Risk Factors Influencing Outcomes of Atrial Fibrillation in ALLHAT.

BACKGROUND AND AIMS: ALLHAT, a randomized, double-blind, active-controlled, multicenter clinical trial of high risk hypertensive participants, compared treatment with an ACE-inhibitor (lisinopril) or calcium channel blocker (amlodipine) with a diuretic (chlorthalidone). Primary outcome was the occurrence of fatal coronary heart disease or nonfatal myocardial infarction. For this report, post-hoc analyses were conducted to determine the contribution of baseline characteristics of participants with or without baseline or incident atrial fibrillation (AF) and atrial flutter (AFL) to stroke, heart failure (HF), coronary heart disease (CHD), and mortality outcomes. METHODS AND RESULTS: Minnesota Coding of baseline and biennial in-trial ECGs was used to determine the 334 baseline and 537 incident AF/AFL cases, respectively participants with AF/AFL: Cox regression was used to estimate hazard ratios of presence versus absence of either baseline or incident AF/AFL (as time-dependent covariate) for occurrence of stroke, CHD, HF, or mortality, while adjusting for selected baseline characteristics. Adjusted Cox regression was used to obtain hazard ratios (HRs) for presence versus absence of selected baseline characteristics among those with and without either baseline or incident AF/AFL. After adjusting for baseline characteristics, baseline AF/AFL was associated with stroke, HF, and mortality (HRs [95% CIs] 3.18, [2.34-4.33]; 2.65 [2.02-3.49]; and 2.10 [CI, 1.73-2.55], respectively, P < 0.05). Incident AF/AFL was a significant risk factor for HF and mortality (HRs 2.80 and 2.06, respectively, P < 0.05). Risk factor profiles for clinical outcomes for those with and without baseline or incident AF/AFL were largely similar. CONCLUSIONS: AF/AFL is a significant risk factor for stroke, HF, and mortality. Additional risk factors for these outcomes were generally similar for participants with and without baseline or incident AF/AFL.

Association between chronic kidney disease and cancer mortality: A report from the ALLHAT.

BACKGROUND/OBJECTIVES: Chronic kidney disease (CKD) and cancer are both common in older patients; whether CKD increases risk for cancer is unclear. This study evaluated CKD as a risk factor for cancer mortality in a large cohort of hypertensive patients. STUDY DESIGN: We did post-hoc analyses of in-trial and post-trial data from participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). SETTING AND PARTICIPANTS: Participants were ≥ 55 years old with hypertension and one other additional risk factor for coronary heart disease. PREDICTOR: Baseline estimated glomerular filtration rate (eGFR). OUTCOMES: Cancer mortality was ascertained by cancer-related deaths reported in national databases during and after the trial. Cox proportional hazard models were used to calculate hazard ratios (HRs) adjusted for possible confounders and were stratified by baseline GFR. RESULTS: Participants' mean age was 66.9 years. After a mean follow-up of 8.9 years, there were 2,338 reported cancer-related deaths. Participants with GFR < 45 mL/min/1.73 m2 were at increased risk of cancer mortality compared to those with GFR ≥ 90 mL/min/1.73 m2 (adjusted HR 1.54 (1.22 - 1.94), p-value for trend 0.004). These findings were consistent across subgroups defined by race, gender, and diabetes. Participants with GFR < 45 mL/min/1.73 m2 were at higher risk for mortality related to colon cancer (p-value for trend 0.048, HR 2.28 (1.12 - 4.62)) and urinary tract cancer (p-value for trend 0.001, adjusted HR 2.95 (1.14 - 7.65)). LIMITATIONS: This is a post hoc analysis of clinical trial data. CONCLUSIONS: In a large cohort of hypertensive patients, GFR < 45 mL/min/1.73 m2 was associated with a higher risk of cancer-related mortality.

Influence of Prevalent and Incident Atrial Fibrillation on Post-Trial Major Events in ALLHAT.

