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Previous Volume 330:1852-1857 June 30, 1994 Number 26 Next

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ABSTRACT

Background The results of trials of the primary prevention of coronary heart disease have suggested that treating hypertension with high doses of thiazide diuretic drugs might increase the risk of sudden death from cardiac causes. In contrast, treatment with low doses of thiazide reduces the risk of coronary heart disease.

Methods To examine the association between thiazide treatment for hypertension and the occurrence of primary cardiac arrest, we conducted a population-based case-control study among enrollees of a health maintenance organization. The case patients were 114 persons with hypertension who had a primary cardiac arrest from 1977 through 1990. The control patients were a stratified random sample of 535 persons with hypertension. The patients' treatment was assessed with the use of a computerized pharmacy data base. Records of their ambulatory care were reviewed to determine other clinical characteristics.

Results The risk of primary cardiac arrest among patients receiving combined thiazide and potassium-sparing diuretic therapy was lower than that among patients treated with a thiazide without potassium-sparing therapy (odds ratio, 0.3; 95 percent confidence interval, 0.1 to 0.7). As compared with low-dose thiazide therapy (25 mg daily), moderate-dose therapy (50 mg daily) was associated with a moderate increase in risk (odds ratio, 1.7; 95 percent confidence interval, 0.7 to 4.5), and high-dose therapy (100 mg daily) was associated with a larger increase in risk (odds ratio, 3.6; 95 percent confidence interval, 1.2 to 10.8) (P value for trend, 0.02). The addition of a potassium-sparing drug to low-dose thiazide therapy was associated with a reduced risk of cardiac arrest (odds ratio, 0.4; 95 percent confidence interval, 0.1 to 1.5).

Conclusions Both the dose of thiazide drugs and the addition of potassium-sparing drugs influence the risk of primary cardiac arrest. These results may explain the differences in the effect of antihypertensive therapy on mortality from coronary heart disease in previous clinical trials.

The dose-related metabolic effects of thiazides, including hypokalemia and hypomagnesemia, are plausible biologic mechanisms for an increased risk of sudden cardiac death among hypertensive patients treated with these drugs^{10,11,12,13,14,15,16,17,18}. Treatment with lower doses of a thiazide or with a thiazide combined with a potassium-sparing drug reduces the renal wasting of potassium and magnesium associated with thiazide therapy. No clinical trial has compared different doses of thiazide or the use of thiazide with and without potassium-sparing drugs in terms of major end points of disease. To examine these questions, we conducted a population-based case-control study to assess the association between thiazide treatment for hypertension and the risk of primary cardiac arrest, also known as sudden cardiac death.

Methods

Study Setting and Design

We conducted a population-based case-control study among patients with hypertension who received their medical care at the Group Health Cooperative of Puget Sound, a health maintenance organization (HMO) with an enrollment of more than 350,000 people, 80 percent of whom live in King County, Washington. The HMO maintains a separate medical record of ambulatory care for each enrollee. The HMO's computerized pharmacy data base includes all prescriptions filled for enrollees since March 1977. Previous surveys suggested that 98 percent of all prescriptions for enrollees were filled at pharmacies included in the data base.

Selection of Case and Control Patients

We sought to identify all incident cases of out-of-hospital primary cardiac arrest occurring among HMO enrollees who were treated for hypertension during a 14-year period from 1977 through 1990. Primary cardiac arrest was defined as a sudden pulseless condition in the absence of a known noncardiac condition as the cause of cardiac arrest¹⁹.

The case patients were identified from two sources: the computerized files of the emergency medical service in Seattle and suburban King County and the Washington State death-registry files²⁰. Each of these files was compared with the HMO enrollment files to identify potential case patients. We then compared the list of potential case patients with the HMO computerized pharmacy files to identify those who had received a prescription for any antihypertensive drug in the year before the event. The index date for each case patient was the date of the cardiac arrest.

