Abstract
Background
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.
Methods
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.
Results
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]).
Conclusions
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.
Introduction
The efficacy of cholesterol-lowering drug therapy in primary and secondary prevention has been firmly established. The combined results of 9 large long-term statin trials (including the ALLHAT-lipid lowering trial (ALLHAT-LLT)) showed a 27% reduction in coronary heart disease (CHD) events and a 14% reduction in all-cause mortality [1–9]. These reductions, however, were average effects of statin therapy for all patients included in the trials. Pharmacogenetic findings suggest that patients may differ in their response to statins because of their genetic constitution [10].
The angiotensin converting enzyme (ACE) is thought to play an important role in the development of coronary artery disease. Plasma and cellular levels of ACE are associated with a large insertion/deletion polymorphism located in intron 16 of the ACE gene. DD carriers have about twice the plasma levels of ACE compared with II carriers, while heterozygotes have intermediate levels [11]. In a meta-analysis including 145 reports with an overall sample size of 49,959, the excess risk in subjects with the DD genotype compared to subjects with the II genotype was 32% for coronary heart disease (30 studies) and 45% for myocardial infarction (20 studies) [12].
Contradictory results have been published on the influence of the ACE I/D polymorphism on the effectiveness of statins. In the Cholesterol And Recurrent Events (CARE) trial no effect was found for the ACE I/D polymorphism alone on the efficacy of pravastatin in reducing the primary endpoint [13]. In the Lipoprotein and Coronary Atherosclerosis (LCAS) study, subjects with the ACE DD genotype had the strongest reduction of coronary atherosclerosis with pravastatin. However, the distribution of clinical events among genotypes was not significantly different [14]. In an observational cohort study among subjects with hypercholesterolemia the beneficial effect of statins on coronary heart disease was different for men with different ACE genotypes. In men with two I alleles, the largest beneficial effects of statins were demonstrated while in men with two D alleles no beneficial effects were demonstrated [15]. The objective of this study was to determine whether the ACE I/D polymorphism interacts with pravastatin to modify the risk of CHD and other cardiovascular endpoints in a large randomized clinical trial of high-risk individuals.
Methods
Study Population and Design
GenHAT is an ancillary study of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The lipid lowering trial (LLT) component of ALLHAT was designed to evaluate the impact of large sustained cholesterol reductions on all-cause mortality in a hypertensive cohort with at least 1 other CHD risk factor and to assess CHD reduction and other benefits in populations that had been excluded or underrepresented in previous trials, particularly older persons, women, racial and ethnic minority groups, and persons with diabetes. A priori secondary outcomes included combination of CHD death [fatal CHD, coronary revascularization related mortality, previous angina or MI and no known potentially lethal non coronary disease process] and non-fatal MI, CVD mortality [mortality due to CHD, stroke, other treated angina, heart failure, peripheral disease], CHD [CHD death, coronary revascularization, hospitalized angina], fatal stroke, other CVD, non-CVD mortality, stroke [fatal and non-fatal] and heart failure. The design of ALLHAT including the LLT, and its participant and clinical site recruitment and selection have been reported elsewhere [9, 16–18]. Briefly, ALLHAT-LLT was a randomized, non-blinded, large simple trial conducted from February 1994 through March 2002 at 513 clinical centers in the United States, Puerto Rico, US Virgin Islands, and Canada. The intervention was open-label pravastatin (40 mg/d) versus usual care. Participants were drawn exclusively from the ALLHAT antihypertensive trial. The protocol of ALLHAT was approved by each participating center’s Institutional Review Board. The GenHAT study was approved by the Institutional Review Boards of the University of Minnesota and The University of Texas Health Science Center at Houston.
Statistical methods
Participants were stratified according to genotype and baseline characteristics were compared using chi-square and t-tests. The efficacy of pravastatin in reducing the risk of the primary outcome (all-cause mortality) and of a-priori secondary outcomes is compared between the genotype strata (II + ID vs DD), using an interaction term in the Cox proportional Hazard model. These analyses were adjusted for potential confounding baseline factors: sex (men/women), race (black/white), current smoking status (yes/no), history of diabetes (yes/no), history of CHD (yes/no), visit 1 systolic blood pressure (mm Hg), and age (years).. Because on our previous finding that the interaction between the ACE I/D polymorphism and effectiveness of statins may be modified by gender [19] a 3-way interaction for gender-ACE genotype-statin therapy was included in the model to compare the interaction between men and women. We also included a three-way interaction for race-ACE genotype-statin therapy in the model to examine whether ethnicity accounted for differences in the pharmacogenetic effect of the ACE ID genotype on the primary and secondary outcomes.
