Faculty Bibliography

CONTEXT: Hypertension guidelines advocate treating systolic blood pressure (BP) to less than 130 mm Hg for patients with diabetes mellitus; however, data are lacking for the growing population who also have coronary artery disease (CAD). OBJECTIVE: To determine the association of systolic BP control achieved and adverse cardiovascular outcomes in a cohort of patients with diabetes and CAD. DESIGN, SETTING, AND PATIENTS: Observational subgroup analysis of 6400 of the 22,576 participants in the International Verapamil SR-Trandolapril Study (INVEST). For this analysis, participants were at least 50 years old and had diabetes and CAD. Participants were recruited between September 1997 and December 2000 from 862 sites in 14 countries and were followed up through March 2003 with an extended follow-up through August 2008 through the National Death Index for US participants. INTERVENTION: Patients received first-line treatment of either a calcium antagonist or beta-blocker followed by angiotensin-converting enzyme inhibitor, a diuretic, or both to achieve systolic BP of less than 130 and diastolic BP of less than 85 mm Hg. Patients were categorized as having tight control if they could maintain their systolic BP at less than 130 mm Hg; usual control if it ranged from 130 mm Hg to less than 140 mm Hg; and uncontrolled if it was 140 mm Hg or higher. MAIN OUTCOME MEASURES: Adverse cardiovascular outcomes, including the primary outcomes which was the first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: During 16,893 patient-years of follow-up, 286 patients (12.7%) who maintained tight control, 249 (12.6%) who had usual control, and 431 (19.8%) who had uncontrolled systolic BP experienced a primary outcome event. Patients in the usual-control group had a cardiovascular event rate of 12.6% vs a 19.8% event rate for those in the uncontrolled group (adjusted hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.25-1.71; P < .001). However, little difference existed between those with usual control and those with tight control. Their respective event rates were 12.6% vs 12.7% (adjusted HR, 1.11; 95% CI, 0.93-1.32; P = .24). The all-cause mortality rate was 11.0% in the tight-control group vs 10.2% in the usual-control group (adjusted HR, 1.20; 95% CI, 0.99-1.45; P = .06); however, when extended follow-up was included, risk of all-cause mortality was 22.8% in the tight control vs 21.8% in the usual control group (adjusted HR, 1.15; 95% CI, 1.01-1.32; P = .04). CONCLUSION: Tight control of systolic BP among patients with diabetes and CAD was not associated with improved cardiovascular outcomes compared with usual control. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00133692

PURPOSE: The exact role of psychosocial status in quality of life (QOL) of patients with heart failure (HF) is not fully clarified. This report investigates the association of depression and social support in 2 subdomains of QOL, overall satisfaction with QOL (S-QOL) and limitations in physical functioning (PF-QOL) in a diverse group of HF patients. METHODS: Baseline data were used from a behavioral clinical trial, with complete information on 695 HF patients, of whom 33% were black and 24% had diastolic dysfunction. Data were collected via structured questionnaires, medical record review, and a 6-minute walk test. QOL outcomes included the Quality of Life Index (QLI) as a measure of S-QOL and the 36-item Short-Form Health Survey Physical Functioning (SF-36 PF) scale as a measure of PF-QOL. RESULTS: After adjustment for sociodemographic variables, clinical and functional characteristics of disease status accounted for 19% of the variance in the QLI. Depressive symptoms and social support were significantly associated with QLI scores (P < .001) and accounted for an additional 26% of the variance. Clinical and functional characteristics accounted for 33% of the variance in SF-36 PF scores, whereas depressive symptoms and social support accounted for an additional 1% of the variance. CONCLUSION: Depression and social support play a substantially greater role in S-QOL than in perceived limitations in basic physical functions. Targeting depression and low social support may be more important to improve overall QOL, whereas medical management of HF symptoms and functional capacity may have a greater impact on reducing basic physical limitations

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 beta-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

