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1.  Mortality and morbidity during and after ALLHAT: Results by gender 
Hypertension  2013;61(5):977-986.
To determine whether an angiotensin-converting enzyme inhibitor (lisinopril) or calcium channel blocker (amlodipine) is superior to a diuretic (chlorthalidone) in reducing cardiovascular disease incidence in gender subgroups, we carried out a prespecified subgroup analysis of 15,638 female and 17,719 male participants in the Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT). Total follow-up (active treatment + passive surveillance using national administrative databases to ascertain deaths and hospitalizations) was 8 to 13 years. The primary outcome was fatal coronary heart disease or nonfatal myocardial infarction. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (coronary heart disease death, nonfatal myocardial infarction, stroke, angina, coronary revascularization, heart failure, or peripheral vascular disease), and end-stage renal disease. In-trial rates of heart failure, stroke, and combined cardiovascular disease were significantly higher for lisinopril compared to chlorthalidone, and rates of heart failure were significantly higher for amlodipine compared to chlorthalidone in both men and women. There were no significant treatment gender interactions. These findings did not persist through the extension period with the exception of the heart failure result for amlodipine versus chlorthalidone, which did not differ significantly by gender. For both women and men, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary coronary heart disease outcome or any other cardiovascular disease outcome, and chlorthalidone-based treatment resulted in the lowest risk of heart failure. Neither lisinopril nor amlodipine is superior to chlorthalidone for initial treatment of hypertension in either women or men.
doi:10.1161/HYPERTENSIONAHA.111.00213
PMCID: PMC4114223  PMID: 23529173
hypertension; gender; diuretic; calcium channel blocker; ACE inhibitor
2.  Risk of Hospitalized Gastrointestinal Bleeding in Persons Randomized to Diuretic, ACE-Inhibitor, or Calcium-Channel Blocker in ALLHAT 
Calcium channel-blockers (CCB) are an important class of medication useful in the treatment of hypertension. Several observational studies have suggested an association between CCB therapy and gastrointestinal hemorrhage. Using administrative databases, we re-examined in a post-hoc analysis whether the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants randomized to the calcium-channel blocker amlodipine had a greater risk of hospitalized gastrointestinal bleeding (a pre-specified outcome) compared to those randomized to the diuretic chlorthalidone or the ACE-inhibitor lisinopril. Participants randomized to chlorthalidone did not have a reduced risk for gastrointestinal bleeding hospitalizations compared to participants randomized to amlodipine (HR, 1.09, 95% CI 0.92-1.28). Those randomized to lisinopril were at increased risk of gastrointestinal bleeding compared those randomized to chlorthalidone (HR, 1.16; 95% CI, 1.00-1.36). In a post-hoc comparison, participants assigned lisinopril therapy had a higher risk of hospitalized gastrointestinal hemorrhage (HR,1.27, 95% CI 1.06-1.51) versus those assigned to amlodipine. In-study use of atenolol prior to first gastrointestinal hemorrhage was related to a lower incidence of GI bleeding (HR, 0.69; 95% CI, 0.57-0.83). In conclusion, hypertensive patients on amlodipine do not have an increased risk of GI bleeding hospitalizations compared to those on either chlorthalidone or lisinopril.
doi:10.1111/jch.12180
PMCID: PMC3844932  PMID: 24283598
3.  Thiazide-type diuretics and beta-adrenergic blockers as first-line drug treatments for hypertension 
Circulation  2008;117(20):2691-2705.
doi:10.1161/CIRCULATIONAHA.107.709931
PMCID: PMC2897820  PMID: 18490537
4.  Heart Failure with Preserved and Reduced Left Ventricular Ejection Fraction in ALLHAT 
Circulation  2008;118(22):2259-2267.
Background
Heart failure (HF) developing in hypertensive patients may occur with preserved or reduced left ventricular ejection fraction [PEF (≥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 pre-specified in the ALLHAT protocol. EF estimated by contrast ventriculography, echocardiography or radionuclide study was available in 910 (66.6%) of 1367 patients 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 [HRs] and 95% CIs were 0.69 (0.53-0.91; p=0.009), 0.74 (0.56-0.97; p=0.032), and 0.53 (0.38-0.73; p<0.001), respectively. Chlorthalidone reduced the risk of HFREF compared with amlodipine or doxazosin; HRs were 0.74 (0.59-0.94; p=0.013) and 0.61 (0.47-0.79; p<0.001), respectively. Chlorthalidone was similar to lisinopril with regard to incidence of HFREF; HR=1.07 (0.82-1.40; p=0.596). Following 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 terminated early chlorthalidone/doxazosin comparison 20.0% (HFPEF) versus 26.0% (HFREF), p=0.185 (median follow-up 1.55 years).