Results
The genotyped population in the lipid lowering arm of ALLHAT included 9,467 participants. Of these 4,741 were in the pravastatin treatment group, and 4,726 were in the usual care group. In Table 1 baseline characteristics according to ACE ID genotype for subjects randomized to pravastatin and subjects in the usual care group are shown.
Table 1.
Baseline characteristics of the pravastatin and usual care subgroups, according to ACE insertion/deletion genotype.
| ACE Genotype |
||||||
|---|---|---|---|---|---|---|
| II | ID | DD | ||||
| Characteristic | Pravastatin | Usual care | Pravastatin | Usual care | Pravastatin | Usual care |
| Sample size | 951 (20.1) | 922 (19.5) | 2376 (50.1) | 2336 (49.4) | 1414 (29.8) | 1468 (31.1) |
| Age | 65.95 (7.5) | 66.13 (7.8) | 66.64 (7.7) | 66.17 (7.4) | 66.32 (7.8) | 66.34 (7.6) |
| Race | ||||||
| White | 551 (57.9) | 567 (61.5) | 1358 (57.2) | 1367 (58.5) | 778 (55.1) | 806 (54.9) |
| Black | 304 (32.0) | 274 (29.7) | 897 (37.8) | 824 (35.3) | 572 (40.4) | 587 (40.0) |
| Other | 96 (10.1) | 81 (8.8) | 121 (5.0) | 145 (6.2) | 64 (4.5) | 75 (5.1) |
| Gender (Male) | 481 (50.6) | 471 (51.1) | 1218 (51.3) | 1185 (50.7) | 735 (52.0) | 747 (50.9) |
| Lipid Meds in last year | 14 (1.5) | 19 (2.1) | 38 (1.6) | 33 (1.4) | 27 (1.9) | 20 (1.4) |
| SBP, mm Hg | 145 (13.9) | 146 (14.2) | 145 (14.1) | 145 (13.9) | 145 (13.7) | 145 (14.1) |
| DBP, mm Hg | 84 (9.7) | 84 (9.9) | 84 (10.0) | 84 (9.7) | 84 (9.6) | 84 (10.0) |
| Smoker | 211 (22.2) | 245 (26.6) | 548 (23.1) | 525 (22.5) | 353 (25.0) | 339 (23.1) |
| History of diabetes | 359 (37.8) | 286 (31.0) | 843 (35.5) | 834 (35.7) | 477 (33.7) | 501 (34.1) |
| History of MI or Stroke | 164 (17.3) | 145 (15.7) | 397 (16.7) | 408 (17.5) | 248 (17.5) | 268 (18.3) |
| History of CHD | 131 (13.8) | 146 (15.8) | 333 (14.0) | 344 (14.7) | 178 (12.6) | 227 (15.5) |
| BMI | 30.1 (6.0) | 29.7 (6.2) | 29.8 (5.9) | 29.9 (6.1) | 29.8 (5.9) | 30.2 (6.2) |
| Total cholesterol | 224.7 (26.2) | 223.1 (26.3) | 223.2 (27.3) | 223.5 (26.3) | 223.5 (26.9) | 223.9 (26.6) |
| HDL cholesterol | 47.0 (13.6) | 46.9 (13.5) | 47.6 (13.4) | 47.2 (13.2) | 47.9 (13.3) | 47.7 (13.9) |
| LDL cholesterol | 145.5 (20.5) | 144.9 (20.9) | 145.2 (21.9) | 145.3 (21.4) | 145.8 (21.1) | 145.5 (21.3) |
| Antihypertensive treatment group | ||||||
| Doxazosin | 180 (18.9) | 194 (21.0) | 497 (20.9) | 508 (21.8) | 316 (22.3) | 309 (21.1) |
| Chlorthalidone | 367 (38.9) | 348 (37.7) | 838 (35.3) | 850 (36.4) | 513 (36.3) | 516 (35.2) |
| Amlodipine | 196 (20.6) | 197 (21.4) | 536 (22.6) | 501 (21.5) | 292 (20.7) | 315 (21.5) |
| Lisinopril | 208 (21.9) | 183 (19.9) | 505 (21.3) | 477 (20.4) | 293 (20.7 | 328 (22.3) |
The proportions and characteristics within each of the three genotypes assigned to each treatment (pravastatin versus usual care) were well balanced. The total number of trial events and the cumulative 6-year Kaplan-Meier event rates of clinical outcomes by ACE genotype and treatment are shown in Table 2. The effects of ACE ID on the clinical outcomes (regardless of pravastatin treatment assignment) can be found in Table 3. Subjects with the ID genotype had a statistically significant lower risk of fatal and nonfatal stroke compared with subjects with the II genotype (HRadj =0.76 [95% CI 0.59–0.99]). This finding was marginally significant for fatal strokes alone (p =0.051).