AIMS: Limited information is available on long-term antihypertensive and lipid-lowering therapy effects on hypertensive patients with atrial fibrillation/flutter (AF/AFL) compared to those without. AF/AFL at baseline or during the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (mean follow-up 4.9 years) markedly increased risk of stroke, heart failure, CHD, and all-cause mortality. We aimed to determine if AF/AFL continued to impact outcomes during post-trial follow-up (mean 3.8 years). METHODS: Patients were randomized to chlorthalidone, amlodipine, or lisinopril, and to pravastatin vs. usual care in the lipid-lowering trial (LLT). Of 31,473 available subjects, AF/AFL occurred in 854; 383/14,371 chlorthalidone (2.7%), 247/8565 amlodipine (2.9%), and 224/8537 lisinopril (2.6%). Post-hoc analyses utilized administrative databases for post-trial data. Individuals with AF/AFL were compared to those without during post-trial. Outcomes were analyzed by treatment groups for the antihypertensive and LLT trials. RESULTS: Among 854 AF/AFL participants, 491 (57.5%) died: 220 in-trial, 271 post-trial. Ten-year all-cause mortality rates for those with in-trial AF/AFL were similar for chlorthalidone and lisinopril, but lower for amlodipine (68, 66, and 49 per 100 persons, respectively); adjusted HR for amlodipine vs. chlorthalidone was 0.68 (95% CI, 0.54-0.87). Ten-year all-cause mortality rates were 57 vs. 65 per 100 persons (pravastatin vs. usual care); non-CVD mortality rates, 18 vs. 39 per 100 persons (pravastatin vs. usual care) (adjusted HR = 0.46, 95% CI, 0.24-0.86). CONCLUSION: Post-trial follow-up revealed continued deleterious AF/AFL effects. The amlodipine (ALLHAT) and pravastatin (ALLHAT-LLT) treatment groups showed lower all-cause and non-CVD mortality compared to the chlorthalidone and usual-care groups, respectively.

Clinical and demographic correlates of medication and visit adherence in a large randomized controlled trial.

BACKGROUND: Patient characteristics are associated with adherence, which has implications for planning clinical research or designing payment systems that reward superior outcomes. It is unclear to what extent clinician efforts to improve adherence can attenuate these associations. METHODS: To identify factors predicting visit and medication adherence in settings designed to optimize adherence, we did a retrospective analysis of participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT recruited participants at 632 sites in North America, Puerto Rico, and the U.S. Virgin Islands for random assignment to antihypertensive treatment with amlodipine, chlorthalidone, or lisinopril. Site investigators reported clinic characteristics at the time they applied to participate in the study and research coordinators used standardized methods to measure patient characteristics. We defined adequate visit adherence as attending at least 80 % of scheduled visits; adequate medication adherence was defined as taking 80 % or more of the randomly assigned medication at all study visits. RESULTS: The 31,250 ALLHAT participants eligible for the visit adherence analysis attended 78.5 % of scheduled study visits; 68.9 % attended more than 80 % of scheduled visits. Clinic setting was predictive of both forms of adherence; adherence was worst at private clinics; clinics that enrolled more study participants had superior adherence. Adjusting for clinic characteristics and clinical factors, women, younger participants, Blacks and smokers were less likely to have adequate visit adherence. Among the 28,967 participants eligible for the medication adherence analysis, 21,261 (73.4 %) reported adequate medication adherence. In adjusted analyses, younger and less educated participants, Blacks, and smokers were less likely to report adequate adherence. CONCLUSIONS: Participant demographics were associated with adherence despite strenuous efforts to optimize adherence. Our results could inform decisions by researchers planning trials and policymakers designing payment systems. TRIAL REGISTRATION: NCT00000542 . Registered 27 October 1999.

Pharmacogenetic effects of 'candidate gene complexes' on stroke in the GenHAT study.

OBJECTIVE: The aim of this study was to investigate whether there is a genotype-by-treatment interaction in patients experiencing stroke and treated with one of three antihypertensive drugs, that is chlorthalidone, amlodipine, or lisinopril. PARTICIPANTS AND METHODS: A population of 436 African Americans and 539 whites who had experienced stroke in the GenHAT study were genotyped for 768 single nucleotide polymorphisms (SNPs) in 280 candidate genes. To detect a genotype-by-treatment interaction, we used the Pearson's χ-test to assess whether the genotype frequencies differed at the single SNP level for the three drug treatment groups. From these single SNP analyses, we derived a summary statistic for the degree of association at the gene and gene complex levels. This was done by grouping SNPs using information on gene locations and defining gene complexes on the basis of protein-protein interactions. To assess the statistical significance of the observed test statistic, we derived an empirical P-value by simulating data under the null hypothesis. RESULTS: We found that, in patients who have experienced stroke, there is a significant genetic difference between hypertension drug treatment groups. In African Americans, SNP rs12143842 showed a significant association (P<0.001) with drug treatment. At the gene level, HNRNPA1P4 and NOS1AP in African Americans and PRICKLE1 and NINJ2 in non-Hispanic whites were significantly associated (P<0.01) with drug treatment, whereas none of the gene complexes tested showed significance. CONCLUSION: On the basis of the genetic differences between drug treatment groups, we conclude that there may be an interaction between certain genotypes and antihypertensive treatment in stroke patients. This needs to be replicated in other studies.