Conclusions
In the ALLHAT trial, using 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.
doi:10.1161/CIRCULATIONAHA.107.762229
PMCID: PMC2775475  PMID: 19001024
antihypertensive therapy; hypertension, detection and control; diuretics; angiotensin-converting enzyme inhibitors; calcium channel blockers; heart failure; ejection fraction
5.  The effects of angiotensinogen gene polymorphisms on cardiovascular disease outcomes during antihypertensive treatment in the GenHAT study 
Previous studies have reported that risk of cardiovascular morbidity and mortality substantially increases in hypertensive patients, especially among those with inadequate blood pressure control. Two common antihypertensive drug classes including thiazide diuretics and angiotensin-converting enzyme (ACE) inhibitors affect different enzymes in the renin-angiotensin-aldosterone system (RAAS). In the RAAS, angiotensinogen is converted into angiotensin II which increases blood pressure through vasoconstriction. Using a case-only design with 3448 high-risk hypertensive individuals from the Genetics of Hypertension Associated Treatment (GenHAT) study, we examined whether seven single nucleotide polymorphisms (SNPs) in the angiotensinogen gene (AGT) interact with three classes of antihypertensive drugs including chlorthalidone (a thiazide diuretic), lisinopril (an ACE inhibitor), and amlodipine (a calcium channel blocker) to modify the risk of incident coronary heart disease (CHD) and heart failure (HF) among Caucasian and African American participants, separately. We found no gene by treatment interactions to be statistically significant after correction for multiple testing. However, some suggestive results were found. African American participants with the minor allele of rs11122576 had over two-fold higher risk of CHD when using chlorthalidone compared to using amlodipine, or lisinopril compared to amlodipine (p = 0.006 and p = 0.01, respectively). Other marginal associations are also reported among both race groups. The findings reported here suggest that rs11122576 could contribute to future personalization of antihypertensive treatment among African Americans though more studies are needed.
doi:10.3389/fphar.2014.00210
PMCID: PMC4165277  PMID: 25278896
AGT gene; antihypertensive drugs; hypertension; coronary heart disease; heart failure
6.  RYR3 gene polymorphisms and cardiovascular disease outcomes in the context of antihypertensive treatment 
The pharmacogenomics journal  2012;13(4):330-334.
Nearly one-third of adults in the U.S. have hypertension, which is associated with increased cardiovascular disease (CVD) morbidity and mortality. The goal of antihypertensive pharmacogenetic research is to enhance understanding of drug response based on the interaction of individual genetic architecture and antihypertensive therapy to improve blood pressure control and ultimately prevent CVD outcomes. In the context of the Genetics of Hypertension Associated Treatment (GenHAT) study and using a case-only design, we examined whether single nucleotide polymorphisms in RYR3 interact with four classes of antihypertensive drugs, particularly the calcium channel blocker amlodipine versus other classes, to modify the risk of coronary heart disease (CHD; fatal CHD and non-fatal myocardial infarction combined) and heart failure in high-risk hypertensive individuals. RYR3 mediates the mobilization of stored Ca+2 in cardiac and skeletal muscle to initiate muscle contraction. There was suggestive evidence of pharmacogenetic effects on heart failure, the strongest of which was for rs877087, with the smallest p-value =.0005 for the codominant model when comparing amlodipine versus all other treatments. There were no pharmacogenetic effects observed for CHD. The findings reported here for the case-only analysis of the antihypertensive pharmacogenetic effect of RYR3 among 3,058 CHD cases and 1,940 heart failure cases show that a hypertensive patient’s genetic profile may help predict which medication(s) might better lower cardiovascular disease risk.
doi:10.1038/tpj.2012.22
PMCID: PMC3435442  PMID: 22664477
RYR3 gene; calcium channel blocker; hypertension; coronary heart disease; heart failure; genetic interaction
7.  Pharmacogenetic effect of the stromelysin (MMP3) polymorphism on stroke risk in relation to antihypertensive treatment: The GenHAT Study 
Stroke; a journal of cerebral circulation  2010;42(2):10.1161/STROKEAHA.110.593798.
Background and Purpose
Atherothrombotic diseases including stroke share a common etiology of atherosclerosis, and susceptibility to atherosclerosis has a genetic component. Stromelysin-1 (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 GenHAT study, ancillary to ALLHAT, we evaluated the 5A/6A polymorphism in MMP3 to determine its association with stroke and determine if it modifies clinical outcome response to blood pressure lowering drugs.
Methods
The effect of the MMP3 5A/6A polymorphism on stroke rates were examined using multivariate-adjusted Cox regression models including testing interactions between genotype and antihypertensive drug class.
Results
Compared to participants treated with chlorthalidone with the 6A/6A genotype, individuals with the 6A/6A genotype randomized to lisinopril had higher stroke rates (HR, 1.32; 95% CI, 1.08-1.61; P = 0.007), 5A/6A individuals taking lisinopril had lower stroke rates (HRinteraction = 0.74; Pinteraction = 0.08; 95% CI, 0.53-1.04), while 5A/5A individuals taking lisinopril had the lowest stroke rate (HRinteraction=0.51; Pinteraction=0.009; 95% CI, 0.31-0.85). There were no pharmacogenetic differences in stroke rate by genotype in patients taking amlodipine or doxazosin versus chlorthalidone.
Conclusions
The MMP3 6A/6A genotype is associated with an increased risk of stroke in hypertensive subjects taking lisinopril compared to patients treated with chlorthalidone, while 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.
doi:10.1161/STROKEAHA.110.593798
PMCID: PMC3859235  PMID: 21183746
hypertension; pharmacogenetics; genetic polymorphism; cardiovascular; Stroke; Matrix Metalloproteinase 3; Antihypertensive Agents
8.  Cardiovascular risk assessment: addition of CKD and race to the Framingham equation 
American heart journal  2012;164(6):925-931.e2.