Table 2.
Total number of trial events and cumulative 6-year Kaplan-Meier risk estimates of clinical outcomes by ACE genotype and lipid treatment group.
| ACE Insertion/Deletion Genotype |
||||||||
|---|---|---|---|---|---|---|---|---|
| ALL |
II |
ID |
DD |
|||||
| Trial Outcome | Prav | UC | Prav | UC | Prav | UC | Prav | UC |
| Sample Size | 4,741 | 4,726 | 951 | 922 | 2,376 | 2,336 | 1,414 | 1,468 |
| All-cause mortality | 584 | 566 | 101 | 108 | 302 | 286 | 181 | 172 |
| 0.1441 | 0.1402 | 0.1328 | 0.1409 | 0.1482 | 0.1460 | 0.1462 | 0.1363 | |
| CVD deaths | 273 | 272 | 45 | 55 | 145 | 139 | 83 | 78 |
| 0.0685 | 0.0670 | 0.0570 | 0.0666 | 0.0732 | 0.0704 | 0.0686 | 0.0617 | |
| CHD | 149 | 150 | 24 | 27 | 82 | 78 | 43 | 45 |
| 0.0371 | 0.0372 | 0.0309 | 0.0314 | 0.0397 | 0.0399 | 0.0377 | 0.0356 | |
| Stroke | 48 | 49 | 9 | 15 | 19 | 17 | 20 | 17 |
| 0.0120 | 0.0127 | 0.0125 | 0.0219 | 0.0088 | 0.0088 | 0.0173 | 0.0139 | |
| Other CVD | 76 | 73 | 12 | 13 | 44 | 44 | 20 | 16 |
| 0.0208 | 0.0184 | 0.0145 | 0.0149 | 0.0263 | 0.0232 | 0.0151 | 0.0134 | |
| Non-CVD mortality | 277 | 259 | 50 | 46 | 141 | 131 | 86 | 82 |
| 0.0711 | 0.0694 | 0.0684 | 0.0693 | 0.0719 | 0.0709 | 0.0720 | 0.0719 | |
| Fatal CHD and nonfatal MI | 349 | 392 | 61 | 70 | 172 | 198 | 116 | 124 |
| 0.0904 | 0.1031 | 0.0830 | 0.0921 | 0.0864 | 0.1063 | 0.1032 | 0.1032 | |
| Fatal and nonfatal stroke | 192 | 212 | 38 | 50 | 84 | 90 | 70 | 72 |
| 0.0552 | 0.0510 | 0.0537 | 0.0727 | 0.0469 | 0.0449 | 0.0593 | 0.0615 | |
| Heart failure (hospitalized or fatal) | 229 | 232 | 40 | 50 | 128 | 107 | 61 | 75 |
| 0.0604 | 0.0616 | 0.0541 | 0.0650 | 0.0677 | 0.0555 | 0.0505 | 0.0678 | |
ACE = Angiotensin converting enzyme; Prav = pravastatin; UC = usual care; CVD = cardiovascular disease; CHD= coronary heart disease; MI = myocardial infarction.
Table 3.
Unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CI) of the ID and DD genotypes relative to the II genotype for combined randomized groups.