How much effect of different antihypertensive medications on cardiovascular outcomes is attributable to their effects on blood pressure?

The debate over whether certain antihypertensive medications have benefits beyond what would be expected from their blood pressure lowering spurred the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, which randomized 42,418 participants to chlorthalidone (15,255), amlodipine (9048), lisinopril (9054), or doxazosin (9061). We compared chlorthalidone, the active control, with each of the other three agents with respect to the primary outcome, fatal coronary heart disease or nonfatal myocardial infarction, and several other clinical endpoints. The arms were similar with respect to the primary endpoint, although some differences were found for other endpoints, most notably heart failure. Although the desire was to achieve similar blood pressure reductions in the four arms, we found some systolic blood pressure and diastolic blood pressure differences. A natural question is to what degree can observed treatment group differences in cardiovascular outcomes be attributed to these blood pressure differences. The purpose of this paper was to delineate the problems inherent in attempting to answer this question, and to present analyses intended to overcome these problems.

Long-term follow-up of participants with heart failure in the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT).

BACKGROUND: In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in high-risk hypertensive participants, risk of new-onset heart failure (HF) was higher in the amlodipine (2.5-10 mg/d) and lisinopril (10-40 mg/d) arms compared with the chlorthalidone (12.5-25 mg/d) arm. Similar to other studies, mortality rates following new-onset HF were very high (≥50% at 5 years), and were similar across randomized treatment arms. After the randomized phase of the trial ended in 2002, outcomes were determined from administrative databases. METHODS AND RESULTS: With the use of national databases, posttrial follow-up mortality through 2006 was obtained on participants who developed new-onset HF during the randomized (in-trial) phase of ALLHAT. Mean follow-up for the entire period was 8.9 years. Of 1761 participants with incident HF in-trial, 1348 died. Post-HF all-cause mortality was similar across treatment groups, with adjusted hazard ratios (95% confidence intervals) of 0.95 (0.81-1.12) and 1.05 (0.89-1.25), respectively, for amlodipine and lisinopril compared with chlorthalidone, and 10-year adjusted rates of 86%, 87%, and 83%, respectively. All-cause mortality rates were also similar among those with reduced ejection fractions (84%) and preserved ejection fractions (81%), with no significant differences by randomized treatment arm. CONCLUSIONS: Once HF develops, risk of death is high and consistent across randomized treatment groups. Measures to prevent the development of HF, especially blood pressure control, must be a priority if mortality associated with the development of HF is to be addressed. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique identifier: NCT00000542.

Gene panels to help identify subgroups at high and low risk of coronary heart disease among those randomized to antihypertensive treatment: the GenHAT study.

OBJECTIVE: To identify panels of genetic variants that predict treatment-related coronary heart disease (CHD) outcomes in hypertensive patients on one of four different classes of initial antihypertensive treatment. The goal was to identify subgroups of individuals on the basis of their genetic profile who benefit most from a particular treatment. METHODS: Candidate genetic variants (n=78) were genotyped in 39 114 participants from Genetics of Hypertension Associated Treatment study, ancillary to Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial. Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial randomized hypertensive participants (≥55 years) to one of four treatments (amlodipine, chlorthalidone, doxazosin, lisinopril). The primary outcome was fatal CHD or nonfatal myocardial infarction (mean follow-up=4.9 years). A pharmacogenetic panel was derived within each of the four treatment groups. Receiver-operating characteristic (ROC) curves estimated the discrimination rate between those with and without a CHD event, on the basis of the addition of the genetic panel risk score. RESULTS: For each treatment group, we identified a panel of genetic variants that collectively improved the prediction of CHD to a small but statistically significant extent. Chlorthalidone (A): NOS3 rs3918226; SELE rs5361; ICAM1 rs1799969; AGT rs5051; GNAS rs7121; ROC comparison, P=0.004; Amlodipine (B): MMP1 rs1799750; Factor5 (F5) rs6025; NPPA rs5065; PDE4D rs6450512; MMP9 rs2274756; ROC comparison, P=0.006; Lisinopril (C): AGT rs5051; PON1 rs705379; MMP12 rs652438; F12 rs1801020; GP1BA rs6065; PDE4D rs27653; ROC comparison, P=0.01; Doxazosin (D): F2 rs1799963; PAI1 rs1799768; MMP7 rs11568818; AGT rs5051; ACE rs4343; MMP2 rs243865; ROC comparison, P=0.007. Each panel was tested for a pharmacogenetic effect; panels A, B, and D showed such evidence (P=0.009, 0.006, and 0.001, respectively) and panel C did not (P=0.09). CONCLUSION: Because each panel was associated with CHD in a specific treatment group but not the others, this research provides evidence that it may be possible to use gene panel scores as a tool to better assess antihypertensive treatment choices to reduce CHD risk in hypertensive individuals.