Background/Aims
The value of the Framingham equation in predicting cardiovascular risk in African Americans and patients with chronic kidney disease (CKD) is unclear. The purpose of the study was to evaluate whether the addition of CKD and race to the Framingham equation improves risk stratification in hypertensive patients.
Methods
Participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) were studied. Those randomized to doxazosin, age greater than 74 years, and those with a history of coronary heart disease (CHD) were excluded. Two risk stratification models were developed using Cox proportional hazards models in a two-thirds developmental sample. The first model included the traditional Framingham risk factors. The second model included the traditional risk factors plus CKD, defined by eGFR categories, and stratification by race (Black vs. Non-Black). The primary outcome was a composite of fatal CHD, nonfatal MI, coronary revascularization, and hospitalized angina.
Results
There were a total of 19,811 eligible subjects. In the validation cohort, there was no difference in C-statistics between the Framingham equation and the ALLHAT model including CKD and race. This was consistent across subgroups by race and gender and among those with CKD. One exception was among Non-Black women where the C-statistic was higher for the Framingham equation (0.68 vs 0.65, P=0.02). Additionally, net reclassification improvement was not significant for any subgroup based on race and gender, ranging from −5.5% to 4.4%.
Conclusion
The addition of CKD status and stratification by race does not improve risk prediction in high-risk hypertensive patients.
doi:10.1016/j.ahj.2012.09.003
PMCID: PMC3511773  PMID: 23194494
coronary disease; chronic renal insufficiency; African Americans; risk assessment; Framingham
9.  Do Bayesian adaptive trials offer advantages for comparative effectiveness research? Protocol for the RE-ADAPT study 
Clinical Trials (London, England)  2013;10(5):807-827.
Background
Randomized clinical trials, particularly for comparative effectiveness research (CER), are frequently criticized for being overly restrictive or untimely for health-care decision making.
Purpose
Our prospectively designed REsearch in ADAptive methods for Pragmatic Trials (RE-ADAPT) study is a ‘proof of concept’ to stimulate investment in Bayesian adaptive designs for future CER trials.
Methods
We will assess whether Bayesian adaptive designs offer potential efficiencies in CER by simulating a re-execution of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study using actual data from ALLHAT.
Results
We prospectively define seven alternate designs consisting of various combinations of arm dropping, adaptive randomization, and early stopping and describe how these designs will be compared to the original ALLHAT design. We identify the one particular design that would have been executed, which incorporates early stopping and information-based adaptive randomization.
Limitations
While the simulation realistically emulates patient enrollment, interim analyses, and adaptive changes to design, it cannot incorporate key features like the involvement of data monitoring committee in making decisions about adaptive changes.
Conclusion
This article describes our analytic approach for RE-ADAPT. The next stage of the project is to conduct the re-execution analyses using the seven prespecified designs and the original ALLHAT data.
doi:10.1177/1740774513497293
PMCID: PMC3834735  PMID: 23983160
10.  Genetic and Adverse Health Outcome Associations with Treatment Resistant Hypertension in GenHAT 
Treatment resistant hypertension (TRH) is defined as uncontrolled hypertension (HTN) despite the use of ≥3 antihypertensive medication classes or controlled HTN while treated with ≥4 antihypertensive medication classes. Risk factors for TRH include increasing age, diminished kidney function, higher body mass index, diabetes, and African American (AA) race. Importantly, previous studies suggest a genetic role in TRH, although the genetics of TRH are largely understudied. With 2203 treatment resistant cases and 2354 treatment responsive controls (36% AA) from the Genetics of Hypertension Associated Treatment Study (GenHAT), we assessed the association of 78 candidate gene polymorphisms with TRH status using logistic regression. After stratifying by race and adjusting for potential confounders, there were 2 genetic variants in the AGT gene (rs699, rs5051) statistically significantly associated with TRH among white participants. The Met allele of rs699 and the G allele of rs5051 were positively associated with TRH: OR = 1.27 (1.12–1.44), P = 0.0001, and OR = 1.36 (1.20–1.53), P < 0.0001, respectively. There was no similar association among AA participants (race interaction P = 0.0004 for rs699 and P = 0.0001 for rs5051). This research contributes to our understanding of the genetic basis of TRH, and further genetic studies of TRH may help reach the goal of better clinical outcomes for hypertensive patients.
doi:10.1155/2013/578578
PMCID: PMC3833110  PMID: 24288596
11.  Gene panels to help identify subgroups at high and low risk of CHD among those randomized to antihypertensive treatment: The GenHAT Study 
Pharmacogenetics and Genomics  2012;22(5):355-366.
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 people based on their genetic profile who benefit most from a particular treatment.
Methods
Candidate genetic variants (n=78) were genotyped in 39,114 participants from GenHAT, ancillary to ALLHAT. ALLHAT randomized hypertensive participants (>=55 years) to one of four treatments (amlodipine, chlorthalidone, doxazosin, lisinopril). The primary outcome was fatal CHD or non-fatal MI (mean follow-up=4.9 years). A pharmacogenetic panel was derived within each of the four treatment groups. ROC curves estimated the discrimination rate between those with and without a CHD event, based on the addition of the genetic panel risk score.
