Chlorthalidone Reduces Cardiovascular Events Compared With Hydrochlorothiazide
A Retrospective Cohort Analysis
There is significant controversy around whether chlorthalidone (CTD) is superior to hydrochlorothiazide (HCTZ) in hypertension management. The objective of this analysis was to evaluate the effects of CTD compared with HCTZ on cardiovascular event (CVE) rates. We performed a retrospective observational cohort study from the Multiple Risk Factor Intervention Trial data set from the National Heart, Lung, and Blood Institute. The Multiple Risk Factor Intervention Trial was a cardiovascular primary prevention trial where participants were men 35 to 57 years of age enrolled and followed beginning in 1973. CVEs were measured yearly, and time to event was assessed by Cox regression. Systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, potassium, glucose, and uric acid were measured yearly. The difference between groups was evaluated by repeated-measures mixed modeling, and each model was adjusted for predictors of each variable. CVEs were significantly lower in those on CTD (adjusted hazard ratio: 0.51 [95% CI: 0.43 to 0.61]; P<0.0001) and on HCTZ (adjusted hazard ratio: 0.65 [95% CI: 0.55 to 0.75]; P<0.0001) compared with those who took neither drug. When comparing the 2 drugs, CTD had significantly fewer CVEs compared with HCTZ (P=0.0016). CTD displayed significantly lower SBP (P<0.0001), lower total cholesterol (P<0.0001), lower low-density lipoprotein cholesterol (P=0.0009), lower potassium (P=0.0003), and higher uric acid (P<0.0001) over time compared with HCTZ. In conclusion, both HCTZ and CTD reduce CVEs compared with neither drug. When comparing both drugs, CTD reduces CVEs more than HCTZ, suggesting that CTD may be the preferred thiazide-type diuretic for hypertension in patients at high risk of CVEs.
See Editorial Commentary, pp 665–666
Thiazide-type diuretics are recommended as a primary choice for the treatment of hypertension.1 In the case of uncomplicated hypertension, without the presence of comorbid conditions that would benefit from another class of antihypertensive drug, the thiazide-type diuretics are considered one of the initial agents to use. If not used as initial therapy, thiazide-type diuretics are recommended as the next agent added to existing therapy, should more aggressive treatment be desired.
Clinicians have several options when prescribing a thiazide-type diuretic. The most commonly prescribed thiazide-type diuretic is hydrochlorothiazide (HCTZ).2 This agent is listed 9 different times as HCTZ or as 1 of 2 agents in a combination drug in the 2008 top 200 drugs prescribed in the United States. Other thiazide-type diuretics include chlorthalidone (CTD), chlorothiazide, metolazone, and indapamide. The choice between HCTZ and CTD for the treatment of hypertension is controversial and has recently been a topic of editorials, meta-analyses, and reviews.3,–,7 CTD may have superior 24-hour blood pressure control compared with HCTZ.8 There are also several studies that demonstrate the efficacy of both CTD and HCTZ,9,–,15 but one recent clinical trial has led some to question the effectiveness of HCTZ.16
The Multiple Risk Factor Intervention Trial (MRFIT) was a large primary prevention trial that began in 1973.17 It was the first study to hint that CTD may be superior to HCTZ. In 1980, the MRFIT Policy Advisory Board changed the hypertension treatment protocol, recommending CTD over HCTZ for initial hypertension therapy.13 This was done because the coronary heart disease (CHD) mortality of special intervention clinics using HCTZ was 44% higher than other clinics (P=0.23). The MRFIT data set provides the opportunity to directly compare HCTZ and CTD, because the documentation of these drugs was done at each follow-up visit. The objective of the current analysis was to evaluate the cardiovascular end points between patients who took HCTZ and CTD. The secondary objective was to compare the change in systolic blood pressure (SBP), total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, potassium, glucose, and uric acid of patients in the 2 groups.
We performed a retrospective observational cohort analysis comparing the clinical effects of CTD with HCTZ. Data for this analysis were collected as part of the MRFIT, which was a randomized cardiovascular primary prevention trial in 12 866 men, 35 to 57 years of age, who were enrolled and followed beginning in 1973. The study tested whether a multifaceted intervention program could reduce mortality from CHD. The specifics of the study have been published previously.17 Briefly, patients were randomized to a special intervention group consisting of treatment for hypertension, smoking cessation counseling, and dietary guidance or to usual care from their healthcare provider with follow-up of 7 years. The hypertension intervention involved a stepped-care approach, which began with HCTZ or CTD at either 50 or 100 mg daily, with weight and sodium reduction. The steps that followed were to add antiadrenergic drug therapy, an arteriolar vasodilator, and then guanethidine in step 4. The goal blood pressure was a diastolic blood pressure of 89 mm Hg or 10-mm Hg less than the average diastolic blood pressure at that visit, whichever is lower. The use of CTD and HCTZ was assessed by interview at each follow-up visit for 7 years, along with many other clinical variables. Our analysis was approved by the University of Michigan Institutional Review Board.