Pharmacogenetic effect of the stromelysin (MMP3) polymorphism on stroke risk in relation to antihypertensive treatment: the genetics of hypertension associated treatment study.

BACKGROUND AND PURPOSE: Atherothrombotic diseases including stroke share a common etiology of atherosclerosis, and susceptibility to atherosclerosis has a genetic component. Stromelysin-1 (matrix metalloproteinase-3 [MMP3]) regulates arterial matrix composition and is a candidate gene for atherothrombosis. A common polymorphism of MMP3 alters expression levels and affects atherosclerotic progression and plaque stability. As part of the Genetics of Hypertension Associated Treatment study, ancillary to the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial, we evaluated the 5A/6A polymorphism in MMP3 to determine its association with stroke and determine whether it modifies clinical outcome response to blood pressure-lowering drugs. METHODS: The effect of the MMP3 5A/6A polymorphism on stroke rates was examined by using multivariate-adjusted Cox regression models, including a test for interactions between genotype and antihypertensive drug class. RESULTS: Compared with participants treated with chlorthalidone with the 6A/6A genotype, individuals with the 6A/6A genotype randomized to lisinopril had higher stroke rates (hazard ratio=1.32; 95% CI, 1.08 to 1.61; P=0.007) and 5A/6A individuals taking lisinopril had lower stroke rates (hazard ratio(interaction)=0.74; 95% CI, 0.53 to 1.04; P(interaction)=0.08), whereas 5A/5A individuals taking lisinopril had the lowest stroke rate (hazard ratio(interaction)=0.51; 95% CI, 0.31 to 0.85; P(interaction)=0.009). There were no pharmacogenetic differences in stroke rate by genotype in patients taking amlodipine or doxazosin vs chlorthalidone. CONCLUSIONS: The MMP3 6A/6A genotype is associated with an increased risk of stroke in hypertensive subjects taking lisinopril compared with patients treated with chlorthalidone, whereas a protective effect was found for 5A/5A individuals treated with lisinopril. Genetic screening for the MMP3 5A/6A genotype might be a useful tool to select optimal antihypertensive therapy if this finding is replicated. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00563901.

Heart failure with preserved and reduced left ventricular ejection fraction in the antihypertensive and lipid-lowering treatment to prevent heart attack trial.

BACKGROUND: Heart failure (HF) developing in hypertensive patients may occur with preserved or reduced left ventricular ejection fraction (PEF [>or=50%] or REF [<50%]). In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 42 418 high-risk hypertensive patients were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin, providing an opportunity to compare these treatments with regard to occurrence of hospitalized HFPEF or HFREF. METHODS AND RESULTS: HF diagnostic criteria were prespecified in the ALLHAT protocol. EF estimated by contrast ventriculography, echocardiography, or radionuclide study was available in 910 of 1367 patients (66.6%) with hospitalized events meeting ALLHAT criteria. Cox regression models adjusted for baseline characteristics were used to examine treatment differences for HF (overall and by PEF and REF). HF case fatality rates were examined. Of those with EF data, 44.4% had HFPEF and 55.6% had HFREF. Chlorthalidone reduced the risk of HFPEF compared with amlodipine, lisinopril, or doxazosin; the hazard ratios were 0.69 (95% confidence interval [CI], 0.53 to 0.91; P=0.009), 0.74 (95% CI, 0.56 to 0.97; P=0.032), and 0.53 (95% CI, 0.38 to 0.73; P<0.001), respectively. Chlorthalidone reduced the risk of HFREF compared with amlodipine or doxazosin; the hazard ratios were 0.74 (95% CI, 0.59 to 0.94; P=0.013) and 0.61 (95% CI, 0.47 to 0.79; P<0.001), respectively. Chlorthalidone was similar to lisinopril with regard to incidence of HFREF (hazard ratio, 1.07; 95% CI, 0.82 to 1.40; P=0.596). After HF onset, death occurred in 29.2% of participants (chlorthalidone/amlodipine/lisinopril) with new-onset HFPEF versus 41.9% in those with HFREF (P<0.001; median follow-up, 1.74 years); and in the chlorthalidone/doxazosin comparison that was terminated early, 20.0% of HFPEF and 26.0% of HFREF patients died (P=0.185; median follow-up, 1.55 years). CONCLUSIONS: In ALLHAT, with adjudicated outcomes, chlorthalidone significantly reduced the occurrence of new-onset hospitalized HFPEF and HFREF compared with amlodipine and doxazosin. Chlorthalidone also reduced the incidence of new-onset HFPEF compared with lisinopril. Among high-risk hypertensive men and women, HFPEF has a better prognosis than HFREF.

