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Biomedical subjects

Henry Black

Publications and source records attributed to Henry Black.

10 recordsLinked to original sources
PubMed2005

Pharmacogenetic association of the angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure and cardiovascular risk in relation to antihypertensive treatment: the Genetics of Hypertension-Associated Treatment (GenHAT) study.

BACKGROUND: Previous studies have reported that blood pressure response to antihypertensive medications is influenced by genetic variation in the renin-angiotensin-aldosterone system, but no clinical trails have tested whether the ACE insertion/deletion (I/D) polymorphism modifies the association between the type of medication and multiple cardiovascular and renal phenotypes. METHODS AND RESULTS: We used a double-blind, active-controlled randomized trial of antihypertensive treatment that included hypertensives > or =55 years of age with > or =1 risk factor for cardiovascular disease. ACE I/D genotypes were determined in 37 939 participants randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatments and followed up for 4 to 8 years. Primary outcomes included fatal coronary heart disease (CHD) and/or nonfatal myocardial infarction. Secondary outcomes included stroke, all-cause mortality, combined CHD, and combined cardiovascular disease. Fatal and nonfatal CHD occurred in 3096 individuals during follow-up. The hazard rates for fatal and nonfatal CHD and the secondary outcomes were similar across antihypertensive treatments. ACE I/D genotype group was not associated with fatal and nonfatal CHD (relative risk of DD versus ID and II, 0.99; 95% CI, 0.91 to 1.07) or any secondary outcome. The 6-year hazard rate for fatal and nonfatal CHD in the DD genotype group was not statistically different from the ID and II genotype group by type of treatment. No secondary outcome measure was statistically different across antihypertensive treatment and ACE I/D genotype strata. CONCLUSIONS: ACE I/D genotype group was not a predictor of CHD, nor did it modify the response to antihypertensive treatment. We conclude that the ACE I/D polymorphism is not a useful marker to predict antihypertensive treatment response.

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PubMed2004

Association between cardiovascular outcomes and antihypertensive drug treatment in older women.

CONTEXT: Diuretic-based therapy is at least as effective as newer classes of agents for hypertension. However, many patients with hypertension require treatment with more than 1 drug class to achieve blood pressure control. The relative benefits or risks of 2-drug-class combinations are not well known. OBJECTIVE: To prospectively evaluate if there are differences in cardiovascular mortality among postmenopausal women with hypertension but no history of cardiovascular disease (CVD) treated with different classes of antihypertensive agents, singly or in combination. DESIGN, SETTING, AND PARTICIPANTS: Women with hypertension enrolled in the Women's Health Initiative Observational Study, a longitudinal multicenter cohort study of 93 676 women aged 50 to 79 years at baseline (1994-1998), assessed for a mean of 5.9 years. MAIN OUTCOME MEASURES: Relationship between baseline use of ACE inhibitors, beta-blockers, calcium channel blockers, or diuretics, or a combination of these, and incidence of coronary heart disease, stroke, and CVD mortality. RESULTS: Among 30,219 women with hypertension but no history of CVD, 19,889 were receiving pharmacological antihypertensive treatment, of whom 11,294 (57%) [corrected] were receiving monotherapy with an ACE inhibitor, beta-blocker, calcium channel blocker, or diuretic, and 4493 (23%) were treated at baseline with a combination of diuretic plus either ACE inhibitor, beta-blocker, or calcium channel blocker or ACE inhibitor plus calcium channel blocker. Monotherapy with calcium channel blockers vs diuretics was associated with greater risk of CVD death (hazard ratio, 1.55; 95% confidence interval, 1.02-2.35), controlling for multiple covariates. Women treated with a diuretic plus a calcium channel blocker had an 85% greater risk of CVD death vs those treated with a diuretic plus a beta-blocker, after adjustment for age, race, smoking, high cholesterol levels requiring medication, body mass index, physical activity, use of hormone therapy, and diabetes. After exclusion of women with diabetes the hazard ratio was 2.16 (95% confidence interval, 1.16-4.03). Analyses adjusting for propensity to be receiving a particular treatment did not change the results. For morbid events of coronary heart disease or stroke, diuretics plus ACE inhibitors or calcium channel blockers did not differ from diuretics plus beta-blockers. CONCLUSIONS: Among women with hypertension but no history of CVD, a 2-drug-class regimen of calcium channel blockers plus diuretics was associated with a higher risk of CVD mortality vs beta-blockers plus diuretics. Risks were similar for ACE inhibitors plus diuretics and beta-blockers plus diuretics. Monotherapy with diuretics was equal or superior to other monotherapy in preventing CVD complications of high blood pressure.

Adrenergic beta-Antagonists↗
PubMed2004

Imputing gene-treatment interactions when the genotype distribution is unknown using case-only and putative placebo analyses--a new method for the Genetics of Hypertension Associated Treatment (GenHAT) study.

There is a sizeable literature on methods for detecting gene-environment interaction in the framework of case-control studies, particularly with reference to the assumption of independence of genotype and exposure. In the context of a clinical trial, wherein gene-drug interactions with regard to outcomes are examined, these methods may be readily applied, as gene and drug are independent by randomization. In an active-controlled trial (experimental treatment vs standard) that has collected genotype information, gene-drug interactions can be estimated. In addition, the effect of the experimental treatment vs placebo can be imputed by using data from a historical placebo-controlled trial (standard vs placebo) if either (a) genotype information is available from the historical trial or (b) assumptions are made about the prevalence of genotype and the odds ratios of genotype and disease in the historical trial using information from other studies. Motivation for these procedures is provided by the Genetics of Hypertension Associated Treatment, a large pharmacogenetics, ancillary study of a hypertension clinical trial, and examples from published hypertension trials will be used to illustrate the methods.

