverse event and, although clinically important, did not lead to compromise of patient safety, trial interruption, termination, or apparent loss of treatment effectiveness.

Background— Patients with chronic kidney disease are at increased risk for cardiovascular morbidity and mortality. We assessed the association between albuminuria and the risks for death and cardiovascular events among patients with stable coronary disease. Methods and Results— We studied patients enrolled in the Prevention of Events with an ACE inhibitor (PEACE) trial, in which patients with chronic stable coronary disease and preserved systolic function were randomized to trandolapril or placebo and followed up for a median of 4.8 years. The urinary albumin to creatinine ratio (ACR) assessed in a core laboratory in 2977 patients at baseline and in 1339 patients at follow-up (mean 34 months) was related to estimated glomerular filtration rate and outcomes. The majority of patients (73%) had a baseline ACR within the normal range (<17 μg/mg for men and <25 μg/mg for women). Independent of the estimated glomerular filtration rate and other baseline covariates, a higher ACR, even within the normal range, was associated with increased risks for all-cause mortality ( P <0.001) and cardiovascular death ( P =0.01). The effect of trandolapril therapy on outcomes was not modified significantly by the level of albuminuria. Nevertheless, trandolapril therapy was associated with a significantly lower mean follow-up ACR (12.5 versus 14.6 μg/mg, P =0.0002), after adjustment for baseline ACR, time between collections, and other covariates. An increase in ACR over time was associated with increased risk of cardiovascular death (hazard ratio per log ACR 1.74, 95% CI 1.08 to 2.82). Conclusions— Albuminuria, even in low levels within the normal range, is an independent predictor of cardiovascular and all-cause mortality.

Background— Data supporting the prognostic significance of high-sensitivity C-reactive protein (hs-CRP) are derived largely from individuals with no overt coronary artery disease or from patients with acute coronary syndromes. In contrast, the ability of hs-CRP to predict outcomes in patients with stable coronary artery disease and the prognostic significance of the Centers for Disease Control/American Heart Association hs-CRP cut points in such a population remain relatively unexplored. Methods and Results— We measured hs-CRP in 3771 patients with stable coronary artery disease from the Prevention of Events With Angiotensin-Converting Enzyme Inhibition (PEACE) trial, a randomized placebo-controlled trial of the angiotensin-converting enzyme inhibitor trandolapril. Patients were followed up for a median of 4.8 years for cardiovascular death, myocardial infarction, or stroke, as well as new heart failure and diabetes. After adjustment for baseline characteristics and treatments, higher hs-CRP levels, even >1 mg/L, were associated with a significantly greater risk of cardiovascular death, myocardial infarction, or stroke (hs-CRP 1 to 3 mg/L: adjusted hazard ratio, 1.39; 95% CI, 1.06 to 1.81; P =0.016; hs-CRP >3 mg/L: adjusted hazard ratio, 1.52; 95% CI, 1.15 to 2.02; P =0.003). Similarly, elevated hs-CRP levels were an independent predictor of new heart failure (adjusted P <0.001 for trend) and new diabetes (adjusted P <0.001 for trend). There were no significant interactions between hs-CRP levels and the effects of trandolapril on any of the above outcomes. Conclusions— In stable coronary artery disease, an elevated hs-CRP level, even >1 mg/L, is a significant predictor of adverse cardiovascular events independently of baseline characteristics and treatments. An elevated hs-CRP does not appear to identify patients with stable coronary artery disease and preserved ejection fraction who derive particular benefit from angiotensin-converting enzyme inhibition.