The control patients were also treated for hypertension. They were selected at random from the pharmacy data base and frequency-matched to the case patients according to age (in decades), sex, and calendar year of treatment. Each control patient was assigned an index date, chosen at random from the distribution of index dates among the case patients.

We excluded case and control patients who were less than 30 or more than 79 years old, as well as nonresidents of King County. From a review of the medical record, we also excluded patients with prior clinically recognized heart disease or other life-threatening conditions, such as end-stage renal disease, liver disease, lung disease, and cancer. Each patient was enrolled in the HMO for at least one year or had four or more visits for ambulatory care. We also confirmed from the medical records that the indication for treatment with the drug or drugs of interest was hypertension and that the patient was receiving treatment on the index date. Finally, since data on pretreatment blood pressures were needed to control for potential confounding by indication related to the severity of hypertension, we excluded approximately one third of the treated patients with hypertension who were already taking drugs for hypertension at the time of their enrollment in the HMO. Our final analysis is based on 114 case patients and 535 control patients. Analyses based on the entire group of patients differed only slightly from those presented here.

Measurement of Exposures

We used the computerized pharmacy data base to assess treatment with antihypertensive drugs²¹. The classes of antihypertensive drugs (and the specific drugs) listed in the HMO formulary during the study period were as follows: thiazide diuretics (hydrochlorothiazide and chlorthalidone), combined thiazide and potassium-sparing diuretics (hydrochlorothiazide and triamterene or spironolactone), -adrenergic-antagonist drugs (propranolol, metoprolol, nadolol, and atenolol), calcium-channel-blocking drugs (nifedipine, diltiazem, and verapamil), angiotensin-converting-enzyme inhibitors (captopril, enalapril, and lisinopril), vasodilators (hydralazine), -adrenergic-antagonist drugs (prazosin), and other drugs (methyldopa, reserpine, and clonidine).

From the pharmacy data base, we estimated whether a patient had received enough of a given drug (a sufficient number of pills) to have been treated with that drug at a specific dose on the index date²¹. In a similar fashion, we defined the exposure status of the case and control patients 30, 60, 90, 120, 150, and 180 days before their index dates. Information from the data base on the total number of pills dispensed in relation to the dosing schedule and on the total number of days of treatment was used to estimate long-term compliance with a specific antihypertensive drug therapy.

We also used the data base to determine the number and timing of prescriptions for potassium supplements. A patient who had a prescription filled for a potassium supplement within three months of the index date was classified as currently taking potassium supplements.

Medical records of ambulatory care were reviewed for all case and control patients to assess potential confounding factors before the index date, including age, sex, pretreatment blood pressure and heart rate, the duration of treatment for hypertension, weight, height, current smoking status, diabetes mellitus, coexisting conditions, marital status, employment, the number of clinic visits in the previous year, and serum electrolyte concentrations. We also reviewed copies of electrocardiograms (ECGs) obtained before the index date. ECGs were available for 78 percent of the case patients and 75 percent of the control patients. ECG abnormalities were interpreted at the Epicore Research Center (University of Alberta) in terms of the Minnesota Code,²² and the Cardiac Infarction Injury Score was computed²³.

Statistical Analysis

We used unconditional logistic-regression analysis to estimate the risk of primary cardiac arrest associated with treatment with antihypertensive drugs. Preliminary models suggested that the relation of hydrochlorothiazide and chlorthalidone therapy to primary cardiac arrest was similar, so these two drugs were combined (assuming dose equivalence) into a single category. To reduce potential confounding by indication, separate analyses were conducted among patients treated with single-drug and multiple-drug antihypertensive therapy. Because data on current smoking status were missing for 16 percent of the case patients and 12 percent of the control patients, we also assessed the effect of missing data on covariates through the approach of multiple imputation²⁴; the missing data had little effect on the findings.

Results

As compared with the control patients, the case patients with primary cardiac arrest were slightly older and more likely to be men, had higher systolic blood pressures and heart rates before treatment, had been treated for hypertension for a longer time, and were more likely to be current smokers or to have diabetes mellitus (Table 1). The proportion who were treated with a single drug for hypertension and the mean number of clinic visits during the year before the index date were similar for the case patients and the control patients.