| II | ID | DD | |||
|---|---|---|---|---|---|
| reference | HR (unadjusted) 95% CI | HR (adjusted)1 95% CI | HR (unadjusted) 95% CI | HR (adjusted) 1 95% CI | |
| All Cause Mortality | 1 | 1.12 (0.96, 1.31) | 1.11 (0.94, 1.29) | 1.09 (0.91, 1.29) | 1.08 (0.91, 1.29) |
| CVD mortality | 1 | 1.13 (0.90, 1.42) | 1.12 (0.89, 1.41) | 1.04 (0.81, 1.33) | 1.03 (0.80, 1.33) |
| CHD | 1 | 1.25 (0.91, 1.71) | 1.25 (0.91, 1.71) | 1.11 (0.79, 1.57) | 1.10 (0.78, 1.56) |
| Stroke | 1 | 0.59 (0.35, 1.00) | 0.59 † (0.35, 0.99) | 1.00 (0.60, 1.67) | 0.96 (0.57, 1.61) |
| Other CVD | 1 | 1.40 (0.90, 2.19) | 1.36 (0.87, 2.13) | 0.93 (0.56, 1.56) | 0.95 (0.57, 1.58) |
| Non-CVD mortality | 1 | 1.13 (0.89, 1.42) | 1.11 (0.88, 1.40) | 1.13 (0.88, 1.45) | 1.14 (0.88, 1.46) |
| Fatal CHD and nonfatal MI | 1 | 1.13 (0.92, 1.38) | 1.14 (0.93, 1.39) | 1.19 (0.96, 1.48) | 1.20 (0.97, 1.49) |
| Stroke (fatal and nonfatal) | 1 | 0.78 (0.61, 1.01) | 0.76 ‡ (0.59, 0.98) | 1.04 (0.80, 1.36) | 1.00 (0.76, 1.31) |
| Heart Failure (hospitalized or fatal) | 1 | 1.04 (0.81, 1.32) | 1.03 (0.81, 1.31) | 0.98 (0.75, 1.27) | 0.98 (0.75, 1.28) |
Adjusted for treatment group (pravastatin/usual care), sex (male/female), race (black/white), and eight baseline variables: current smoking status (yes/no), history of diabetes (yes/no), history of CHD (yes/no), systolic blood pressure level (mm Hg), and age (years).
p = 0.047
p = 0.038
Hazard ratios of the effect of statin use are shown, by genotype, in Table 4. Three-way analyses of the ACE I/D genotypes, treatment and primary clinical outcome (all-cause mortality) identified no differences in efficacy of pravastatin between subjects with the II and DD genotype (interaction hazard ratio 0.81 [95% CI 0.58–1.14] p=0.31), or between subjects with the ID and DD genotype (interaction hazard ratio 0.90 [95% CI 0.69–1.17] p=0.42) (Table 4). The secondary endpoints were consistent with these negative findings. No significant gene drug interactions were found. We evaluated gene-drug interactions in relation to the primary and secondary outcomes in subgroups based on gender and on race. There were no apparent gene-treatment interactions across gender-gene-drug or race-gene-drug subgroups (data not shown).
Table 4.
Adjusted hazard ratios (HRadj) and 95% confidence limits of the effect of pravastatin versus usual care on study outcomes, according to II, ID, and DD genotype strata. In addition, the adjusted interaction hazard ratios 1 (IHRadj) of the II versus the DD genotype and the ID versus DD genotype are given. The interaction hazard ratio estimates for a given outcome were obtained from respective Cox proportional hazards models incorporating treatment, genotype (II/DD and ID/DD), treatment by genotype interactions, and seven baseline covariates.
| HRadj (95% CI) | HRadj (95% CI) | HRadj(95% CI) | IHRadj (95% CI) | IHRadj (95% CI) | |
|---|---|---|---|---|---|
| Trial Outcome | II | ID | DD | II vs DD, p-value2 | ID vs DD, p-value2 |
| All-Cause Mortality | 0.90 (0.68, 1.18) | 0.99 (0.84, 1.16) | 1.09 (0.89, 1.35) | 0.81 (0.58, 1.14), 0.23 | 0.90 (0.69, 1.17), 0.42 |
| CVD Mortality | 0.79 (0.53, 1.18) | 0.98 (0.78, 1.24) | 1.10 (0.81, 1.50) | 0.70 (0.42, 1.15), 0.16 | 0.87 (0.59, 1.29), 0.49 |
| CHD | 0.84 (0.48, 1.46) | 1.00 (0.73, 1.37) | 1.01 (0.66, 1.53) | 0.82 (0.41, 1.64), 0.58 | 0.98 (0.58, 1.65), 0.94 |
| Fatal Stroke | 0.60 (0.26, 1.39) | 1.02 (0.53, 1.97) | 1.22 (0.64, 2.33) | 0.47 (0.16, 1.34), 0.16 | 0.83 (0.33, 2.10), 0.70 |
| Other CVD | 0.93 (0.42, 2.05) | 0.91 (0.60, 1.39) | 1.22 (0.63, 2.36) | 0.71 (0.26, 1.99), 0.52 | 0.71 (0.33, 1.55), 0.39 |
| Non-CVD Mortality | 1.04 (0.69, 1.55) | 1.00 (0.79, 1.27) | 1.09 (0.81, 1.48) | 0.95 (0.58, 1.57), 0.85 | 0.92 (0.63, 1.35), 0.67 |
| Fatal CHD and nonfatal MI | 0.84 (0.59, 1.18) | 0.84 (0.68, 1.03) | 0.99 (0.77, 1.27) | 0.84 (0.55, 1.29), 0.43 | 0.85 (0.61, 1.17), 0.31 |
| Stroke (fatal and nonfatal) | 0.73 (0.48, 1.11) | 0.88 (0.66, 1.19) | 1.03 (0.74, 1.43) | 0.69 (0.41, 1.19), 0.18 | 0.86 (0.55, 1.35), 0.52 |
| Heart Failure (hospitalized or fatal) | 0.75 (0.50, 1.14) | 1.15 (0.89, 1.48) | 0.85 (0.61, 1.20) | 0.87 (0.51, 1.49), 0.61 | 1.32 (0.86, 2.02), 0.20 |
Adjusted for differences in sex (male/female), race (black/white), and five baseline variables: current smoking status (yes/no), history of diabetes (yes/no), history of CHD (yes/no), systolic blood pressure level (mm Hg), age (years).