Eligible patients for the MRFIT were in the upper 15% of risk for death from CHD based on risk factors of elevated cholesterol, elevated diastolic blood pressure, and cigarette smoking from the Framingham Heart Study. Patients also could not have had preexisting, definite clinical CHD before entering the study.
The use of CTD or HCTZ was considered first line therapy for the hypertension intervention in the MRFIT. Use of either CTD or HCTZ was documented yearly. It was assumed that if the patient indicated taking the diuretic at the follow-up assessment, they had taken the medication in the year before that visit. This exposure was then used as a time-dependent variable to include all of the follow-up time points in which patients were exposed to either drug. Based on the time-dependent nature of this analysis, an individual patient could cross over from one drug group to the other over time. If a patient reported stopping either drug during the follow-up, then those time points were defined as “stopped drug.” This definition of exposure was undertaken to capture the cross over that is seen in the data set. Figure 1 provides further explanation. For the secondary outcomes, the exposure was defined as those patients who stated adherence to either CTD or HCTZ for 6 of the 7 yearly visits.
The full Outcome Measures section defining each end point is described in the online Data Supplement (please see http://hyper.ahajournals.org). The primary outcome of this analysis was cardiovascular events that were adjudicated and prespecified in the MRFIT data set. Nonfatal events consisted of clinical myocardial infarction (MI), MI determined by annual ECG, stroke, coronary artery bypass surgery, ECG-defined left ventricular hypertrophy, heart failure, angina determined by Rose questionnaire, and peripheral artery occlusive disease. Nonfatal CVEs were documented at the yearly follow-up in the MRFIT data set; the specific dates of each event were not recorded. Cause-specific mortality is based on death certificates coded by trained nosologists using the International Classification of Diseases, 9th Revision. The study personnel adjudicated these cardiovascular deaths to be caused by coronary surgery, congestive heart failure, sudden death, MI, hypertension with renal failure, hypertension with left ventricular failure, stroke, and other cardiovascular disease. Secondary outcomes were the change in SBP, TC, LDL cholesterol, HDL cholesterol, triglyceride, potassium, glucose, and uric acid at each time point of follow-up between CTD and HCTZ.
The primary outcome was the time from first follow-up documenting CTD or HCTZ exposure during the study to the first cardiovascular event. A time-to-event analysis was performed using Cox regression, stratifying by the MRFIT follow-up clinic. The covariates of primary interest were the prescription of CTD, HCTZ, or neither drug, entered in the model as time-dependent covariates. This method allowed us to define exposure at each time point for a specific patient and examine the events when patients were in that exposure time. Models were adjusted for baseline age, race, smoking status, MRFIT randomized group, diuretic dose, SBP, LDL, HDL, and baseline hypertension treatment, which are either known predictors of CVEs or had significant treatment imbalance at baseline. Patients without an event were censored at last follow-up. Secondary analyses were performed to investigate differences in the mean levels of SBP, TC, LDL, HDL, triglyceride, potassium, glucose, and uric acid between those on CTD versus HCTZ over time. Mixed-model analyses controlling for baseline predictors for each variable were used with a random slope and intercept for each patient. Tests for a difference between those on CTD versus HCTZ were performed overall, as well as at each time point. All of the statistical analyses were performed using SAS software version 9.2 (SAS Institute, Inc).
Of the 12 866 patients in the MRFIT, 6441 were initially prescribed either CTD (N=2392) or HCTZ (N=4049) with a median follow-up of 6 years. Seventy-five percent of the initial HCTZ patients and 76% of the initial CTD patients crossed over into either the other drug group or the drug-stopped group. Of the initial HCTZ patients, 29% crossed over into the CTD group, whereas 37% of the initial CTD patients crossed over into the HCTZ group sometime during follow-up. Overall, 46% of the time patients were in the HCTZ group, 32% in the CTD group, and 23% in the stopped-drug group, accounting for 33 614 years of exposure among the 6441 patients. Baseline characteristics of patients based on the initial diuretic are presented in Table 1. There were no statistically significant baseline differences in demographics, cardiovascular risk factors, and metabolic parameters. However, significantly more CTD patients were randomized to the MRFIT intervention than the control and were taking higher doses of a thiazide-type diuretic. The HCTZ group had a significantly greater proportion of patients receiving hypertensive drug therapy at baseline. A total of 1244 cardiovascular events were documented over the 7 years of follow-up.