Results
For each treatment group, we identified a panel of genetic variants that collectively improved 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=.004; Amlodipine (B): MMP1, rs1799750; F5, rs6025; NPPA, rs5065; PDE4D, rs6450512; MMP9, rs2274756; ROC comparison p=.006; Lisinopril (C): AGT, rs5051; PON1, rs705379; MMP12, rs652438; F12, rs1801020; GP1BA, rs6065; PDE4D, rs27653; ROC comparison p=.01; Doxazosin (D): F2, rs1799963; PAI1, rs1799768; MMP7, rs11568818; AGT, rs5051; ACE, rs4343; MMP2, rs243865; ROC comparison p=.007. Each panel was tested for a pharmacogenetic effect; panels A, B and D showed such evidence (p=.009, .006, and .001 respectively), panel C did not (p=.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.
doi:10.1097/FPC.0b013e3283516ff8
PMCID: PMC3325375  PMID: 22388798
pharmacogenetics; antihypertensive pharmacogenetics; CVD; gene panels
12.  CLINICAL SIGNIFICANCE OF INCIDENT HYPOKALEMIA AND HYPERKALEMIA IN TREATED HYPERTENSIVE PATIENTS IN ALLHAT 
Hypertension  2012;59(5):926-933.
Concerns exist that diuretic-induced changes in serum potassium may have adverse effects in hypertensive patients. ALLHAT, a large practice-based clinical trial made it possible to examine consequences of observed changes in potassium during care in conventional practice settings. Normokalemic participants randomized to chlorthalidone versus amlodipine or lisinopril as first-step drug were stratified by year-1 potassium. Post-year-1 outcomes among hypokalemics (potassium<3.5mmol/L) and hyperkalemics (potassium>5.4mmol/L) were compared to normokalemics (potassium 3.5–5.4 mmol/L). Year-1 hypokalemia incidence was 6.8%; incidence in chlorthalidone (12.9%) differed from amlodipine (2.1%; p<0.001) and lisinopril (1.0%; p<0.01). Hyperkalemia incidence (2.0%) was greater in lisinopril (3.6%) than chlorthalidone (1.2%; p<0.01) or amlodipine (1.9%; p<0.01). Coronary heart disease occurred in 8.1% with hypokalemia, 8.0% with normokalemia, and 11.1% with hyperkalemia. Overall, mortality was higher in hypokalemics than normokalemics (Cox hazard ratio =1.21; 95% confidence interval=1.02–1.44) with statistically significant (interaction p<0.01) disparity in hazard ratios for the three treatment arms (hazard ratios: chlorthalidone=1.21, amlodipine=1.60, lisinopril=3.82). Hyperkalemia was associated with increased risk of combined cardiovascular disease (hazard ratio=1.58; 1.15–2.18) without significant treatment interactions. In conventional practice settings, the uncommon appearance of hyperkalemia was associated with increased cardiovascular disease risk. Hypokalemia was associated with increased mortality; however, the statistically significant heterogeneity in hazard ratios across treatment groups strongly suggests that the observed increase in mortality is unrelated to the specific effects of chlorthalidone. Thus, for most patients, concerns about potassium levels should not influence clinician’s decision about initiating hypertension treatment with low-moderate doses of thiazide diuretics (12.5–25 mg of chlorthalidone).
doi:10.1161/HYPERTENSIONAHA.111.180554
PMCID: PMC3373273  PMID: 22431578
hypertension; hypokalemia; hyperkalemia; diuretic; calcium-channel blocker; ACE-inhibitor
13.  Long-Term Effects of Incident Diabetes Mellitus on Cardiovascular Outcomes in People Treated for Hypertension 
Background
Thiazide-type diuretics are associated with an increased incidence of diabetes as compared to other anti-hypertension medications. In this study we determined long-term cardiovascular disease (CVD) consequences of incident diuretic-associated diabetes compared to the effects of incident diabetes associated with calcium channel and ACE inhibitor use.
Methods and Results
22,418 participants from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial with baseline diabetes, incident diabetes (7.5% with chlorthalidone, 5.6% with amlodipine, and 4.3% with lisinopril), or no diabetes at 2 years of in-trial follow-up were followed for a mean total of 6.9 years (2.9 years in-trial and 4 additional years post-trial through the use of national data bases). The primary outcome was CVD mortality (death due to coronary heart disease [CHD], stroke, heart failure, or other CVD). Among other outcomes were all-cause mortality, non-CVD mortality, and CHD (nonfatal myocardial infarction/fatal CHD). Participants on chlorthalidone with incident diabetes versus no diabetes had consistently lower, non-significant risk for CVD mortality (hazard ratio [HR] 1.04, 95% confidence interval (CI 0.74–1.47), all-cause mortality (HR 1.04, 95% CI 0.82–1.30), and non-CVD mortality (HR 1.05, 95% CI 0.77–1.42) than participants with incident diabetes on amlodipine or lisinopril (HR’s 1.22–1.53). Participants with incident diabetes had elevated CHD risk compared to those with no diabetes (HR 1.46, 95% CI 1.09–1.96) but those on chlorthalidone had significantly lower risk than those on lisinopril (HR 1.18 versus 2.57, p for interaction = 0.04).
