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Outcomes Among hypertensive patients with concomitant peripheral and coronary artery disease: findings from the INternational VErapamil-SR/Trandolapril STudy

Bavry, Anthony A; Anderson, R David; Gong, Yan; Denardo, Scott J; Cooper-Dehoff, Rhonda M; Handberg, Eileen M; Pepine, Carl J
Hypertension is a common risk factor for peripheral arterial disease (PAD). Guidelines suggest treating PAD patients to a blood pressure <130/80 mm Hg; therefore, our objective was to explore whether attainment of this target blood pressure is associated with improved outcomes. We performed a post hoc analysis of the INternational VErapamil-SR/Trandolapril STudy, a randomized clinical trial, which included hypertensive patients with concomitant PAD and coronary artery disease. There were 2699 PAD patients followed for a mean of 2.7 years (60 970 patient-years). The primary outcome, all-cause death, nonfatal myocardial infarction, or nonfatal stroke, occurred in 16.3% of PAD patients versus 9.2% without PAD (adjusted hazard ratio: 1.26 [95% CI: 1.13 to 1.40]; P<0.0001). The primary outcome occurred least frequently among PAD patients treated to an average systolic blood pressure of 135 to 145 mm Hg and an average diastolic blood pressure of 60 to 90 mm Hg. PAD patients displayed a J-shape relationship with systolic blood pressure and the primary outcome, although individuals without PAD did not. PAD patients may require a different target blood pressure than those without PAD
PMID: 19996066
ISSN: 0194-911x
CID: 106520

Systolic Blood Pressure and Subjective Well-Being in Patients with Coronary Artery Disease

Gong, Yan; Handberg, Eileen M; Gerhard, Tobias; Cooper-Dehoff, Rhonda M; Ried, L Douglas; Johnson, Julie A; Pepine, Carl J
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.
PMID: 19711440
ISSN: 0160-9289
CID: 101907

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

Cooper-DeHoff, Rhonda M; Handberg, Eileen M; Mancia, Giuseppe; Zhou, Qian; Champion, Annette; Legler, Udo F; Pepine, Carl J
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
PMID: 19900016
ISSN: 1477-9072
CID: 106518

Quality of Life in a Diverse Population of Patients With Heart Failure: BASELINE FINDINGS FROM THE HEART FAILURE ADHERENCE AND RETENTION TRIAL (HART)

de Leon, Carlos F Mendes; Grady, Kathleen L; Eaton, Claudia; Rucker-Whitaker, Cheryl; Janssen, Imke; Calvin, James; Powell, Lynda H
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
PMID: 19471136
ISSN: 1932-7501
CID: 99151

Characteristics and outcomes of revascularized patients with hypertension: an international verapamil SR-trandolapril substudy

Denardo, Scott J; Messerli, Franz H; Gaxiola, Efrain; Aranda, Juan M Jr; Cooper-Dehoff, Rhonda M; Handberg, Eileen M; Gong, Yan; Champion, Annette; Zhou, Qian; Pepine, Carl J
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
PMID: 19237684
ISSN: 1524-4563
CID: 100038

beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension

Pacanowski, M A; Gong, Y; Cooper-Dehoff, R M; Schork, N J; Shriver, M D; Langaee, T Y; Pepine, C J; Johnson, J A
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
PMID: 18615004
ISSN: 1532-6535
CID: 97809

The Heart Failure Adherence and Retention Trial (HART): design and rationale

Powell, Lynda H; Calvin, James E Jr; Mendes de Leon, Carlos F; Richardson, Dejuran; Grady, Kathleen L; Flynn, Kristin J; Rucker-Whitaker, Cheryl S; Janssen, Imke; Kravitz, Glenda; Eaton, Claudia
BACKGROUND: Heart failure (HF) is increasing in prevalence and is associated with prolonged morbidity, repeat hospitalizations, and high costs. Drug therapies and lifestyle changes can reduce hospitalizations, but nonadherence is high, ranging from 30% to 80%. There is an urgent need to identify cost-effective ways to improve adherence and reduce hospitalizations. TRIAL DESIGN: The Heart Failure Adherence and Retention Trial (HART) evaluated the benefit of patient self-management (SM) skills training in combination with HF education, over HF education alone, on the composite end points of death/HF hospitalizations and death/all-cause hospitalizations in patients with mild to moderate systolic or diastolic dysfunction. Secondary end points included progression of HF, quality of life, adherence to drug and lifestyle regimens, and psychosocial function. The HART cohort was composed of 902 patients including 47% women, 40% minorities, and 23% with diastolic dysfunction. After a baseline examination, patients were randomized to SM or education control, received 18 treatment contacts over 1 year, annual follow-ups, and 3-month phone calls to assess primary end points. Self-management treatment was conducted in small groups and aimed to activate the patient to implement HF education through training in problem-solving and 5 SM skills. The education control received HF education in the mail followed by a phone call to check comprehension. CONCLUSIONS: The significance of HART lies in its ability to determine the clinical value of activating the patient to collaborate in his or her care. Support for the trial hypotheses would encourage interdisciplinary HF treatment, drawing on an evidence base not only from medicine but also from behavioral medicine
PMID: 18760125
ISSN: 1097-6744
CID: 99184

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

Bangalore, Sripal; Messerli, Franz H; Cohen, Jerome D; Bacher, Peter H; Sleight, Peter; Mancia, Giuseppe; Kowey, Peter; Zhou, Qian; Champion, Annette; Pepine, Carl J
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
PMID: 18657652
ISSN: 1097-6744
CID: 97808

Alpha-adducin polymorphism associated with increased risk of adverse cardiovascular outcomes: results from GENEtic Substudy of the INternational VErapamil SR-trandolapril STudy (INVEST-GENES)

Gerhard, Tobias; Gong, Yan; Beitelshees, Amber L; Mao, Xianyun; Lobmeyer, Maximilian T; Cooper-DeHoff, Rhonda M; Langaee, Taimour Y; Schork, Nicholas J; Shriver, Mark D; Pepine, Carl J; Johnson, Julie A
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
PMID: 18657677
ISSN: 1097-6744
CID: 97939

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

Kolloch, Rainer; Legler, Udo F; Champion, Annette; Cooper-Dehoff, Rhonda M; Handberg, Eileen; Zhou, Qian; Pepine, Carl J
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
PMID: 18375982
ISSN: 1522-9645
CID: 99297