View this table: [in this window] [in a new window]   Table 1. Risk Factors for Primary Cardiac Arrest among the Case and Control Patients Treated with Drugs for Hypertension.

 
As compared with treatment with a thiazide without a potassium-sparing drug, combined treatment with a thiazide and a potassium-sparing diuretic agent was associated with a reduced risk of primary cardiac arrest (odds ratio, 0.3; 95 percent confidence interval, 0.1 to 0.7 for patients treated with single or multiple drugs), after adjustment for age, sex, pretreatment systolic blood pressure and heart rate, duration of treatment, current smoking, and diabetes (Table 2). The reduction in risk was similar among patients treated with a single antihypertensive drug. In contrast to therapy with potassium-sparing agents, the addition of potassium supplements to a thiazide had little effect on the risk of primary cardiac arrest (odds ratio, 0.9; 95 percent confidence interval, 0.4 to 2.1). Further adjustment for other factors, including calendar year of treatment, compliance, number of clinic visits, employment, marital status, weight, height, and Cardiac Infarction Injury Score, had no effect on the results.

View this table: [in this window] [in a new window]   Table 2. Thiazide Diuretic Therapy and the Risk of Primary Cardiac Arrest in Patients with Hypertension, According to the Number of Antihypertensive Drugs.

 
There was little evidence of a significant modification of the effect by age, sex, ECG abnormalities, or current smoking (Figure 1). In each subgroup, the risk of primary cardiac arrest associated with combined therapy was lower than the risk associated with thiazide therapy without a potassium-sparing drug, although the 95 percent confidence limits for several of these estimates included 1.

View larger version (12K): [in this window] [in a new window]   Figure 1. Risk of Primary Cardiac Arrest Associated with Combined Thiazide and Potassium-Sparing Diuretic Therapy, as Compared with Thiazide without Potassium-Sparing Therapy, among Patients Treated with Single or Multiple Antihypertensive Drugs, According to Age, Sex, Electrocardiographic (ECG) Abnormalities, and Cigarette-Smoking Status. The odds ratios were adjusted for age, sex, pretreatment systolic blood pressure and heart rate, duration of hypertension, current smoking, and diabetes mellitus, when appropriate. CI denotes confidence interval.

 
We studied the use of thiazide therapy regardless of the use of potassium supplementation to examine the relation between the daily dose of thiazide and the risk of cardiac arrest (Table 3). As compared with a low dose of thiazide (25 mg) and after adjustment for potential confounding variables, treatment with a moderate dose of thiazide (50 mg) was associated with a moderate increase in the risk of cardiac arrest (odds ratio, 1.7; 95 percent confidence interval, 0.7 to 4.5), and treatment with a high dose of thiazide (100 mg) was associated with a larger increase in risk (odds ratio, 3.6; 95 percent confidence interval, 1.2 to 10.8) among patients treated with single or multiple antihypertensive drugs (P = 0.02 by the chi-square test for trend). The dose-response findings were similar for patients treated with single-drug therapy.

View this table: [in this window] [in a new window]   Table 3. Daily Dose of Thiazide Therapy and the Risk of Primary Cardiac Arrest in Patients with Hypertension, According to the Number of Antihypertensive Drugs.

 
We also examined the risk of cardiac arrest associated with both the thiazide dose and the addition of a potassium-sparing agent to thiazide therapy (Table 4). As compared with a low dose of thiazide (25 mg), combined therapy with thiazide (25 mg) and a potassium-sparing diuretic agent was associated with a reduced risk of cardiac arrest (odds ratio, 0.4; 95 percent confidence interval, 0.1 to 1.5) among patients treated with single or multiple antihypertensive drugs. Similarly, as compared with a moderate dose of thiazide (50 mg), combined therapy with thiazide (50 mg) and a potassium-sparing diuretic agent was associated with a reduced risk of cardiac arrest (odds ratio, 0.5; 95 percent confidence interval, 0.2 to 1.4). As compared with moderate-dose (50 mg) and high-dose (100 mg) thiazide therapy, combined therapy with thiazide (25 mg) and a potassium-sparing diuretic agent was associated with a larger reduction in the risk of cardiac arrest.