Conclusions
Our findings suggest that thiazide-related incident diabetes has less adverse long-term CVD impact than incident diabetes that develops on other antihypertensive medications.
doi:10.1161/CIRCOUTCOMES.111.962522
PMCID: PMC3359874  PMID: 22396585
diabetes mellitus; diuretics; cardiovascular diseases; mortality; ALLHAT
14.  Mortality and Morbidity during and after the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial 
A randomized, double-blind, active-controlled, multicenter trial assigned 32,804 participants aged ≥55 years with hypertension and ≥1 other coronary heart disease risk factors, to receive chlorthalidone (n=15,002); amlodipine (n=8898); or lisinopril (n=8904) for 4 to 8 years, when double-blind therapy was discontinued. Passive surveillance continued for a total follow-up of 8 to 13 years, using national administrative databases to ascertain deaths and hospitalizations. During the post-trial period, fatal outcomes and nonfatal outcomes were available for 98% and 65% of participants, respectively, due to lack of access to administrative databases for the remainder. This paper assesses whether mortality and morbidity differences persisted or new differences developed over the extended follow-up. Primary outcome was cardiovascular mortality; secondary outcomes were mortality, stroke, coronary heart disease, heart failure, cardiovascular disease, and end-stage renal disease. For the post-trial period, data are not available on medications or blood pressure levels.
No significant differences (p < .05) appeared in cardiovascular mortality for amlodipine (HR 1.00 [0.93–1.06]) or lisinopril (HR 0.97 [0.90–1.03]), each compared to chlorthalidone. The only significant differences in secondary outcomes were for heart failure, higher for amlodipine (HR 1.12 [1.02–1.22]), and stroke mortality, higher for lisinopril (HR 1.20 [1.01–1.41]), each compared to chlorthalidone. Similar to the previously reported in-trial result, there was a significant treatment by race interaction for cardiovascular disease for lisinopril versus chlorthalidone; Blacks had higher risk than non-Blacks on lisinopril compared with chlorthalidone.. After accounting for multiple comparisons, none of these results were significant. These findings suggest that neither calcium channel blockers nor angiotensin converting-enzyme inhibitors are superior to diuretic in long-term prevention of major cardiovascular complications of hypertension.
doi:10.1111/j.1751-7176.2011.00568.x
PMCID: PMC3261592  PMID: 22235820
antihypertensive therapy; clinical trials; hypertension—general; pharmacologic (drug) therapy; clinical management of high blood pressure
15.  Long-Term Follow-up of Participants with Heart Failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) 
Circulation  2011;124(17):1811-1818.
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/day) and lisinopril (10-40 mg/day) arms compared with the chlorthalidone (12.5-25 mg/day) 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
Using national databases, post-trial 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 development of HF is to be addressed.
doi:10.1161/CIRCULATIONAHA.110.012575
PMCID: PMC3217334  PMID: 21969009
heart failure; hypertension; diuretics; mortality; ejection fraction
16.  Pharmacogenetic Association of NOS3 Variants with Cardiovascular Disease in Patients with Hypertension: The GenHAT Study 
PLoS ONE  2012;7(3):e34217.
Nitric oxide synthase 3 (NOS3) catalyzes production of NO in the endothelium and may play a role in cardiovascular disease (CVD). We assessed the pharmacogenetic associations of three NOS3 polymorphisms and three antihypertensive drugs with CVD outcomes. Hypertensive subjects (n = 30,280) from a multi-center, double-blind clinical trial were randomized to chlorthalidone, amlodipine, or lisinopril treatment (mean follow up, 4.9 years). Outcomes included coronary heart disease (CHD: fatal CHD and nonfatal myocardial infarction); stroke; heart failure (fatal, requiring hospitalization, or outpatient treatment); all-cause mortality; and end-stage renal disease (ESRD). Main effects of NOS3 variants on outcome and genotype-treatment interactions were tested. For NOS3 −690 C>T (rs3918226), a higher hazard ratio (HR) was found in minor allele carriers for CHD (CC = 1.00, CT+TT = 1.12 (95% confidence interval (CI) = 1.00–1.26), P = 0.048). For NOS3 −922 A>G (rs1800779), a higher HR was found in minor allele carriers for heart failure (AA = 1.00, AG+GG = 1.10 (CI = 1.00–1.21), P = 0.046). Significant pharmacogenetic findings were observed for stroke and all-cause mortality. For −690 C>T, a lower HR was observed for stroke in minor allele carriers when treated with amlodipine versus lisinopril (CC = 0.85 (CI = 0.73–0.99), CT+TT = 0.49 (CI = 0.31–0.80), P = 0.04). For glu298asp G>T (rs1799983), a lower HR was observed for all-cause mortality in minor allele carriers when treated with amlodipine versus lisinopril (GG = 1.01 (CI = 0.91–1.13), GT+TT = 0.85 (CI = 0.75–0.97), P = 0.04). We observed significant associations with NOS3 variants and CHD and heart failure and significant pharmacogenetic effects for stroke and all cause mortality. This suggests that NOS3 variants may potentially provide useful clinical information with respect to treatment decisions in the future.
doi:10.1371/journal.pone.0034217
PMCID: PMC3314599  PMID: 22470539
17.  Pharmacogenetic Association of Hypertension Candidate Genes with Fasting Glucose in the GenHAT Study 
Journal of hypertension  2010;28(10):2076-2083.
