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.
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.
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).
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.
pharmacogenetics; antihypertensive pharmacogenetics; CVD; gene panels
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).
Our findings suggest that thiazide-related incident diabetes has less adverse long-term CVD impact than incident diabetes that develops on other antihypertensive medications.
diabetes mellitus; diuretics; cardiovascular diseases; mortality; ALLHAT
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.
antihypertensive therapy; clinical trials; hypertension—general; pharmacologic (drug) therapy; clinical management of high blood pressure
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.
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.
ACE; SCNN1A; RAAS; Lisinopril; Chlorthalidone; Amlodipine; Thiazide Diuretics; Hypertension Treatment
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.
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.
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).
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.
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).
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.
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.
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.
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.
heart failure; hypertension; clinical trials; diuretics
Conventional dissemination of clinical trial results has inconsistent impact on physician practices. A more comprehensive plan to influence determinants of prescribing practices is warranted.
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.
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.
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.
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.
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.
dissemination; translation research; physician behavior change; education; impact; implementation
Dyslipidemia is common in patients with chronic kidney disease. The role of statin therapy on the progression of kidney disease is unclear.
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.
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).
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.
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.
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.
hyperlipidemia; glomerular filtration rate; pravastatin
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.
Blood Pressure Control; Antihypertensive Agents; Randomized Controlled Trial
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.
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.
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).
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.
FGB -455; fibrinogen gene; pharmacogenetics; hypertension; antihypertensive medication; cardiovascular disease
This paper re-evaluates the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) considering information from new clinical trials, meta-analyses, and recent ALLHAT analyses, especially those regarding heart failure and the association of drug treatment with new-onset diabetes (NOD) and its cardiovascular disease (CVD) consequences.
Subgroup and explanatory analyses from a long-term 4-arm double-blind randomized antihypertensive treatment trial in diverse North American settings.
Chlorthalidone was superior to 1) doxazosin in preventing combined CVD (CCVD) (RR=1.20, 95% CI 1.13-1.27), especially HF (RR=1.80, CI 1.40-2.22) and stroke (RR=1.26, CI 1.10-1.46); 2) lisinopril, in preventing CCVD (RR=1.10, CI 1.05-1.16), including stroke (in Black persons only) and HF (RR=1.20, CI 1.09-1.34); and 3) amlodipine, in preventing HF, overall (by 28%) and in hospitalized/fatal cases (by 26%). Central independent blinded re-review of HF hospitalizations confirmed each comparison. Results were consistent by age, sex, race (except for stroke and CCVD), diabetic status, metabolic syndrome status, and renal function level. Neither amlodipine nor lisinopril was superior to chlorthalidone in preventing end-stage renal disease overall, by diabetes status or by renal function level. In the chorthalidone arm, NOD was not significantly associated with CCVD (RR=0.96, CI 0.88-2.42).
Evidence from subsequent analyses of ALLHAT and other clinical outcome trials confirm that neither α-blockers, ACE-inhibitors nor calcium channel blockers surpass thiazide-type diuretics (at appropriate dosage) as initial therapy for reduction of cardiovascular or renal risk. Thiazides are superior in preventing heart failure, and new-onset diabetes associated with thiazides does not increase CVD outcomes.
Pharmacogenetic research has shown that genetic variation may influence statin responsiveness. Statins exert a variety of beneficial effects beyond lipid lowering, including antithrombotic effects, which contribute to the risk reduction of cardiovascular disease. Statins have been shown to influence the expression of coagulation factors II, V, VII, XII and XIII.
AimData from a large randomized clinical trial of pravastatin, designed to show efficacy relative to usual care, were used to investigate whether a pharmacogenetic effect of polymorphisms in genes coding for coagulation factors II, V, VII, XII and XIII is associated with reduced fatal coronary heart disease (CHD) and nonfatal myocardial infarction, combined CHD and all-cause mortality.
The Genetics of Hypertension Associated Treatment is an ancillary study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. The genotyped population in the lipid-lowering trial of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial included 9624 participants randomly assigned to pravastatin or to usual care. The efficacy of pravastatin in reducing risk of all-cause mortality, CHD plus nonfatal myocardial infarction and combined CHD, was compared among genotype strata by examining an interaction term in a proportional hazards modelAQ2.
None of the polymorphisms were associated with the clinical outcomes. For the F7 (−323) del/ins polymorphism there was no interaction with pravastatin for either outcome. For both the F5 Arg506Gln G>A (rs6025) polymorphism and F7 Arg353Gln G>A (rs6046) polymorphism there were no interactions with pravastatin in relation to all-cause mortality, but there were significant interactions with combined CHD [interaction hazard ratioλ=λ1.33, 95% confidence interval (1.01−1.76) and interaction hazard ratioλ=λ1.92, 95% confidence interval (1.00−3.65), respectively]AQ3. There were no interactions between the polymorphisms in the other coagulation genes and pravastatin in relation to any outcome.