CVEs were significantly lower in those on CTD (adjusted hazard ratio [aHR]: 0.51 [95% CI: 0.43 to 0.61]; P<0.0001) and on HCTZ (aHR: 0.65 [95% CI: 0.55 to 0.75]; P<0.0001) compared with those on neither drug, adjusting for baseline age, race, smoking status, MRFIT randomized intervention group, diuretic dose, SBP, LDL, HDL, and hypertension treatment. When comparing the 2 drugs, those on CTD had significantly fewer CVEs compared with those on HCTZ (aHR: 0.79 [95% CI: 0.68 to 0.92]; P=0.0016). Figure 2 displays the adjusted event-free probabilities for each group over time for a subject with the covariate values specified in the Figure 2 legend. The adjusted HR for each individual component of the composite primary outcome is represented in Table 2. The individual events that contributed most importantly to the difference between HCTZ and CTD were clinical MI, ECG MI, coronary artery bypass, Rose angina, and peripheral artery occlusive disease. The unadjusted estimates of the individual components of the composite primary outcome are available in the online Data Supplement Table S1 (please see http://hyper.ahajournals.org).
Interactions among the drug variables, the MRFIT intervention groups, and time were tested. The MRFIT intervention significantly altered the effects of the drugs (drug by study intervention interaction P=0.0003). The MRFIT intervention group enhanced the effect of CTD compared with no drug in the intervention group (aHR: 0.47 [95% CI: 0.38 to 0.60]; P<0.0001), and the corresponding effect of HCTZ was similar to the main effects compared with no drug (aHR: 0.67 [95% CI: 0.53 to 0.84]; P=0.0006). Within the MRFIT intervention, those on CTD had fewer events than those on HCTZ, but the difference was not statistically significant (aHR: 0.79 [95% CI: 0.59 to 1.08]; P=0.15). There was also a significant interaction among drug, MRFIT intervention, and time. Over time, the initial hazard reduction seen with both drug groups diminished significantly (HCTZ by time interaction aHR: 1.19 [95% CI: 1.08 to 1.32], P=0.0004; CTD by time interaction aHR: 1.15 [95% CI: 1.03 to 1.27], P=0.01). Those in the MRFIT intervention group receiving CTD had significant reductions in CVE compared with those on neither drug at year 1 (aHR: 0.29 [95% CI: 0.19 to 0.44]; P<0.0001) and 3 (aHR: 0.38 [95% CI: 0.29 to 0.50]; P<0.0001). Those in the MRFIT intervention group receiving HCTZ had significant reductions in CVE compared with those on neither drug at year 1 (aHR: 0.38 [95% CI: 0.26 to 0.56]; P<0.0001) and 3 (aHR: 0.54 [95% CI: 0.42 to 0.70]; P<0.0001).
Differential Effects of CTD Compared With HCTZ
Figure 3 shows each variable over time adjusted for baseline predictors with asterisks delineating the time points that are significantly different between groups. In the longitudinal models comparing CTD with HCTZ over time, CTD patients displayed significantly lower SBP (overall P<0.0001), TC (overall P<0.0001), LDL (overall P=0.0009), and serum potassium (overall P=0.0003) and higher uric acid over time (overall P<0.0001) compared with HCTZ. Glucose over time (overall P=0.1595) and triglyceride over time (overall P=0.2648) did not differ between the groups. The specific values are available in the online Data Supplement Table S2.
Based on a post hoc analysis of a primary prevention study, currently the only study that allows for direct comparison between HCTZ and CTD on cardiovascular outcomes, we were able to demonstrate that CTD significantly reduced CVEs as compared with HCTZ. This finding is analogous to the morality data after a 10.5-year follow-up from MRFIT.13 In March 1980, the CHD mortality of special intervention clinics using HCTZ was 44% higher than other clinics (P=0.23). This led to a change in study protocol to the use of CTD as the thiazide-type diuretic of choice. From April 1980, the rate of CHD mortality in those clinics decreased by 28% (P=0.04, for comparison of percentage difference in mortality in the 2 time points).