Coronary heart disease in moderately hypercholesterolemic, hypertensive black and non-black patients randomized to pravastatin versus usual care: the antihypertensive and lipid lowering to prevent heart attack trial (ALLHAT-LLT).

BACKGROUND: In previous analyses in ALLHAT, blacks had a significantly lower risk of coronary heart disease (CHD) in the pravastatin group compared to the usual care group, whereas non-blacks had no benefit from pravastatin. No previous statin trial has reported results separately in blacks. OBJECTIVES: The study aimed to determine if apparent racial differences in CHD in ALLHAT are explained by differences in baseline characteristics, adherence during the trial, or achieved blood pressure and lipid lowering. METHODS: This was a prespecified subgroup analysis of a randomized controlled trial. Hypertensive, moderately hypercholesterolemic participants were assigned to open-label pravastatin (40 mg/d) or usual care. The outcome was a composite of nonfatal myocardial infarction and fatal CHD. We performed intention-to-treat survival analyses using Cox proportional hazards models, adjusting for baseline covariates (age, sex, aspirin use, history of CHD and diabetes, and baseline hypertension treatment) and time-varying levels of blood pressure and total cholesterol. RESULTS: After adjustment for baseline characteristics, there remained a significant interaction between race and treatment group (P = .02). In stratified models, blacks in the pravastatin group had a 29% lower risk of CHD (hazard ratio [HR] 0.71, 95% CI 0.57-0.90, P = .005) compared to those in the usual care group, whereas non-blacks had no benefit (HR 1.00, 95% CI 0.85-1.19, P = .95). With further adjustment for achieved blood pressure and total cholesterol, the HR in blacks was 0.65 (95% CI 0.45-0.96, P = .03) and in non-blacks was 1.07 (95% CI 0.81-1.41, P = .65). CONCLUSIONS: Our results suggest that pravastatin is effective in preventing CHD in blacks.

Blood pressure control by drug group in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

Blood pressure (BP) control rates and number of antihypertensive medications were compared (average follow-up, 4.9 years) by randomized groups: chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9048), or lisinopril 10-40 mg/d (n=9054) in a randomized double-blind hypertension trial. Participants were hypertensives aged 55 or older with additional cardiovascular risk factor(s), recruited from 623 centers. Additional agents from other classes were added as needed to achieve BP control. BP was reduced from 145/83 mm Hg (27% control) to 134/76 mm Hg (chlorthalidone, 68% control), 135/75 mm Hg (amlodipine, 66% control), and 136/76 mm Hg (lisinopril, 61% control) by 5 years; the mean number of drugs prescribed was 1.9, 2.0, and 2.1, respectively. Only 28% (chlorthalidone), 24% (amlodipine), and 24% (lisinopril) were controlled on monotherapy. BP control was achieved in the majority of each randomized group-a greater proportion with chlorthalidone. Over time, providers and patients should expect multidrug therapy to achieve BP <140/90 mm Hg in a majority of patients.

Pharmacogenetic association of the NPPA T2238C genetic variant with cardiovascular disease outcomes in patients with hypertension.