Controlled Clinical Trials as Topic↗
PubMed2004

Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.

CONTEXT: Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain. OBJECTIVE: To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women's Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10 739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity. INTERVENTION: Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo. MAIN OUTCOME MEASURES: The primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects. RESULTS: In February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index, 1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years. CONCLUSIONS: The use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women.

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PubMed2004

Cardiovascular outcomes using doxazosin vs. chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT study.

Insulin resistance underlies most glucose disorders in adults and is associated with an increased risk of cardiovascular disease. Alpha blockers decrease insulin resistance, whereas diuretics increase insulin resistance. The authors studied the effects of these two classes of hypertension medications (doxazosin, an a blocker, and chlorthalidone, a diuretic) on cardiovascular disease outcomes in adults aged >55 years with hypertension and glucose disorders who were participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (8749 had known diabetes mellitus and 1690 had a newly diagnosed glucose disorder [fasting glucose >/=110 mg/dL]). There was no difference in either group between the chlorthalidone- and doxazosin-based treatments with regard to fatal or nonfatal myocardial infarction or all-cause mortality. There was, however, a difference for combined cardiovascular disease (myocardial infarction, revascularization procedures, angina, stroke, heart failure, and peripheral arterial disease) in favor of the diuretic. This difference was due primarily to an increased heart failure risk in those treated with doxazosin (relative risk, 1.85; 95% confidence interval, 1.56-2.19) in the known diabetes mellitus group and a relative risk of 1.63 (95% confidence interval, 1.05-2.55) in those with a newly diagnosed glucose disorder despite lower glucose levels on follow-up in those treated with a blockers. The authors conclude that treatment of hypertension with doxazosin in adults with glucose disorders incurs the same risk of coronary heart disease as treatment with chlorthalidone; however, treatment with doxazosin increases the risk of combined cardiovascular disease and heart failure despite lower glucose levels.

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PubMed2003

Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial.

CONTEXT: The Women's Health Initiative (WHI) trial of estrogen plus progestin was stopped early because of adverse effects, including an increased risk of stroke in the estrogen plus progestin group. OBJECTIVE: To assess the effect of estrogen plus progestin on ischemic and hemorrhagic stroke and in subgroups, and to determine whether the effect of estrogen plus progestin was modified by baseline levels of blood biomarkers. DESIGN: Multicenter double-blind, placebo-controlled, randomized clinical trial involving 16 608 women aged 50 through 79 years with an average follow-up of 5.6 years. Baseline levels of blood-based markers of inflammation, thrombosis, and lipid levels were measured in the first 140 centrally confirmed stroke cases and 513 controls. INTERVENTIONS: Participants received 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102). MAIN OUTCOME MEASURES: Overall strokes and stroke subtype and severity were centrally adjudicated by stroke neurologists. RESULTS: One hundred fifty-one patients (1.8%) in the estrogen plus progestin and 107 (1.3%) in the placebo groups had strokes. Overall 79.8% of strokes were ischemic. For combined ischemic and hemorrhagic strokes, the intention-to-treat hazard ratio (HR) for estrogen plus progestin vs placebo was 1.31 (95% confidence interval [CI], 1.02-1.68); with adjustment for adherence, the HR was 1.50 (95% CI, 1.08-2.08). The HR for ischemic stroke was 1.44 (95% CI, 1.09-1.90) and for hemorrhagic stroke, 0.82 (95% CI, 0.43-1.56). Point estimates of the HRs indicate that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin. Other risk factors for stroke, including smoking, blood pressure, diabetes, lower use of vitamin C supplements, blood-based biomarkers of inflammation, higher white blood cell count, and higher hematocrit levels did not modify the effect of estrogen plus progestin on stroke risk. CONCLUSIONS: Estrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin appeared to be present in all subgroups of women examined.

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PubMed2002

Amlodipine versus chlorthalidone versus placebo in the treatment of stage I isolated systolic hypertension.

The study was to compare the effects of amlodipine (calcium channel antagonist), chlorthalidone (diuretic), and placebo in adults more than 50 years of age with stage 1 isolated systolic hypertension (ISH). After a 4-week placebo run-in phase, 150 patients were randomly assigned in a double-blind fashion to treatment with 5 mg of amlodipine (n = 48), 15 mg of chlorthalidone (n = 50), or placebo (n = 52). Patients who failed to meet the systolic blood pressure (BP) reduction goal by week 4 had their dose increased to 10 mg of amlodipine or 30 mg of chlorthalidone, and maintained at this increased dose for 12 weeks. Results showed a mean reduction (mean +/- SD) in sitting systolic BP from baseline to the last treatment visit of -14.6+/-12.2 mm Hg (95% confidence interval [CI] -18.2, -11.0), -14.0+/-13.46 mm Hg (95% CI -17.8, -10.2), and -3.4+/-11.83 mm Hg (95% CI -6.7, -0.1) for the amlodipine, chlorthalidone, and the placebo treatment groups, respectively. Both active treatments showed significantly greater reductions than the placebo group (P < or = .001), but were not significantly different from each other. Sixty-seven percent of the amlodipine, 69% of the chlorthalidone, and 25% of the placebo-treated patients reached the protocol defined systolic BP goal (P = .001). Both active treatment groups showed a trend of better systolic BP response in older patients (> or =65 years). Secondary efficacy measures including pulse pressure, standing systolic, diastolic, and the 24-h ambulatory BP were also statistically significantly improved for both active treatments at the end of treatment, except for chlorthalidone in standing diastolic BP. Adverse events that occurred during the study were as expected and were well tolerated. The results of this study support the efficacy and safety of amlodipine and chlorthalidone for the treatment of stage 1 ISH during 20 weeks of treatment.

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