Polymorphisms in anticoagulation genes (F5 and F7) seem to modify the efficacy of pravastatin in reducing risk of cardiovascular events.
anticoagulation factor; pharmacogenetics; statin
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).
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.
antihypertensive therapy; hypertension, detection and control; diuretics; angiotensin-converting enzyme inhibitors; calcium channel blockers; heart failure; ejection fraction
The aim of this study was to determine whether the ACE insertion-deletion (I/D) polymorphism interacts with pravastatin to modify the risk of CHD and other cardiovascular endpoints in a large clinical trial.
GenHAT is an ancillary study of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The ACE ID genotyped population in the lipid lowering arm of ALLHAT included 9,467 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 non-fatal MI, CVD mortality, CHD, stroke, other CVD, non-CVD mortality, stroke and heart failure) was compared between the genotype strata (dominant model ID+II versus DD, additive model II vs ID vs DD), by examining an interaction term in a Cox proportional Hazard model.
The relative risk of fatal CHD and nonfatal MI among subjects randomized to pravastatin compared to subjects randomized to usual care was similar in subjects with the II genotype (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]).
We found no evidence that ACE I/D genotype was a major modifier of the efficacy of pravastatin in reducing the risk of cardiovascular events.
High homocysteine blood concentrations predispose to coronary artery disease and statins influence homocysteine levels.
To study whether genes that regulate homocysteine metabolism interact with statins to modify the risk of CHD and other cardiovascular outcomes.
GenHAT is an ancillary study of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The genotyped population in the lipid lowering trial (LLT) of ALLHAT included 9,624 participants randomly assigned to pravastatin or to usual care. The efficacy of pravastatin in reducing risk of all-cause mortality and CHD was compared among genotype strata (MTHFR 677 CC, CT and TT, MTHFR 1298 AA, AC, and CC, CBSins DD and I+) by examining an interaction term in a proportional hazards model.
There was no evidence of a pharmacogenetic effect on statins with the MTHFR 1298 A>C genotype for CHD risk. However, in persons with the CC variant for the MTHFR 677 C>T genotype a significantly protective effect against CHD (0.71 (95% CI 0.58–0.87)) was shown. While in the CT (1.25 (95% CI 0.97–1.61) and TT groups (0.80 (95% CI 0.50–1.28) there were no such effects (interaction hazard ratio p=0.004) The CBSins, I+ variant was associated with a significantly reduced risk for CHD among those on statin treatment (0.58 (95% CI 0.44–0.78)) while the DD genotype showed no effect from statin therapy (1.01 (95% CI 0.84–1.20; p=0.002 for interaction). For the endpoint all-cause mortality, no significant differences in efficacy were noted.
Polymorphisms in genes in the homocysteine pathway (MTHFR 677 C>T and CBSins) appear to modify the efficacy of pravastatin in reducing risk of cardiovascular events.
To evaluate the cost-effectiveness of first-line treatments for hypertension.
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) found that first-line treatment with lisinopril or amlodipine was not significantly superior to chlorthalidone in terms of the primary endpoint, so differences in costs may be critical for optimizing decision-making.
Cost-effectiveness analysis was performed using bootstrap resampling to evaluate uncertainty.
Over a patient’s lifetime, chlorthalidone was always least expensive (mean $4,802 less than amlodipine, $3,700 less than lisinopril). Amlodipine provided more life-years (LYs) than chlorthalidone in 84% of bootstrap samples (mean 37 days) at an incremental cost-effectiveness ratio of $48,400 per LY gained. Lisinopril provided fewer LYs than chlorthalidone in 55% of bootstrap samples (mean 7-day loss) despite a higher cost. At a threshold of $50,000 per LY gained, amlodipine was preferred in 50%, chlorthalidone in 40%, and lisinopril in 10% of bootstrap samples, but these findings were highly sensitive to the cost of amlodipine and the cost-effectiveness threshold chosen. Incorporating quality of life did not appreciably alter the results. Overall, no reasonable combination of assumptions led to 1 treatment being preferred in over 90% of bootstrap samples.