Several clinical studies report increased risk of diabetes mellitus (DM) with pharmacologic treatment for hypertension (HTN). HTN genes may modify glycemic response to antihypertensive treatment. The current study examined the association of 24 single nucleotide polymorphisms (SNPs) in 11 HTN candidate genes with fasting glucose measured at 2, 4, and 6 years after treatment initiation. The study sample included participants free of diabetes at baseline in the Genetics of Hypertension Associated Treatment (GenHAT) study (N=9,309). GenHAT participants were randomized to receive treatment with a diuretic (chlorthalidone), calcium channel blocker (amlodipine), or ACE inhibitor (lisinopril). Mixed models for repeated measures were employed to test for gene and pharmacogenetic associations with fasting glucose during follow-up. Fasting glucose at year 2 increased on average 6.8 mg/dL, 4.8 mg/dL and 3.0 mg/dL from baseline in the chlorthalidone, amlodipine and lisinopril groups, respectively. Carrying the I allele (rs1799752) of the angiotensin-converting enzyme (ACE) I/D polymorphism was associated with lower fasting glucose levels (P=0.02). Additionally, an ACE promoter polymorphism (−262, rs4291) was associated with lower fasting glucose for the model AA/AT vs. TT which remained significant after correction for multiple testing (P=0.001). Finally, a SNP in the α-subunit of the amiloride-sensitive epithelial sodium channel (SCNN1A, rs2228576) modified the association of amlodipine versus chlorthalidone treatment with fasting glucose (P<0.001). Further examination of these genes and their relationships with cardiometabolic disease could foster development of pharmacogenetic guidelines aimed to prevent increases in fasting glucose during antihypertensive treatment.
doi:10.1097/HJH.0b013e32833c7a4d
PMCID: PMC2957368  PMID: 20577119
ACE; SCNN1A; RAAS; Lisinopril; Chlorthalidone; Amlodipine; Thiazide Diuretics; Hypertension Treatment
18.  Pharmacogenetic Associations of MMP9 and MMP12 Variants with Cardiovascular Disease in Patients with Hypertension 
PLoS ONE  2011;6(8):e23609.
Objectives
MMP-9 and -12 function in tissue remodeling and may play roles in cardiovascular disease (CVD). We assessed associations of four MMP polymorphisms and three antihypertensive drugs with cardiovascular outcomes.
Methods
Hypertensives (n = 42,418) from a double-blind, randomized, clinical trial were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin treatment (mean follow up, 4.9 years). The primary outcome was coronary heart disease (CHD). Secondary outcomes included combined CHD, all CVD outcomes combined, stroke, heart failure (HF), and mortality. Genotype-treatment interactions were tested.
Results
There were 38,698 participants genotyped for at least one of the polymorphisms included here. For MMP9 R668Q (rs2274756), lower hazard ratios (HRs) were found for AA subjects for most outcomes when treated with chlorthalidone versus amlodipine (eg., CCHD: GG = 1.00, GA = 1.01, AA = 0.64; P = 0.038). For MMP9 R279Q (rs17576), modest pharmacogenetic findings were observed for combined CHD and the composite CVD outcome. For MMP12 N122S (rs652438), lower HRs were observed for CHD in subjects carrying at least one G allele and being treated with chlorthalidone versus lisinopril (CHD: AA = 1.07, AG = 0.80, GG = 0.49; P = 0.005). In the lisinopril-amlodipine comparison, higher HRs were observed for participants having at least one G allele at the MMP12 N122S locus (CHD: AA = 0.94, AG = 1.19, GG = 1.93; P = 0.041). For MMP12 −82A>G (rs2276109), no pharmacogenetic effect was found for the primary outcome, although lower HRs were observed for AA homozygotes in the chlorthalidone-amlodipine comparison for HF (P = 0.015).
Conclusions
We observed interactions between antihypertensive drugs and MMP9 and MMP12 for CHD and composite CVD. The data suggest that these genes may provide useful clinical information with respect to treatment decisions.
doi:10.1371/journal.pone.0023609
PMCID: PMC3160956  PMID: 21887284
19.  Impact of the ALLHAT/JNC7 Dissemination Project on Thiazide-type Diuretic Use 
Archives of internal medicine  2010;170(10):851-858.
Background
Strategies are needed to improve the translation of clinical trial results into practice. We assessed the impact of the ALLHAT/JNC7 Dissemination Project’s academic detailing component on thiazide-type diuretic prescribing (ALLHAT indicates Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: JNC7 indicates the Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure).
Methods
We used two national databases available from IMS Health: a physician survey of medications reported for hypertension and a pharmacy dispensing database on antihypertensive medications. At a county level, we correlated medication data with Dissemination Project intensity. Practices before the Dissemination Project in 2004 were compared to those after its completion in 2007. We also examined 2000–2008 national trends.
Results
Academic detailing reached 18,524 physicians in 1698 venues via 147 investigator-educators. We noted an association between ALLHAT/JNC7 academic detailing activities and increased prescribing of thiazide-type diuretics. Physician survey data showed that the percentage of hypertension visits where the physician recorded where a thiazide-type diuretic was noted increased the most in counties with the greatest activities (8.6%, from 37.9% to 46.5%) compared to counties with moderate-level (2% change), low-level (−2%) and no activities (2%, p for trend <0.05). Pharmacy dispensing data showed that thiazide-type diuretic prescribing increased by 8.7% in counties with Dissemination Project activities compared to 3.9% in those without activities (p<0.001). Nationally, thiazide-type diuretic use did not increase between 2004 and 2008.
