Annette Champion

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

Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the INternational VErapamil-SR/trandolapril STudy (INVEST)

AIM To determine the relationship between resting heart rate (RHR) and adverse outcomes in coronary artery disease (CAD) patients treated for hypertension with different RHR-lowering strategies. METHODS AND RESULTS Time to adverse outcomes (death, non-fatal myocardial infarction, or non-fatal-stroke) and predictive values of baseline and follow-up RHR were assessed in INternational VErapamil-SR/trandolapril STudy (INVEST) patients randomized to either a verapamil-SR (Ve) or atenolol (At)-based strategy. Higher baseline and follow-up RHR were associated with increased adverse outcome risks, with a linear relationship for baseline RHR and J-shaped relationship for follow-up RHR. Although follow-up RHR was independently associated with adverse outcomes, it added less excess risk than baseline conditions such as heart failure and diabetes. The At strategy reduced RHR more than Ve (at 24 months, 69.2 vs. 72.8 beats/min; P < 0.001), yet adverse outcomes were similar [Ve 9.67% (rate 35/1000 patient-years) vs. At 9.88% (rate 36/1000 patient-years, confidence interval 0.90-1.06, P = 0.62)]. For the same RHR, men had a higher risk than women. CONCLUSION Among CAD patients with hypertension, RHR predicts adverse outcomes, and on-treatment RHR is more predictive than baseline RHR. A Ve strategy is less effective than an At strategy for lowering RHR but has a similar effect on adverse outcomes.

Blood Pressure Control and Improved Cardiovascular Outcomes in the International Verapamil SR-Trandolapril Study

Uncontrolled blood pressure (BP) increases cardiovascular risk, independent of type of treatment. In this posthoc International Verapamil SR-Trandolapril Study analysis, we determined whether adverse outcomes are related to consistency of BP control, defined as the proportion of visits in which BP was in control. A total of 22 576 patients with hypertension and coronary artery disease were divided into 4 groups according to the proportion of visits in which BP was in control (<140/90 mm Hg): <25%, 25% to <50%, 50% to <75%, and ≥75%. Risk of primary outcome (first occurrence of death, nonfatal myocardial infarction, or nonfatal stroke), myocardial infarction, and stroke decreased progressively from the group with <25% to the group with ≥75% of visits with BP control. Adjusted risks of primary outcome (heart rate: 0.60; 95% CI: 0.53 to 0.67), myocardial infarction (heart rate: 0.58; 95% CI: 0.48 to 0.70), and stroke (heart rate: 0.50; 95% CI: 0.37 to 0.67) were less in the group with ≥75% of visits with BP control compared with the group with <25% of visits with BP control. Baseline BP was not predictive of outcomes. Proportion of visits with BP control was associated with mean follow-up systolic BP (r2=0.64), both being independently related to primary outcome. As proportion of visits with BP control increases, there is an associated steep reduction in cardiovascular risk, independent of baseline characteristics and mean on-treatment BP. Consistency of BP control during treatment provides additional information on the protective effect of antihypertensive treatment. Physicians need to be concerned at each visit if BP is not controlled.

Blood pressure and outcomes in very old hypertensive coronary artery disease patients: an INVEST substudy.

BACKGROUND Our understanding of the growing population of very old patients (aged >or=80 years) with coronary artery disease and hypertension is limited, particularly the relationship between blood pressure and adverse outcomes. METHODS This was a secondary analysis of the INternational VErapamil SR-Trandolapril STudy (INVEST), which involved 22,576 clinically stable hypertensive coronary artery disease patients aged >or=50 years. The patients were grouped by age in 10-year increments (aged >or=80, n=2180; 70-<80, n=6126; 60-<70, n=7602; <60, n=6668). Patients were randomized to either verapamil SR- or atenolol-based treatment strategies, and primary outcome was first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS At baseline, increasing age was associated with higher systolic blood pressure, lower diastolic blood pressure, and wider pulse pressure (P <.001). Treatment decreased systolic, diastolic, and pulse pressure for each age group. However, the very old retained the widest pulse pressure and the highest proportion (23.6%) with primary outcome. The adjusted hazard ratio for primary outcomes showed a J-shaped relationship among each age group with on-treatment systolic and diastolic pressures. The systolic pressure at the hazard ratio nadir increased with increasing age, highest for the very old (140 mm Hg). However, diastolic pressure at the hazard ratio nadir was only somewhat lower for the very old (70 mm Hg). Results were independent of treatment strategy. CONCLUSION Optimal management of hypertension in very old coronary artery disease patients may involve targeting specific systolic and diastolic blood pressures that are higher and somewhat lower, respectively, compared with other age groups.