BACKGROUND: Limited information exists regarding the association between subjective well-being (SWB) and systolic blood pressure (SBP) among hypertensive patients with coronary artery disease (CAD). HYPOTHESIS: We tested the hypothesis that there is an association between SBP and SWB. METHODS: We studied 22,576 hypertensive CAD patients >/= 50 years old in the INternational VErapamil SR-Trandolapril Study (INVEST), a randomized, blinded-endpoint trial of antihypertensive therapy in stable CAD patients. At each study visit, patients rated their SWB in the previous 4 weeks as 'excellent,' 'good,' 'fair,' or 'poor' prior to SBP recordings. The outcome measure was SWB of 'fair' or 'poor.' A longitudinal analysis using generalized estimating equations was performed to assess the association between SBP and odds of reporting fair/poor SWB, controlling for baseline SWB of fair/poor and angina reported during the study. RESULTS: Patients with higher SBP had higher odds of reporting fair/poor SWB. Specifically, compared with patients with SBP of </= 120, patients with SBP 140-150 > 150 - </= 160 and > 160 had about 90% and 2.5 times greater odds of feeling fair/poor, respectively (adjusted odds ratio [OR]: 1.5990, 95% confidence interval [CI]: 1.81-2.00 and adjusted OR: 2.53, 95% CI: 2.41-2.66). Those who reported angina in the 4 wks prior to a protocol visit had 2.2 times greater odds of reporting fair/poor SWB (adjusted OR: 2.2, 95% CI: 2.13-2.27). Female gender, black race, history of smoking, diabetes, myocardial infarction, stroke, and cancer also increased the odds of reporting fair/poor SWB. CONCLUSIONS: Among hypertensive CAD patients, higher on-treatment SBP is associated with greater odds of fair/poor SWB during follow-up.

Our understanding of the growing population of revascularized patients with hypertension is limited. We retrospectively analyzed the International Verapamil SR-Trandolapril Study, which randomized coronary artery disease patients with hypertension to either verapamil SR- or atenolol-based treatment strategies, focusing on characteristics and outcomes of 6166 previously revascularized patients compared with 16 410 nonrevascularized patients. Revascularized patients had a history of coronary artery bypass grafting (45.2%), percutaneous coronary intervention (42.1%), or both (12.8%). Compared with nonrevascularized patients, revascularized patients at baseline demonstrated a higher prevalence of coronary artery disease risk factors and risk conditions (P<0.001). This higher prevalence was the principal cause of a higher incidence of primary outcome (death, nonfatal myocardial infarction, or nonfatal stroke) among revascularized patients (14.2% versus 8.5% for nonrevascularized patients; P<0.001). However, both patient groups demonstrated a relatively low incidence of subsequent revascularization (5.1% versus 1.5% respectively; P<0.0001). Associations between adjusted hazard ratio for primary outcome and follow-up blood pressure appeared 'J shaped' for both patient groups. Because, as a group, revascularized patients with hypertension had worse outcomes compared with nonrevascularized patients, management of blood pressure to a specific target in future studies could result in improved outcomes

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

BACKGROUND: The alpha-adducin (ADD1) Gly460Trp polymorphism has been associated with hypertension and response to diuretic therapy, but controversy exists. METHODS: The present study was conducted to prospectively investigate the relationship among the ADD1 Gly460Trp polymorphism, diuretic use, and adverse cardiovascular outcomes among 5,979 patients with hypertensive coronary artery disease, who participated in the INVEST and provided genomic DNA. The primary outcome was defined as the first occurrence of nonfatal stroke, nonfatal myocardial infarction, or all-cause death. Secondary outcomes were the components of the primary outcome. Ancestry informative markers were used to control for population stratification. RESULTS: In blacks, ADD1 variant carriers were at higher risk for a primary outcome event than wild-type homozygotes (adjusted hazard ratio 2.62, 95% CI 1.23-5.58, P = .012), with a similar trend in whites and Hispanics, albeit a smaller magnitude of effect (adjusted hazard ratio 1.43, 0.86-2.39 in Hispanics; 1.24, 0.90-1.71 in whites). Secondary outcome analysis showed that the all-cause death was driving the differences in primary outcomes by genotype. There was no interaction between the ADD1 polymorphism and diuretic use for either primary outcome or secondary outcomes. CONCLUSIONS: In hypertensive patients with coronary artery disease, black ADD1 variant carriers showed a 2.6-fold excess risk for a primary outcome event and an 8-fold increase risk of death. White and Hispanic ADD1 variant carriers showed an increased but nonsignificant excess risk. However, the effect of diuretic use on risk of cardiovascular outcomes did not vary by ADD1 carrier status