The interaction hazard ratio is a ratio of ratios: Prav/UC for II stratum over Prav/UC for DD stratum, and similarly for ID versus DD.
Test of null hypothesis: IHRadj = 1.0.
Discussion
The GenHAT-LLT study is a large pharmacogenetic trial of pravastatin versus usual care. Based on genotype data collected from almost 10,000 individuals, who were followed for cardiovascular events using standard, well-defined definitions for cardiovascular outcomes, we found no compelling evidence that ACE I/D genotype is a major determinant of the efficacy of pravastatin in reducing the risk of cardiovascular events. We did not find any significant interactions in the response to therapy, despite the large number of tests performed. We did observe that participants with the II and ID genotypes tended to fare better on pravastatin than usual care for most of the outcomes examined, while the opposite was true for the DD participants. The IIvs DD and the ID vs DD interaction hazards ratios were below 1.00 for all outcomes except heart failure, ranging from 0.47 for fatal strokes (II vs DD) to 0.98 for CHD (ID vs DD). This is in concordance with what would be expected based on a previous study [15].
The GenHAT study selected individuals based on pre-existing coronary risk factors and hypertension. Therefore there is some uncertainty about the applicability of the findings of this study to the association in subjects without these risk factors.
In the ALLHAT study no overall beneficial effect of pravastatin was demonstrated on the primary outcome. After 6 years of follow-up 26% of subjects in the usual care arm used statins, and 16% in the pravastatin arm did not use a lipid lowering drug anymore. There was no significant differential in crossovers among ACE genotypes, and therefore would not affect the interaction between pravastatin and the ACE polymorphism.
Our finding that the ACE I/D polymorphism did not modify the efficacy of statins were in concordance with three studies [13, 14, 19]. Results were different from the results of the Rotterdam study that found a significant interaction in men [15]. Even though no statistically significant interaction was found in GenHAT, there was a trend towards better efficacy in the subjects with the II and ID genotype compared with the DD genotype. For example, subjects with the ID genotype tended to fare better on pravastatin than usual care for fatal CHD and nonfatal MI (HRadj 0.84 [95% CI 0.68–1.03]), while there was no effect of pravastatin in subjects with the DD genotype (adjusted HR 0.99 [95% CI 0.77–1.27]). This result is similar to the findings in the Rotterdam study. However, we did not find evidence that there were differences in efficacy between men and women as was found in the Rotterdam Study. The physiological role of the renin-angiotensin system varies with sodium intake, age and disease status [20]. Since this trial included high risk hypertensives, while the Rotterdam cohort study included a hypercholesterolemic subset of the general population, this might be an explanation for the different findings in men. A strength of the GenHAT study, however, is that it was performed in a large clinical trial with reasonable event rates in both subjects randomized to pravastatin and in subjects randomized to usual care. Furthermore since only the I/D polymorphism was studied an effect of other polymorphisms in the ACE gene on pravastatin cannot be ruled out. These pharmacogenetic analyses of the ALLHAT-LLT in combination with results from earlier studies provide no rationale for using ACE I/D genotype to guide decisions about treatment with pravastatin. Since there was a trend towards less efficacy in subjects with the DD genotype, more research in larger settings, possibly combinations of different trials/cohort studies, is necessary.
Footnotes
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