Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous?

Context Experts debate the consequences of excessive lowering of diastolic pressure in patients with hypertension and coronary artery disease. Contribution This report is a secondary analysis of data from a large trial of 2 antihypertensive drug regimens in patients with known coronary artery disease. The authors found a J-shaped relationship between diastolic blood pressure and all-cause death and myocardial infarction, with the increased risk occurring at diastolic blood pressures below 70 to 80 mm Hg, that is, the lower the diastolic pressure, the higher the risk. Cautions The study examined associations between blood pressure and outcomes; it could not prove that the antihypertensive therapy that lowered diastolic pressure too much caused the adverse outcomes. The Editors For 2 decades, the hypertension literature has been haunted by the phenomenon of a paradoxical increase in morbidity and mortality with an excessive decrease in blood pressure (J-curve). Indeed, several reports have shown that low diastolic pressure is associated with an increased risk for coronary heart disease and related mortality in older adults and in patients taking antihypertensive medications (1-13). After doing a review and meta-analysis of pertinent studies, Farnett and colleagues (14) concluded that although there was no consistent J-shaped relationship between stroke and systolic or diastolic pressure, there was a consistent J-shaped relationship for cardiac events and diastolic pressure. These authors stated that this dichotomy in the relationship between diastolic pressure and target organ disease may leave a clinician with the uncomfortable choice of whether to prevent stroke or renal disease at the expense of coronary heart disease. These findings were at variance with the generally accepted dogma formulated by the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) (15), which stated that the relationship between pressure and risk was strong, continuous, independent, predictive and etiologically significant. Within the past decade, the phenomenon of a J-curve has been studied in several large trials of normotensive and hypertensive patients (16-30). Not surprisingly, arguments regarding whether a J-curve could be clinically significant have become somewhat contentious. That is, some rely on evidence that on-treatment diastolic pressure below 70 mm Hg does not increase risk for cardiovascular disease and thus deny an impairment of vital organ perfusion within the usual values achievable by antihypertensive treatment. Others, however, consider the J-curve a more real possibility, particularly for the heart. In contrast to other organs, the heart is perfused mostly during diastole and thus could be more vulnerable to diastolic pressure reduction. If a J-curve did exist, it should be most evident in patients with limited coronary perfusion, in other words, in those with manifest coronary artery disease (CAD). Optimal blood pressure in patients with hypertension and CAD remains controversial because few randomized clinical trials have been done in this population (31, 32). The International Verapamil-Trandolapril Study (INVEST) (33), a randomized trial, evaluated more than 22000 patients with CAD and hypertension. This patient profile, together with unprecedented levels of blood pressure control, provided a unique opportunity to critically investigate the hypothesis that the risk for CAD would increase with an excessive decrease in diastolic pressure. Methods Study Design and Intervention The INVEST design, methods, and principal results have been previously published (33). The trial used an open design with blinded end point assessment. In brief, clinically stable patients with CAD and hypertension were randomly assigned to a verapamil sustained-releasebased or atenolol-based strategy. Patients with previous myocardial infarction (MI) within 3 months of enrollment or class IV or V congestive heart failure were excluded. Blood pressure goals were based on JNC VI (systolic pressure <140 mm Hg and diastolic pressure <90 mm Hg or systolic pressure <130 mm Hg and diastolic pressure <85 mm Hg in patients with diabetes or renal impairment) (15). The addition of trandolapril or hydrochlorothiazide was recommended when necessary to achieve blood pressure goals. Trandolapril was also recommended for patients with heart failure, diabetes, or renal impairment. Documented CAD was defined as any of the following: remote (3 months before enrollment) confirmed MI, coronary angiography showing more than 50% narrowing of at least 1 major coronary artery, diagnosis of classic angina pectoris, or concordant abnormalities on 2 different signals (electrocardiography, echocardiography, or radionuclide scans) from stress test findings concordant for ischemia (for example, ST-segment depression or perfusion defects on radionuclide scanning or wall-motion abnormalities on