In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial, carvedilol added to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers had neutral or beneficial effects on glycemic measures compared with metoprolol tartrate. For the 1235 diabetic hypertensive GEMINI patients, the authors assessed treatment differences by race (white/black/other), age (continuous variable), and sex on hemoglobin A(1c), insulin resistance (homeostasis model assessment-insulin resistance [HOMA-IR]), and blood pressure. Both treatments significantly reduced blood pressure in all subgroups, but the metabolic effects of carvedilol were more beneficial in subgroups of race and sex. Carvedilol did not affect hemoglobin A(1c) but improved HOMA-IR results in all subgroups, significantly in males and 'other race' subgroups. Metoprolol significantly increased hemoglobin A(1c) in all subgroups except 'other race,' with no effect on HOMA-IR findings. Differences vs metoprolol significantly favored carvedilol for hemoglobin A(1c) in white and female subgroups and favored carvedilol for HOMA-IR in black, 'other race,' and male subgroups. Carvedilol effects were favorable to adjustment of age as a covariate. In hypertensive patients with diabetes, carvedilol may be a more appropriate choice when beta-blockade is indicated

Cardiac patients often have sinus arrhythmia of nonrespiratory origin (erratic sinus rhythm [ESR]). ESR was quantified using hourly Poincare and power spectral heart rate variability plots from normal-to-normal interbeat intervals and hourly values of the short-term fractal scaling exponent and correlations of normal-to-normal intervals in n = 60 nonsurvivors and n = 66 randomly selected survivors in the Cardiac Arrhythmia Suppression Trial. Hours were coded (ABN) as normal (0), borderline (0.5), or ESR (1). t Tests compared ABN for n = 2413 paired hours at baseline and on therapy. ABN was higher in nonsurvivors (0.38 +/- 0.44 vs 0.28 +/- 0.40, baseline, and 0.51 +/- 0.45 vs 0.34 +/- 0.43, on therapy, P < .001). Increased ABN with treatment were greater in nonsurvivors. Normal hours at baseline (relative risk = 0.77; 095% confidence interval, 0.62-0.96, P = .018) and on treatment (relative risk = 0.47; 95% confidence interval, 0.39-0.58) were significantly associated with decreased mortality compared with ESR. Quantification of ESR may identify more vulnerable patients or help monitor the effects of pharmacologic treatment

Numerous studies have demonstrated that beta(1)- and beta(2)-adrenergic receptor gene (ADRB1 and ADRB2) variants influence cardiovascular risk and beta-blocker responses in hypertension and heart failure. We evaluated the relationship between ADRB1 and ADRB2 haplotypes, cardiovascular risk (death, nonfatal myocardial infarction (MI), and nonfatal stroke), and atenolol-based vs. verapamil sustained-release (SR)-based antihypertensive therapy in 5,895 coronary artery disease (CAD) patients. After an average of 2.8 years, death rates were higher in patients carrying the ADRB1 Ser49-Arg389 haplotype (hazard ratio (HR) 3.66, 95% confidence interval (95% CI) 1.68-7.99). This mortality risk was significant in patients randomly assigned to verapamil SR (HR 8.58, 95% CI 2.06-35.8) but not atenolol (HR 2.31, 95% CI 0.82-6.55), suggesting a protective role for the beta-blocker. ADRB2 haplotype associations were divergent within the treatment groups but did not remain significant after adjustment for multiple comparisons. ADRB1 haplotype variation is associated with mortality risk, and beta-blockers may be preferred in subgroups of patients defined by ADRB1 or ADRB2 polymorphisms