Pulse pressure and risk of cardiovascular outcomes in patients with hypertension and coronary artery disease: an INternational VErapamil SR-trandolapril STudy (INVEST) analysis

The purpose of this study was to assess the relationship between pulse pressure (PP) and cardiovascular outcomes in a large, elderly, coronary artery disease (CAD) population with hypertension, and compare the predictive power of PP with other blood pressure measures. In INternational VErapamil-trandolapril STudy, 22 576 CAD patients with hypertension (mean age 66 years) were randomized to verapamil-SR or atenolol-based strategies and followed for 2.7 years (mean). Primary outcome (PO) was time to first occurrence of death (all-cause), non-fatal myocardial infarction (MI), or non-fatal stroke. Mean follow-up PP was summarized by 5 mmHg subgroups for association with incidence of PO. Stepwise Cox proportional hazards models were used to estimate adjusted relative hazard ratios (HR) for the risk of PO with follow-up PP as a continuous variable, with linear and quadratic terms. Similar models were constructed for follow-up systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressures (MAP). A -2 log-likelihood statistic was used to assess the predictive power of PP compared with SBP, DBP, and MAP. For follow-up PP, the incidence and adjusted HR for the PO formed a J- or U-shaped curve. After adjusting for baseline covariates, both linear and quadratic terms for PP were significant (P < 0.0001 for both), with a nadir of 54 mmHg (bootstrapping 95% CI 42-60 mmHg). Similar quadratic relationships were found between PP and all-cause mortality or MI; the relationship between PP and stroke was linear. Pulse pressure was a predictor of PO even after including SBP (P = 0.007 linear term) or DBP (P < 0.0001 for both linear and quadratic terms) or MAP (P < 0.01 for both liner and quadratic terms) in the model. Using -2 log-likelihood differences, SBP (-2 log-likelihood difference 77.1 vs. 7.3 for PP), DBP (-2 log-likelihood difference 138.5 vs. 44.6 for PP), and MAP (-2 log-likelihood difference 125.0 vs. 13.4 for PP) were stronger predictors of PO than PP. In CAD patients with hypertension, PP (on anti-hypertensive treatment) is a weaker predictor of cardiovascular outcomes than SBP, DBP, or MAP.