echocardiography or radionuclide scanning). Patient Monitoring and Follow-up Protocol visits were scheduled every 6 weeks for the first 6 months and then biannually until 2 years after the last patient was enrolled. Patients were assessed for response to treatment, symptoms, treatment adherence, and adverse effects at each visit and at the end of the study as detailed elsewhere (33). Patient follow-up was complete when we received a final assessment form through the online data system or a death report. The Internet-based electronic data collection method used in INVEST did not accept the entry until all required fields were complete. Blood pressure was measured by using a standard mercury sphygmomanometer with an appropriately sized cuff applied to the upper nondominant arm at heart level. By auscultation at the brachial artery, systolic pressure was recorded at the first Korotkoff sound and diastolic pressure was recorded at the disappearance of the fifth Korotkoff sound. Blood pressure was measured twice, at least 2 minutes apart, and the measurements were averaged. Study Outcomes The primary outcome was the first occurrence of all-cause death, nonfatal MI, or nonfatal stroke by intention-to-treat analysis. The MI and stroke definitions are detailed elsewhere (34). These 3 components individually were the main secondary outcomes. For this analysis, additional outcomes included fatal and nonfatal MI, fatal and nonfatal stroke, and average on-treatment blood pressure before outcome or censoring. Ascertainment and blinded adjudication of outcomes were described previously (32). Follow-up data were available for 22008 (97.5%) patients. Statistical Analysis The main conclusions of INVEST were that the 2 treatment strategies were equivalent with respect to the primary outcome, main secondary outcomes, and on-treatment systolic and diastolic pressures. Thus, data for all enrolled patients were combined and included in these analyses following the intention-to-treat principle. A P value of 0.05 or less was considered statistically significant. Patients without a primary outcome event were censored at their latest follow-up visit. Average follow-up systolic and diastolic pressures were calculated for each patient by using all post-baseline results, up to the date of primary outcome or censoring. The baseline value was substituted for patients with no post-baseline data (n= 1154). In this exploratory analysis, the proportions of patients were pooled by 10mm Hg strata of average follow-up systolic pressure, and the distribution of primary outcome event rate was evaluated to determine whether the relationship was linear. A similar presentation was prepared for diastolic pressure. Because the frequency distributions seemed consistent with a quadratic curve, a quadratic Cox proportional hazards model was formed for the time to primary outcome for each blood pressure variable, with factors for blood pressure and blood pressure squared. Similarly, the relationship between each 10mm Hg stratum of average systolic pressure and diastolic pressure and all-cause death, fatal and nonfatal MI, and fatal and nonfatal stroke was evaluated. For the time to primary outcome, a second model was fitted, adjusting for the following baseline covariates: age (10-year increments), sex, race and ethnicity (white, Asian, black, Hispanic, multiracial, or other), previous MI, heart failure (classes I to III), body mass index in increments of 5 kg/m2, U.S. residency, renal impairment, peripheral vascular disease, left ventricular hypertrophy, smoking history, coronary revascularization, dyslipidemia, stroke or transient ischemic attack, angina pectoris, arrhythmia, diabetes, cancer, aspirin use, and average systolic pressure or diastolic pressure and systolic pressure squared or diastolic pressure squared. To identify clinically relevant interactions between the J-shaped curve and baseline diastolic pressure, demographic characteristics, and comorbid conditions for the primary outcome, a 2-step procedure was used. First, baseline covariates were tested individually by adding the variable and 2 interaction terms (variablediastolic pressure and variable[diastolic pressure squared]) to the Cox proportional hazards model. Variables included were age older than 70 years, sex, previous MI, heart failure (classes I to III), previous stroke or transient ischemic attack, diabetes, cancer, renal impairment, hypercholesterolemia, peripheral vascular disease, smoking history, U.S. residency, body mass index greater than 29 kg/m2 (mean baseline body mass index), and diastolic pressure greater than 86 mm Hg (mean baseline diastolic pressure). The change in log likelihood was used to assess the significance of simultaneously adding the 2 interaction terms. The second step in identifying clinically relevant interactions between the J-shaped curve and baseline covariates was to plot the hazard ratios for the primary outcome versus diastolic pressure in the pr