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

AIM 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. METHODS AND RESULTS 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. CONCLUSION In CAD patients with hypertension, PP (on anti-hypertensive treatment) is a weaker predictor of cardiovascular outcomes than SBP, DBP, or MAP.

Verapamil-sustained release–based treatment strategy is equivalent to atenolol-based treatment strategy at reducing cardiovascular events in patients with prior myocardial infarction: An INternational VErapamil SR-Trandolapril (INVEST) substudy

BACKGROUND In patients with prior myocardial infarction (MI), beta-blockers reduce mortality by 23% to 40%. However, despite this favorable effect, adverse effects limit compliance to this medication. The purpose of the study was to compare a beta-blocker-based strategy with a heart rate-lowering calcium antagonists-based strategy in patients with prior MI. METHODS We evaluated 7,218 patients with prior MI enrolled in the INternational VErapamil SR-Trandolapril (INVEST) substudy randomized to verapamil-sustained release (SR)- or atenolol-based strategies. Primary outcome was time to first occurrence of death (all-cause), nonfatal MI, or nonfatal stroke. Secondary outcomes included death, total MI (fatal and nonfatal), and total stroke (fatal and nonfatal) considered separately. RESULTS During the 2.8 +/- 1.0 years of follow-up, patients assigned to the verapamil-SR-based and atenolol-based strategies had comparable blood pressure control, and the incidence of the primary outcome was equivalent. There was no difference between the 2 strategies for the outcomes of either death or total MI. However, more patients reported excellent/good well-being (82.3% vs 78.0%, P = .02) at 24 months with a trend toward less incidence of angina pectoris (12.0% vs 14.3%, adjusted P = .07), nonfatal stroke (1.4% vs 2.0%; P = .06), and total stroke (2.0% vs 2.5%, P = .18) in the verapamil-SR-based strategy group. CONCLUSIONS In hypertensive patients with prior MI, a verapamil-SR-based strategy was equivalent to a beta-blocker-based strategy for blood pressure control and prevention of cardiovascular events, with greater subjective feeling of well-being and a trend toward lower incidence of angina pectoris and stroke in the verapamil-SR-based group.

Risk factor assessment for new onset diabetes: Literature review

Metabolic syndrome (MS), typified by hypertension, abdominal obesity, dyslipidaemia and impaired glucose metabolism, is a precursor of type 2 diabetes. Thiazide diuretics (TD) and beta‐blockers are associated with increased risk of diabetes in patients with hypertension; however, the role of these agents in development of diabetes in MS patients is unknown. We reviewed the literature regarding risk factors for diabetes development and compared this with data from the Study of Trandolapril/Verapamil SR And Insulin Resistance (STAR), which investigated the effects of two fixed‐dose combinations (FDCs) [trandolapril/verapamil SR and losartan/hydrochlorothiazide (L/H)] on glucose control and new diabetes in MS patients. In STAR, logistic regression modelling identified haemoglobin A1c [odds ratio (OR) 4.21 per 1% increment; p = 0.003), L/H treatment (OR 4.04; p = 0.002) and 2‐h oral glucose tolerance test glucose levels (OR 1.39 per 10 mg/dl increments; p < 0.001) as baseline predictors of diabetes. These data support prior analyses and suggest that choice of antihypertensive agent is important. Patients with MS may be at lower risk of diabetes when using a FDC calcium channel blocker + angiotensin‐converting enzyme inhibitor compared with an angiotensin receptor blocker + TD.

Coronary Revascularization Strategy and Outcomes According to Blood Pressure (from the International Verapamil SR-Trandolapril Study [INVEST])

