Statistical power considerations in the use of win ratio in cardiovascular outcome trials.

BACKGROUND: In cardiovascular outcome trials, the win ratio (WR) method models the composite endpoint under a hierarchical structure to account for clinical priorities. It also can be applied to both survival and nonsurvival outcomes. METHODS: In this article, we assess the performance of the WR method via extensive simulation studies and real data analyses and discuss power considerations of the method with respect to hierarchical order, variable type, magnitude of treatment effect, and event rates when applied to clinical studies. RESULTS AND CONCLUSION: In the hierarchy of the WR method, the first-ordered component (e.g., death) plays a dominant role in statistical power, especially when that component has a large treatment effect and a high event rate. This is in contrast with the score test of the Cox proportional hazards model in which the power is more likely affected by the nonfatal events that are usually observed earlier. Furthermore, when adding an additional component to the composite endpoint, the performance of the WR method varies depending on the treatment effect, event rate, and hierarchical position of the component. If the additional component has a relatively smaller or no treatment effect, the statistical power will decrease; if the additional component has a relatively larger treatment effect and higher event rate, the statistical power will increase. When adding a nonsurvival continuous outcome (e.g., 6-min walk distance) with even a tiny treatment effect, the statistical power could dramatically increase.

Heart Failure Population with Therapeutic Response to Sacubitril/Valsartan, Spironolactone and Candesartan: FDA Perspective.

Sacubitril/valsartan was approved by the Food and Drug Administration in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure (HHF) in patients with chronic heart failure with reduced ejection fraction defined as left ventricular ejection fraction (LVEF) ≤ 40%. This approval was based on PARADIGM-HF trial. Subsequently, PARAGON-HF was conducted to support a claim for sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF), defined as LVEF ≥ 45%. PARAGON-HF failed to meet the pre-defined threshold for statistical significance for the primary composite endpoint. However, analysis of the primary endpoint by LVEF as a continuous variable demonstrated that sacubitril/valsartan was efficacious in patients with mildly abnormal LVEF similar to patients with LVEF ≤ 40% evaluated in PARADIGM-HF. This led to a broader indication for sacubitril/valsartan-"to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. LVEF is a variable measure, so use clinical judgment in deciding whom to treat." This article describes the rationale for a revised indication for sacubitril/valsartan, emphasizes the need to go beyond a dichotomous classification of HF based on a traditional LVEF cut-off and clarifies that the product label for sacubitril/valsartan does not refer to HFpEF.

Correction to: FDA Approval of Angiotensin II for the Treatment of Hypotension in Adults with Distributive Shock.

The author name that previously read.

FDA Approval of Angiotensin II for the Treatment of Hypotension in Adults with Distributive Shock.

Distributive shock is a subset of shock marked by decreased systemic vascular resistance, organ hypoperfusion and altered oxygen extraction. Despite the use of intravenous fluids and either higher dose of catecholamines or other additional exogenous vasopressors to maintain blood pressure in the target range, the rate of mortality remains higher in patients with septic shock. Therefore, there is clearly an unmet need for additional safe and effective treatments. The use of angiotensin II to raise the mean arterial pressure (MAP) could provide additional therapy and the opportunity to evaluate a catecholamine-sparing effect by decreasing the dose of concomitant catecholamines while maintaining a target MAP. ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock phase 3; ClinicalTrials.gov number, NCT02338843) was an adequate and well-controlled trial. The primary endpoint was the rate of MAP response at hour 3 of treatment with study drug, defined as either a 10-mmHg increase from baseline in MAP or a MAP of at least 75 mmHg. The secondary endpoints were changes from baseline in Sequential Organ Failure Assessment (SOFA) scores (total and cardiovascular). Mortality was an exploratory endpoint. The trial provided substantial evidence of the effectiveness of angiotensin II in raising blood pressure over placebo in patients with distributive shock, while keeping catecholamine levels constant. There was no change in the secondary endpoint of total SOFA scores relative to placebo when catecholamine use was reduced in lieu of angiotensin II treatment. There was a slight decrease in the secondary endpoint of cardiovascular SOFA score relative to placebo during the catecholamine-sparing phase, reflecting the catecholamine-sparing effect. There was a consistent trend in decreased mortality relative to placebo over the 28-day study period. Based on the agreements emanating from the special protocol assessment to assess blood pressure effects, the data from this single study supported approval of angiotensin II by the Food and Drug Administration for marketing in the USA.