CONTEXT: The NPPA gene codes for the precursor of atrial natriuretic polypeptide, suggesting that NPPA may modulate the efficacy of some antihypertensive drugs. OBJECTIVE: To test whether participants with minor NPPA alleles in the T2238C or G664A variants had different rates of cardiovascular disease or blood pressure (BP) changes than common allele homozygotes when treated with a diuretic vs other antihypertensive medications. DESIGN, SETTING, AND PATIENTS: Post hoc analysis of 38,462 participants with hypertension from ALLHAT, a multicenter randomized clinical trial conducted in the United States and Canada. Genotyping was performed from February 2004 to January 2005. INTERVENTION: Participants were randomly assigned to receive a diuretic (chlorthalidone; n = 13,860), a calcium antagonist (amlodipine; n = 8174), an angiotensin-converting enzyme inhibitor (lisinopril; n = 8233), or an alpha-blocker (doxazosin; n = 8195). MAIN OUTCOME MEASURE: The primary outcome measure was coronary heart disease (CHD), defined as fatal CHD or nonfatal myocardial infarction (mean follow-up, 4.9 years). Secondary outcomes were stroke, all-cause mortality, combined cardiovascular disease outcomes, and 6-month systolic and diastolic BP changes. Genotype x treatment interactions were tested where genotypes were modeled additively and dominantly. RESULTS: Depending on genotype, the event rates per 1000 person-years were 15.3 to 19.7 for CHO, 9.6 to 15.4 for stroke, and 27.4 to 30.7 for all-cause mortality. For the NPPA T2238C variant, lower event rates were found for the C allele carriers than for the TT homozygous individuals when comparing chlorthalidone and amlodipine (CHD: CC = 0.86; TC = 0.90; TT = 1.09; P = .03 [dominant model]; stroke: CC = 1.18; TC = 0.82; TT = 1.26; P = .01 [additive and dominant models]; all-cause mortality: CC = 0.87; TC = 0.98; TT = 1.12; P = .05 [dominant model]). Combined end points yielded similar results. Consistent with these clinical findings, 6-month changes in systolic BP for those with the CC genotype showed larger reductions with chlorthalidone (-6.5 mm Hg) than with amlodipine (-3.8 mm Hg), lisinopril (-2.4 mm Hg), or doxazosin (-3.8 mm Hg). Among those with the TT genotype, systolic BP differences between drugs were less (range, -5.4 to -7.5 mm Hg; P value, <.001 to .003 for interaction); diastolic BP showed similar results. We found no pharmacogenetic associations with the NPPA G664A variant. CONCLUSIONS: The NPPA T2238C variant was associated with modification of antihypertensive medication effects on cardiovascular disease and BP. Minor C allele carriers experienced more favorable cardiovascular disease outcomes when randomized to receive a diuretic, whereas TT allele carriers had more favorable outcomes when randomized to receive a calcium channel blocker.

Absence of an interaction between the angiotensin-converting enzyme insertion-deletion polymorphism and pravastatin on cardiovascular disease in high-risk hypertensive patients: the Genetics of Hypertension-Associated Treatment (GenHAT) study.

BACKGROUND: The aim of this study was to determine whether the angiotensin-converting enzyme (ACE) insertion-deletion (ID) polymorphism interacts with pravastatin to modify the risk of coronary heart disease (CHD) and other cardiovascular end points in a large clinical trial. METHODS: GenHAT is an ancillary study of the ALLHAT. The ACE ID genotyped population in the lipid-lowering arm of ALLHAT included 9467 participants randomly assigned to pravastatin (n = 4741) or to usual care (n = 4726). The efficacy of pravastatin in reducing the risk of primary outcome (all-cause mortality) and secondary outcomes (fatal CHD and nonfatal myocardial infarction, cardiovascular disease [CVD] mortality, CHD, stroke, other CVD, non-CVD mortality, stroke, and heart failure) was compared between the genotype strata (dominant model ID + II vs DD, additive model II vs ID vs DD), by examining an interaction term in a Cox proportional hazards model. RESULTS: The relative risk of fatal CHD and nonfatal myocardial infarction among subjects randomized to pravastatin compared with subjects randomized to usual care was similar in subjects with the II genotype (hazard ratio [HR] 0.84, 95% CI 0.59-1.18), the ID genotype (HR 0.84, 95% CI 0.68-1.03), and the DD genotype (HR 0.99, 95% CI 0.77-1.27). CONCLUSIONS: We found no evidence that the ACE ID genotype was a major modifier of the efficacy of pravastatin in reducing the risk of cardiovascular events.

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.