Conclusions
The ALLHAT/JNC7 Dissemination Project was associated with a small effect on thiazide-type diuretic use consistent with its small dose and the potential of external factors to diminish its impact. Academic detailing may increase physicians’ implementation of clinical trial results thereby making prescribing more consistent with evidence.
doi:10.1001/archinternmed.2010.130
PMCID: PMC2989728  PMID: 20498411
20.  The Scientific Foundation for Personal Genomics: Recommendations from a National Institutes of Health–Centers for Disease Control and Prevention Multidisciplinary Workshop 
The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed.
doi:10.1097/GIM.0b013e3181b13a6c
PMCID: PMC2936269  PMID: 19617843
behavioral sciences; epidemiologic methods; evidence-based medicine; genetics; genetic testing; genomics; medicine; public health
21.  HEART FAILURE IN ALLHAT: DID BLOOD PRESSURE MEDICATION AT STUDY ENTRY INFLUENCE OUTCOME? 
Lower heart failure (HF) rates in individuals on chlorthalidone versus amlodipine, lisinopril, or doxazosin were unanticipated in ALLHAT. HF differences appeared early, leading to questions about the possible influence of pre-enrollment antihypertensive drugs. A post-hoc study evaluated hospitalized HF events. During year one, 479 individuals had HF, with pre-entry antihypertensive medication data obtained on 301 (63%). Case-only analysis examined interactive effects (interaction odds ratio [ratio of odds ratios]) of previous medication and ALLHAT treatment on HF outcomes, e.g., did treatment effect differ by pre-entry antihypertensive class? Among cases, 39%, 37%, 17%, and 47% were on pre-entry diuretics, ACE-inhibitors, beta-blockers, and calcium-channel-blockers, respectively. Interaction odds ratio for year one HF for amlodipine versus chlorthalidone for those on versus not on diuretics pre-entry was 1.08(95%CI,0.53-2.21,p=0.83); for lisinopril versus chlorthalidone, 1.33(95%CI,0.65-2.74,p=0.44); and for doxazosin versus chlorthalidone, 1.13(95%CI,0.57-2.25,p=0.73). Controlling for other pre-entry antihypertensives yielded similar results. There was no significant evidence that pre-entry drug type explained observed hospitalized HF differences by ALLHAT treatment.
doi:10.1111/j.1751-7176.2009.00149.x
PMCID: PMC2788785  PMID: 19751458
heart failure; hypertension; clinical trials; diuretics
22.  Getting clinical trial results into practice: design, implementation, and process evaluation of the ALLHAT Dissemination Project 
Background
Conventional dissemination of clinical trial results has inconsistent impact on physician practices. A more comprehensive plan to influence determinants of prescribing practices is warranted.
Purpose
To report the response from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial to the National Heart, Lung, and Blood Institute’s requirement for dissemination and evaluation of trials with potential immediate public health applicability.
Methods
ALLHAT’s dissemination plan had two-components: 1) a traditional approach of media coverage, scientific presentation and publication; and 2) a theory-based approach targeting determinants of clinician behavior. Strategies included (1) academic detailing, in which physicians approach colleagues regarding blood pressure management, (2) direct patient messages to stimulate communication with physicians regarding blood pressure control, (3) approaches to formulary systems to use educational and economic incentives for evidence-based prescription, and (4) direct professional organization appeals to clinicians.
Results
One hundred and forty-seven Investigator Educators reported 1698 presentations to 18,524 clinicians in 41 states and the District of Columbia. The pre- and post-test responses of 1709 clinicians in the face-to-face meetings indicated significant changes in expectations for positive patient outcomes and intention to prescribe diuretics. Information was mailed to 55 individuals representing 20 professional organizations and to eight formulary systems. Direct-to-patient messages were provided to 14 sites that host patient newsletters and Web sites such as health plans and insurance companies, 62 print mass media outlets, and 12 broadcast media sites.
Limitations
It was not within the scope of the project to conduct a randomized trial of the impact of the dissemination. However, impact evaluation using quasi-experimental designs is ongoing.
Conclusions
A large multi-method dissemination of clinical trial results is feasible. Planning for dissemination efforts, including evaluation research, should be considered as a part of the funding and design of the clinical trial and should begin early in trial planning.
doi:10.1177/1740774509338234
PMCID: PMC2897824  PMID: 19587068
dissemination; translation research; physician behavior change; education; impact; implementation
23.  Progression of Kidney Disease in Moderately Hypercholesterolemic, Hypertensive Patients Randomized to Pravastatin Versus Usual Care: A Report From the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) 
Background
Dyslipidemia is common in patients with chronic kidney disease. The role of statin therapy on the progression of kidney disease is unclear.
Study Design
Prospective randomized clinical trial, post hoc analyses.
Setting and participants
10,060 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (lipid-lowering component) stratified by baseline eGFR: <60, 60–89, ≥90 mL/min/1.73 m2. Mean follow-up was 4.8 years.
Intervention
Randomized, pravastatin 40 mg/day or usual care.
