Effect of Visit‐to‐Visit Variation of Heart Rate and Systolic Blood Pressure on Outcomes in Chronic Systolic Heart Failure: Results From the Systolic Heart Failure Treatment With the I f Inhibitor Ivabradine Trial (SHIFT) Trial

BACKGROUND Elevated resting heart rate (HR) and low systolic blood pressure (SBP) are related to poor outcomes in heart failure (HF). The association between visit-to-visit variation in SBP and HR and risk in HF is unknown. METHODS AND RESULTS In Systolic Heart Failure Treatment with the If inhibitor ivabradine Trial (SHIFT) patients, we evaluated relationships between mean HR, mean SBP, and visit-to-visit variations (coefficient of variation [CV]=SD/mean×100%) in SBP and HR (SBP-CV and HR-CV, respectively) and primary composite endpoint (cardiovascular mortality or HF hospitalization), its components, all-cause mortality, and all-cause hospitalization. High HR and low SBP were closely associated with risk for primary endpoint, all-cause mortality, and HF hospitalization. The highest number of primary endpoint events occurred in the highest HR tertile (38.8% vs 16.4% lowest tertile; P<0.001). For HR-CV, patients at highest risk were those in the lowest tertile. Patients in the lowest thirds of mean SBP and SBP-CV had the highest risk. The combination of high HR and low HR-CV had an additive deleterious effect on risk, as did that of low SBP and low SBP-CV. Ivabradine reduced mean HR and increased HR-CV, and increased SBP and SBP-CV slightly. CONCLUSIONS Beyond high HR and low SBP, low HR-CV and low SBP-CV are predictors of cardiovascular outcomes with additive effects on risk in HF, but with an unknown effect size. Beyond HR reduction, ivabradine increases HR-CV. Low visit-to-visit variation of HR and SBP might signal risk of cardiovascular outcomes in systolic HF. CLINICAL TRIAL REGISTRATION URL: http://www.isrctn.com/. Unique identifier: ISRCTN70429960.