The optimal blood pressure (BP) to prevent major adverse outcomes (death, myocardial infarction, and stroke) for patients with hypertension and coronary artery disease who have undergone previous revascularization is unknown but might be influenced by the type of revascularization procedure. We analyzed data from the INternational VErapamil SR-Trandolapril STudy, focusing on the relation between BP and the outcomes of 6,166 previously revascularized patients, using the 16,410 nonrevascularized patients as a reference group. The previous revascularization strategy consisted of coronary artery bypass grafting (CABG, 45.2%), percutaneous coronary intervention (PCI, 42.1%), or both (CABG+PCI, 12.8%). Patients who had undergone both CABG+PCI and CABG-only had a greater adverse outcome risk (adjusted hazard ratio 1.27% and 1.20%, 95% confidence interval 1.06 to 1.53 and 1.07 to 1.35, respectively). The risk was similar for PCI-only patients (adjusted hazard ratio 1.04, 95% confidence interval 0.92 to 1.19). The relations between the adjusted hazard ratio and on-treatment BP appeared J-shaped for each revascularization strategy, accentuated for PCI and diastolic BP (DBP), but excepting CABG only and DBP for which the relation was linear and positive. In conclusion, major adverse outcomes were more frequent in patients with coronary artery disease who had undergone previous CABG, with or without PCI, compared to those with previous PCI only. This likely reflected more severe vascular disease. The relation to systolic BP was J-shaped for each strategy. Among those patients with previous CABG only, the linear relation with DBP suggested that more complete revascularization might attenuate hypoperfusion at a low DBP. The management of BP might, therefore, require modification of targets according to the revascularization strategy to improve outcomes.

INVEST revisited: review of findings from the International Verapamil SR–Trandolapril Study

The International Verapamil SR–Trandolapril Study (INVEST), a randomized trial of 22,576 predominantly elderly patients with an average 2.7-year follow-up, compared a calcium antagonist-led strategy (verapamil SR plus trandolapril) with a β-blocker-led strategy (atenolol plus hydrochlorothiazide) for hypertension treatment and prevention of cardiovascular outcomes in coronary artery disease patients. Patients received individualized dose and drug titration following a flexible, multi-drug, guideline-based treatment algorithm, with the objective of achieving optimal blood pressure (BP) control individualized for comorbidities (e.g., diabetes). The primary outcome (PO) was first occurrence of death (all-cause), nonfatal myocardial infarction or nonfatal stroke. The strategies resulted in significant and very similar BP reduction, with approximately 70% of patients in both strategies achieving BP control (<140/90 mmHg). Increasing number of office visits with BP in control was associated with reduced risk of the PO. Overall, there was no difference in the PO comparing the strategies; however, new-onset diabetes occurred more frequently in those assigned the atenolol strategy. This report summarizes findings from INVEST and puts them in perspective with our current state of knowledge derived from other large hypertension treatment trials. INVEST findings support that BP reduction is important for prevention of adverse cardiovascular morbidity and mortality, and selection of antihypertensive agents should be based on patient comorbidities and other risk factors (e.g., risk for diabetes) and not necessarily that any one drug be given to all.

Predicting Stroke Risk in Hypertensive Patients With Coronary Artery Disease A Report From the INVEST

Background and Purpose— Our understanding of factors influencing stroke risk among patients with coronary artery disease is incomplete. Accordingly, factors predicting stroke risk in hypertensive, clinically stable coronary artery disease patients were determined with data from the INternational VErapamil SR-trandolapril STudy (INVEST). Methods— The effect of baseline characteristics and on-treatment blood pressure (BP) were analyzed to determine the risk of stroke (fatal or nonfatal) among the 22 576 patients enrolled. Cox proportional-hazards models (unadjusted, adjusted, and time dependent) were used to identify predictors of stroke among subgroups with these characteristics present at entry and on-treatment BP. Results— Excellent BP control (at 24 months, >70% <140/90 mm Hg) was achieved during 61 835 patient-years of follow-up, as 377 patients had a stroke (6.1 strokes/1000 patient-years) and 28% of those patients had a fatal stroke. Increased age, black race, US residency, and history of prior myocardial infarction, smoking, stroke/transient ischemic attack, arrhythmia, diabetes, and coronary bypass surgery were associated with an increased risk of stroke. Achieving a systolic BP <140 mm Hg and a diastolic BP <90 mm Hg was associated with a decreased risk of stroke. There was no statistically significant difference in stroke risk comparing the verapamil SR–based with the atenolol-based treatment strategy (adjusted hazard ratio=0.87; 95% CI, 0.71 to 1.06; P=0.17). Conclusions— Among hypertensive patients with chronic coronary artery disease, stroke was an important complication associated with significant mortality. Black race, US residency, and conditions associated with increased vascular disease severity and arrhythmia predicted increased stroke risk, whereas achieving a BP <140/90 mm Hg on treatment predicted a reduced stroke risk.