Incidence and predictors of angioedema in elderly hypertensive patients at high risk for cardiovascular disease: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

Angioedema is a rare, potentially life-threatening condition that has been associated with angiotensin-converting enzyme inhibitors since their introduction in the 1980s. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the largest antihypertensive study conducted to date, randomized 42,418 participants to a diuretic (chlorthalidone), a calcium channel blocker (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), or an alpha-blocker (doxazosin). Patients who developed angioedema were compared for baseline characteristics and changes in antihypertensive drug administration. Fifty-three participants developed angioedema during active follow-up: 55% were black, 60% men, and 70% were assigned to lisinopril (including 62% of black participants with angioedema), 15% to chlorthalidone, 9% to doxazosin, and 6% to amlodipine. Six percent occurred within a day of randomization and 23% within the first week. Over half did not have an increase in their assigned (blinded) antihypertensive drug before angioedema onset; 3 (6%) had a dose increase within a week before onset. One patient died following an angioedema episode. The occurrence of angioedema in the angiotensin-converting enzyme inhibitor arm corresponds with previously reported angioedema-angiotensin-converting enzyme inhibitor associations.

Should Antihypertensive Treatment Recommendations Differ in Patients With and Without Coronary Heart Disease? (from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]).

Thiazide-type diuretics have been recommended for initial treatment of hypertension in most patients, but should this recommendation differ for patients with and without coronary heart disease (CHD)? The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind hypertension treatment trial in 42,418 participants with high risk of combined cardiovascular disease (CVD) (25% with preexisting CHD). This post hoc analysis compares long-term major clinical outcomes in those assigned amlodipine (n = 9048) or lisinopril (n = 9,054) with those assigned chlorthalidone (n = 15,255), stratified by CHD status. After 4 to 8 years, randomized treatment was discontinued. Total follow-up (active treatment + passive surveillance using national databases for deaths and hospitalizations) was 8 to 13 years. For most CVD outcomes, end-stage renal disease, and total mortality, there were no differences across randomized treatment arms regardless of baseline CHD status. In-trial rates of CVD were significantly higher for lisinopril compared with chlorthalidone, and rates of heart failure were significantly higher for amlodipine compared with chlorthalidone in those with and without CHD (overall hazard ratios [HRs] 1.10, p <0.001, and 1.38, p <0.001, respectively). During extended follow-up, significant outcomes according to CHD status interactions (p = 0.012) were noted in amlodipine versus chlorthalidone comparison for CVD and CHD mortality (HR 0.88, p = 0.04, and 0.84, p = 0.04, respectively) in those with CHD at baseline (HR 1.06, p = 0.15, and 1.08, p = 0.17) and in those without. The results of the overall increased stroke mortality in lisinopril compared with chlorthalidone (HR 1.2; p = 0.03) and hospitalized heart failure in amlodipine compared with chlorthalidone (HR 1.12; p = 0.01) during extended follow-up did not differ by baseline CHD status. In conclusion, these results provide no reason to alter our previous recommendation to include a properly dosed diuretic (such as chlorthalidone 12.5 to 25 mg/day) in the initial antihypertensive regimen for most hypertensive patients.

Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril.

CONTEXT: Few cardiovascular outcome data are available for blacks with hypertension treated with angiotensin-converting enzyme (ACE) inhibitors or calcium channel blockers (CCBs). OBJECTIVE: To determine whether an ACE inhibitor or CCB is superior to a thiazide-type diuretic in reducing cardiovascular disease (CVD) incidence in racial subgroups. DESIGN, SETTING, AND PARTICIPANTS: Prespecified subgroup analysis of ALLHAT, a randomized, double-blind, active-controlled, clinical outcome trial conducted between February 1994 and March 2002 in 33,357 hypertensive US and Canadian patients aged 55 years or older (35% black) with at least 1 other cardiovascular risk factor. INTERVENTIONS: Antihypertensive regimens initiated with a CCB (amlodipine) or an ACE inhibitor (lisinopril) vs a thiazide-type diuretic (chlorthalidone). Other medications were added to achieve goal blood pressures (BPs) less than 140/90 mm Hg. MAIN OUTCOME MEASURES: The primary outcome was combined fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI), analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined CVD (CHD death, nonfatal MI, stroke, angina, coronary revascularization, heart failure [HF], or peripheral vascular disease), and end-stage renal disease. RESULTS: No significant difference was found between treatment groups for the primary CHD outcome in either racial subgroup. For amlodipine vs chlorthalidone only, HF was the only prespecified clinical outcome that differed significantly (overall: relative risk [RR], 1.37; 95% confidence interval [CI], 1.24-1.51; blacks: RR, 1.46; 95% CI, 1.24-1.73; nonblacks: RR, 1.32; 95% CI, 1.17-1.49; P<.001 for each comparison) with no difference in treatment effects by race (P = .38 for interaction). For lisinopril vs chlorthalidone, results differed by race for systolic BP (greater decrease in blacks with chlorthalidone), stroke, and combined CVD outcomes (P<.001, P = .01, and P = .04, respectively, for interactions). In blacks and nonblacks, respectively, the RRs for stroke were 1.40 (95% CI, 1.17-1.68) and 1.00 (95% CI, 0.85-1.17) and for combined CVD were 1.19 (95% CI, 1.09-1.30) and 1.06 (95% CI, 1.00-1.13). For HF, the RRs were 1.30 (95% CI, 1.10-1.54) and 1.13 (95% CI, 1.00-1.28), with no significant interaction by race. Time-dependent BP adjustment did not significantly alter differences in outcome for lisinopril vs chlorthalidone in blacks. CONCLUSIONS: In blacks and nonblack subgroups, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary CHD or any other prespecified clinical outcome, and diuretic-based treatment resulted in the lowest risk of heart failure. While the improved outcomes with chlorthalidone were more pronounced for some outcomes in blacks than in nonblacks, thiazide-type diuretics remain the drugs of choice for initial therapy of hypertension in both black and nonblack hypertensive patients.