View this table: [in this window] [in a new window]   Table 4. Combined Therapy with Thiazide and a Potassium-Sparing Diuretic, as Compared with Thiazide without Potassium-Sparing Therapy, and the Risk of Primary Cardiac Arrest in Patients with Hypertension, According to the Number of Antihypertensive Drugs.

 
There was little evidence that reductions in either diastolic blood pressure or the serum potassium level, as determined in the last measurements obtained before the index date, accounted for the differences in the risk of cardiac arrest associated with the type and dose of thiazide.

In the analysis of the risk of cardiac arrest associated with thiazide therapy, we also used -adrenergic-antagonist drugs as the reference category. Among patients receiving only one antihypertensive drug, thiazide therapy overall was not associated with a higher risk of cardiac arrest than treatment with -adrenergic-antagonist drugs (odds ratio, 1.0; 95 percent confidence interval, 0.4 to 2.4). However, the pattern of the reduction in risk among hypertensive patients treated with low doses of thiazide or the addition of a potassium-sparing drug was similar when patients treated with -adrenergic-antagonist drugs were used as the reference group (Figure 2). After adjustment for potential confounders, combined therapy with thiazide (25 mg) and a potassium-sparing diuretic agent was associated with an estimated relative risk of 0.3 (95 percent confidence interval, 0.1 to 1.0), as compared with -adrenergic-antagonist therapy.

View larger version (12K): [in this window] [in a new window]   Figure 2. Risk of Primary Cardiac Arrest Associated with Thiazide Therapy with and without Potassium-Sparing Diuretic Therapy, as Compared with Beta-Adrenergic-Antagonist Drug Therapy, among Patients Treated with Single Antihypertensive Drugs. The odds ratios were adjusted for age, sex, pretreatment systolic blood pressure and heart rate, duration of hypertension, current smoking, and diabetes mellitus. Eleven case patients and 47 control patients were treated with a -adrenergic-antagonist drug alone. CI denotes confidence interval.

 
We compared the risks of cardiac arrest associated with specific medicines, using alternative definitions of exposure. For each category of antihypertensive drug, estimates of risk based on treatment 30, 60, 90, 120, 150, and 180 days before the index date were similar to those for treatment on the index date. In short, there was little evidence that the risk estimates were biased by recent changes in antihypertensive therapy among case patients who may have had prodromal symptoms before their cardiac arrest.

Discussion

Studies of the safety of commonly used medicines are subject to confounding by the indication for the specific drug therapy. We sought to minimize the potential for such confounding in the design and analysis of our study. We excluded hypertensive patients with known heart disease, since such disease might have influenced both the choice of antihypertensive therapy and the risk of cardiac arrest. We also examined the effects of thiazide drugs separately among patients treated for hypertension with a single drug and those treated with multiple drugs, as well as the potential effect of recent changes in antihypertensive therapy.

We were not able to determine directly whether the case and control patients were taking the prescribed drugs. However, we found the expected associations between treatment with a thiazide and a lower serum potassium concentration and treatment with a -adrenergic-antagonist drug and a lower resting heart rate (data not shown). Furthermore, among the case and control patients treated with thiazide and a potassium-sparing drug combined, serum potassium concentrations were higher than among those treated with a thiazide without potassium-sparing therapy.

The addition of a potassium supplement had little effect on the risk of cardiac arrest associated with thiazide therapy. Potential explanations for this finding include the lack of efficacy of potassium supplements,¹⁵ poor compliance (25 percent of the patients for whom a potassium supplement was prescribed in the preceding year filled only one prescription), and limited statistical power to evaluate the effect of such supplements. Treatment with higher doses of a thiazide was also slightly more common among the patients who were also treated with potassium.