Initial treatment with chlorthalidone is less expensive than lisinopril or amlodipine, but amlodipine provided a nonsignificantly greater survival benefit and may be a cost-effective alternative. A randomized trial with power to exclude “clinically important” differences in survival will often have inadequate power to determine the most cost-effective treatment.
hypertension; cost-effectiveness; diuretic; angiotensin-converting enzyme inhibitors; calcium channel blockers
The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, double-blind, active-controlled trial designed to compare the rate of coronary heart disease events in high-risk hypertensive participants initially randomized to a diuretic (chlorthalidone) versus each of three alternative antihypertensive drugs: alpha-adrenergic blocker (doxazosin), ACE-inhibitor (lisinopril), and calcium-channel blocker (amlodipine). Combined cardiovascular disease risk was significantly increased in the doxazosin arm compared to the chlorthalidone arm (RR 1.25; 95% CI, 1.17–1.33; P < .001), with a doubling of heart failure (fatal, hospitalized, or non-hospitalized but treated) (RR 2.04; 95% CI, 1.79–2.32; P < .001). Questions about heart failure diagnostic criteria led to steps to validate these events further.
Methods and Results
Baseline characteristics (age, race, sex, blood pressure) did not differ significantly between treatment groups (P < .05) for participants with heart failure events. Post-event pharmacologic management was similar in both groups and generally conformed to accepted heart failure therapy. Central review of a small sample of cases showed high adherence to ALLHAT heart failure criteria. Of 105 participants with quantitative ejection fraction measurements provided, (67% by echocardiogram, 31% by catheterization), 29/46 (63%) from the chlorthalidone group and 41/59 (70%) from the doxazosin group were at or below 40%. Two-year heart failure case-fatalities (22% and 19% in the doxazosin and chlorthalidone groups, respectively) were as expected and did not differ significantly (RR 0.96; 95% CI, 0.67–1.38; P = 0.83).
Results of the validation process supported findings of increased heart failure in the ALLHAT doxazosin treatment arm compared to the chlorthalidone treatment arm.
heart failure; alpha-blocker; diuretic; clinical trial
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).
hypertension; hypokalemia; hyperkalemia; diuretic; calcium-channel blocker; ACE-inhibitor
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.
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.
heart failure; hypertension; diuretics; mortality; ejection fraction
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.
behavioral sciences; epidemiologic methods; evidence-based medicine; genetics; genetic testing; genomics; medicine; public health
Antihypertensive drugs with favorable metabolic effects on glucose and lipid levels are advocated for first-line therapy in hypertensive patients with metabolic/cardiometabolic syndrome (MetS). We compared outcomes by race in black and nonblack hypertensive individuals with and without MetS treated with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), an α-blocker (doxazosin mesylate), or an angiotensin-converting enzyme inhibitor (lisinopril).
A post hoc subgroup analysis from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, active-controlled hypertension treatment trial in 42 418 participants. We defined MetS as hypertension plus at least 2 of the following: fasting serum glucose level of at least 100 mg/dL, body mass index (calculated as weight in kilograms divided by height in meters squared) of at least 30 kg/m2, fasting triglyceride levels of at least 150 mg/dL, and high-density lipoprotein cholesterol levels of less than 40 mg/dL in men (or less than 50 mg/dL in women).
Significantly higher rates of heart failure were consistent across all treatment comparisons in those with MetS. Relative risks (RRs) were 1.50 (95% confidence interval [CI], 1.18–1.90), 1.49 (95% CI, 1.17–1.90), and 1.88 (95% CI, 1.42–2.47) in black participants and 1.25 (95% CI, 1.06–1.47), 1.20 (95% CI, 1.01–1.41), and 1.82 (95% CI, 1.51–2.19) in nonblack participants for amlodipine, lisinopril, and doxazosin comparisons with chlorthalidone, respectively. Higher rates for combined cardiovascular disease were observed with lisinopril-chlorthalidone (RR, 1.24 [95% CI, 1.09–1.40] and 1.10 [95% CI, 1.02–1.19], respectively) and doxazosin-chlorthalidone comparisons (RR, 1.37 [95% CI, 1.19–1.58] and 1.18 [95% CI, 1.08– 1.30], respectively), in black and nonblack participants with MetS. Higher rates of stroke were seen in black participants only (RR, 1.37 [95% CI, 1.07–1.76] for the lisinopril-chlorthalidone comparison; RR, 1.49 [95% CI, 1.09–2.03] for the doxazosin-chlorthalidone comparison). Black patients with MetS also had higher rates of end-stage renal disease (RR, 1.70 1 [95% CI, 1.13– 2.55]) with lisinopril compared with chlorthalidone.
The ALLHAT findings fail to do not support the preference of for calcium channel blockers, α-blockers, or angiotensin-converting enzyme inhibitors compared with thiazide-type diuretics in patients with the MetS, despite their more favorable metabolic profiles. This was particularly true for black participants.