Characteristics and lipid distribution of a large, high-risk, hypertensive population: the lipid-lowering component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) consisted of 42,418 participants randomized to one of four antihypertensive treatment groups: chlorthalidone, amlodipine, lisinopril, or doxazosin. A subset of these participants with fasting low-density lipoprotein cholesterol levels 100-189 mg/dL were randomized into a lipid-lowering component: 5170 to receive pravastatin (40 mg daily) and 5185 to receive usual care. This report describes the characteristics and lipid distribution of these participants. There were no important differences between the randomized treatment groups. Women had higher total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol than men. There was a similar finding for black participants compared with whites, except blacks had lower triglycerides. Diabetics had lower high-density lipoprotein cholesterol and higher triglycerides than nondiabetics, and patients with body mass index <25 kg/m(2) had higher high-density lipoprotein cholesterol but lower low-density lipoprotein cholesterol and triglycerides than patients with higher body mass index. The success of the randomization of this large, diverse population and the differences in the lipid distributions among its subgroups will allow further understanding of optimal lipid-lowering treatment.

Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT).

CONTEXT: Blood pressure control (<140/90 mm Hg) rates for hypertension fall far short of the US national goal of 50% or more. Achievable control rates in varied practice settings and geographic regions and factors that predict improved blood pressure control are not well identified. OBJECTIVE: To determine the success and predictors of blood pressure control in a large hypertension trial involving a multiethnic population in diverse practice settings. DESIGN: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial is a randomized, double-blind, active-controlled clinical trial with a mean follow-up of 4.9 years. Participant enrollment began in February 1994 and follow-up was completed in March 2002. SETTING: A total of 623 centers in the United States, Canada, and the Caribbean. PARTICIPANTS: A total of 33,357 participants (aged > or =55 years) with hypertension and at least one other coronary heart disease risk factor. INTERVENTIONS: Participants were randomly assigned to receive (double-blind) chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9048), or lisinopril 10-40 mg/d (n=9054) after other medication was discontinued. Doses were increased within these ranges and additional drugs from other classes were added as needed to achieve blood pressure control (<140/90 mm Hg). MAIN OUTCOME MEASURES: The outcome measures for this report are systolic and diastolic blood pressure, the proportion of participants achieving blood pressure control (<140/90 mm Hg), and the number of drugs required to achieve control in all three groups combined. RESULTS: Mean age was 67 years, 47% were women, 35% black, 36% diabetic; 90% were on antihypertensive drug treatment at entry. At the first of two pre-randomization visits, blood pressure was <140/90 mm Hg in only 27.4% of participants. After 5 years of follow-up, the percent controlled improved to 66%. Systolic blood pressure was <140 mm Hg in 67% of participants, diastolic blood pressure was <90 mm Hg in 92%, the mean number of drugs prescribed was 2.0+/-1.0, and the percent on > or =2 drugs was 63%. Blood pressure control varied by geographic regions, practice settings, and demographic and clinical characteristics of participants. CONCLUSIONS: These data demonstrate that blood pressure may be controlled in two thirds of a multiethnic hypertensive population in diverse practice settings. Systolic blood pressure is more difficult to control than diastolic blood pressure, and at least two antihypertensive medications are required for most patients to achieve blood pressure control. It is likely that the majority of people with hypertension could achieve a blood pressure <140/90 mm Hg with the antihypertensive medications available today.