Outcomes and measurements
Total cholesterol, HDL- and LDL-cholesterol; end stage renal disease (ESRD), estimated glomerular filtration rate (eGFR).
Results
Through year six, total cholesterol declined in the pravastatin (−20.7%) and usual care groups (−11.2%). No significant differences were seen between the groups for rates of ESRD (1.36 vs 1.45/100 patient years, P=0.9), composite endpoints of ESRD and 50% or 25% decline in eGFR, or rate of change of eGFR. Findings were consistent across eGFR strata. In patients with eGFR≥90 mL/min/1.73 m2, the pravastatin arm tended to have a higher eGFR.
Limitations
Proteinuria data unavailable, post hoc analyses, unconfirmed validity of the Modification of Diet in Renal Disease Study equation in normal eGFR range, statin drop-in rate in usual care group with small cholesterol differential between groups.
Conclusions
In hypertensive patients with moderate dyslipidemia and reduced eGFR, pravastatin was not superior to usual care in preventing clinical renal outcomes. This was consistent across the strata of baseline eGFR. However, benefit from statin therapy may depend on degree of cholesterol reduction achieved.
doi:10.1053/j.ajkd.2008.05.027
PMCID: PMC2897819  PMID: 18676075
hyperlipidemia; glomerular filtration rate; pravastatin
24.  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=9,048), or lisinopril 10-40 mg/d (n=9,054) in a randomized double-blind hypertension trial. Participants were hypertensives age t55 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 mmHg (27% control) to 134/76 mmHg (chlorthalidone, 68% control), 135/75 mmHg (amlodipine, 66% control), and 136/76 mmHg (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. A majority achieved BP control in each randomized group--a greater proportion with chlorthalidone. Over time, providers and patients should expect multidrug therapy to achieve BP<140/90 mmHg in a majority of patients.
doi:10.1111/j.1751-7176.2008.00015.x
PMCID: PMC2897821  PMID: 19090876
Blood Pressure Control; Antihypertensive Agents; Randomized Controlled Trial
25.  Antihypertensive Pharmacogenetic Effect of Fibrinogen-beta Variant -455 G>A on Cardiovascular Disease, End-Stage Renal Disease and Mortality: The GenHAT Study 
Pharmacogenetics and genomics  2009;19(6):415-421.
Objective
The FGB gene codes for fibrinogen-beta, a polypeptide of the coagulation factor fibrinogen, which is positively associated with cardiovascular diseases. Studies show ACE inhibitors lower plasma fibrinogen concentrations, whereas diuretics and calcium channel blockers do not. Since carriers of the FGB-455 minor “A” allele have higher levels of fibrinogen while ACE inhibitors lower it, we hypothesize that “A” allele carriers benefit more from antihypertensive treatment with ACE inhibitors than calcium channel blockers or diuretics, relative to “GG” genotype individuals.
Methods
The GenHAT study (ancillary to ALLHAT) genotyped hypertensive participants for several hypertension-related candidate genes, making this a post-hoc analysis of a randomized trial. In total, 90.1% of the ALLHAT population was successfully genotyped for FGB-455. We included participants (n=30,076) randomized to one of three antihypertensive medications (lisinopril, amlodipine, chlorthalidone), with two treatment comparisons: lisinopril versus chlorthalidone and lisinopril versus amlodipine. The primary outcome of ALLHAT/GenHAT was coronary heart disease, defined as fatal CHD or non-fatal MI, and secondary outcomes included stroke, heart failure, all-cause mortality and end-stage renal disease (ESRD) with mean follow-up time of 4.9 years. Genotype-by-treatment interactions (pharmacogenetic effects) were tested with Cox regression.
Results
Stroke: Common “GG” homozygotes had higher risk on lisinopril versus amlodipine (HR=1.38, p<0.001), while minor “A” allele carriers had slightly lower risk (HR=0.96, p=0.76; p-value for interaction=0.03). Mortality: “GG” homozygotes had higher risk on lisinopril versus amlodipine (HR=1.12, p=0.02) or chlorthalidone (1.05, p=0.23), while “A” allele carriers had slightly lower risk (HR=0.92, p=0.33 for lisinopril versus amlodipine, HR=0.88, p=0.08 for lisinopril versus chlorthalidone; p-value for interactions 0.04 and 0.03, respectively). ESRD: “GG” homozygotes had higher risk on lisinopril versus chlorthalidone (HR=1.27, p=0.08), while “A” allele carriers had lower risk (HR=0.64, p=0.12; p-value for interaction=0.03).
Conclusions
There was evidence of pharmacogenetic effects of FBG-455 on stroke, ESRD and mortality, suggesting that relative to those homozygous for the common allele, variant allele carriers of the FGB gene at position -455 have a better outcome if randomized to lisinopril than chlorthalidone (for mortality and ESRD) or amlodipine (for mortality and stroke). For the models in which a pharmacogenetic effect was observed, the outcome rates among “GG” homozygotes were higher in those randomized to lisinopril versus amlodipine or chlorthalidone, whereas minor “A” allele carriers had lower event rates when randomized to lisinopril versus the other medications.
doi:10.1097/FPC.0b013e32832a8e81
PMCID: PMC2764310  PMID: 19352213
FGB -455; fibrinogen gene; pharmacogenetics; hypertension; antihypertensive medication; cardiovascular disease

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