The results from our study further enhance the notion that CTD may be the preferred thiazide-type diuretic for treatment of hypertension. Obviously, one question that needs to be addressed is why CTD showed better efficacy in reducing cardiovascular events as compared with HCTZ when both agents work in a pharmacologically similar fashion. Based on our findings, an answer may be that CTD at the doses studied is a more potent antihypertensive agent resulting in greater blood pressure lowering and better outcomes. Recent data in the literature support our findings that CTD appears to lower SBP more than HCTZ.8
Another reason why patients in the CTD group had improved outcomes may relate to metabolic profile of the drugs. When evaluating the metabolic profile, the CTD group had lower LDL and glucose values as compared with the HCTZ group. The lower the LDL levels the greater the chance of reducing cardiovascular events. Similarly, impaired glucose tolerance may also contribute to cardiovascular disease. The trends in glucose values were higher in the HCTZ group compared with the CTD group. The reason for the improved metabolic profile seen in the CTD group is not known. However, more CTD patients were in the study intervention group where lifestyle interventions were performed. We controlled for this intervention within our models, but there may have been residual effects that were not accounted for by that covariate. In contrast to these positive findings, the CTD group had lower potassium levels and higher uric acid levels. The reason for these findings may again relate to the potency of CTD and the doses used in the study. Despite the lower potassium levels and higher uric acid levels, increases in events were not seen in the CTD group. These findings are consistent with a previous MRFIT subgroup analysis in patients with baseline rest ECG abnormalities, suggesting that hypokalemia did not contributed to coronary artery disease mortality rate in the special intervention group at 48 months of follow-up.12
Other reasons for improved outcomes with CTD may relate to differences in pharmacokinetic and pharmacodynamic properties between CTD and HCTZ. With regard to pharmacokinetics, the half-life of CTD (45 to 60 hours) is much longer than the half-life of HCTZ (16 to 24 hours), and CTD has a larger volume of distribution. In addition, CTD is thought to be 1.5 to 2.0 times more potent than HCTZ, with 24-hour ambulatory blood pressure monitoring demonstrating lower blood pressure with CTD during the nighttime hours.8 Furthermore, a recent meta-analysis also suggested that CTD has greater effects on systolic blood pressure reductions as compared with HCTZ.5 Greater systolic blood pressure reductions in concert with more consistent effects over 24 hours with the use of CTD may have contributed to our study findings.
There are inherent limitations in an observational study design, in that we cannot exclude unmeasured confounding, selection bias, and information bias that may have occurred during the study. Unmeasured confounding could exist, because the treating physician determined antihypertensive drug selection, and we could not determine why HCTZ or CTD was chosen as initial therapy or why patients switched from one drug to another. We have attempted to reduce selection bias by comparing the HCTZ and CTD groups in a time-dependent fashion to a time period when people stopped taking either drug; we believe that this gives more strength to the conclusions of this analysis. Another limitation to this analysis is that we could access only the data collected in MRFIT. The nonfatal events were only documented during each yearly follow-up so the exact time of each event is not known. We hope that defining drug exposure for the year before the documented event limits bias for each group studied. Also, data on why patients stopped taking CTD or HCTZ are unavailable and may pose information bias. Despite these limitations, our finding that both the HCTZ and CTD groups have better outcomes as compared with the stopped drug group gives a measure confidence in our approach to the data.
Our study demonstrates that both HCTZ and CTD reduce CVEs compared with neither drug. When comparing both drugs, CTD reduces CVEs more than HCTZ, suggesting that CTD may be the preferred thiazide-type diuretic for hypertension in patients at high risk of cardiovascular events. Prospective randomized, controlled trials are needed to confirm the effects on clinical end points, because this class of medications is so commonly prescribed for hypertension.
Sources of Funding
The MRFIT Study was conducted and supported by the National Institutes of Health/National Heart, Lung, and Blood Institute in collaboration with the MRFIT Study Investigators. This manuscript was prepared using a limited access dataset obtained from the NHLBI and does not necessarily reflect the opinions or views of the MRFIT or the NHLBI.
This article was prepared using a limited access data set obtained from the National Heart, Lung, and Blood Institute and does not necessarily reflect the opinions or views of the MRFIT or the National Heart, Lung, and Blood Institute.
- Received August 18, 2010.
- Revision received September 7, 2010.
- Accepted January 31, 2011.
- © 2011 American Heart Association, Inc.
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