Our results suggest that the addition of a potassium-sparing agent to a thiazide lowers the risk associated with diuretic therapy. This finding was true even at low doses of thiazide, although the precision of our estimates at such doses was limited. The absorption of a thiazide is reduced by more than half when it is combined with a potassium-sparing diuretic drug^25,26,27. The reduction in risk associated with combined therapy may in fact reflect an extension of the dose-response relation observed among patients treated with a thiazide, rather than an effect of adding a potassium-sparing drug. Whether adverse metabolic effects occur in patients treated with low doses of a thiazide and, if so, whether the addition of a potassium-sparing drug mitigates these effects are unknown.

We examined several potential mechanisms that might explain our results^27,28,29. There was little evidence that excessive reduction of diastolic blood pressure accounted for the differences in the risk of cardiac arrest. Low serum potassium concentrations before the index date were associated with an increased risk of cardiac arrest (data not shown). However, differences in serum potassium concentrations did not explain the results. Serum magnesium was not measured. In other studies, both the type and dose of thiazide influenced serum magnesium concentrations,^15,16 which are related to the occurrence of life-threatening ventricular arrhythmias in patients with acute ischemic heart disease³⁰.

Our finding of a dose-response relation between thiazide therapy and the risk of cardiac arrest may explain the results of previous clinical trials^5,6,7,8,9. An adverse effect of a high dose of thiazide in regard to cardiac arrest may have offset the potential benefits of blood-pressure reduction on mortality from coronary heart disease in early trials of treatment for hypertension and in the Multiple Risk Factor Intervention Trial¹. Moreover, the use of low doses of thiazide or a potassium-sparing drug in recent trials of hypertension treatment may account for the beneficial effect of diuretic therapy on mortality from coronary heart disease^7,8,9.

Our findings related to the addition of a potassium-sparing drug to a thiazide may also explain differences in the outcomes of several recent trials^7,8. In one trial,⁸ combined therapy with a low-dose thiazide and a potassium-sparing diuretic agent reduced the occurrence of sudden death (relative risk, 0.3; 95 percent confidence interval, 0.1 to 1.1). In contrast, another study⁷ found that low-dose thiazide treatment without a potassium-sparing drug was not associated with a reduced risk of sudden cardiac death (relative risk, 1.00; 95 percent confidence interval, 0.6 to 1.8). In the recent Medical Research Council trial,⁹ combined therapy with a low-dose thiazide and a potassium-sparing diuretic reduced mortality from coronary heart disease by 40 percent, as compared with a reduction of 5 percent among patients treated with a -adrenergic-antagonist drug.

We could not assess the cardiac safety of the newer classes of antihypertensive agents, such as calcium-channel-blocking drugs and angiotensin-converting-enzyme inhibitors, because these drugs were not widely used to treat hypertension at the HMO during the study period. In the absence of direct evidence about the risk of cardiac arrest or coronary events associated with newer drugs, claims about the relative safety and efficacy of newer agents as compared with low-dose thiazide therapy remain unsubstantiated.

Recently, the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommended therapy with a low-dose thiazide diuretic agent and a -adrenergic-antagonist drug as the initial drug therapy for patients with hypertension³¹. Our findings and those of recent clinical trials^7,8,9 support the recommendation to treat hypertension with low doses of a thiazide. They also suggest that combined therapy with a low-dose thiazide and a potassium-sparing diuretic may further reduce mortality from coronary heart disease among patients with hypertension.

Supported by a grant (HL42456-03) from the National Heart, Lung, and Blood Institute.

We are indebted to Noel S. Weiss, M.D., Dr.P.H., for his suggestions; to Mary Wikel Chauncey, Mary Sunderland, Jean Yee, Yu Shen, Linda Page, Gene Hart, Peter Pretkel, Richard Schaadt, Esther Normand, Mary Pat Larson, and Carol Fahrenbruch for their help with this project; and to the Seattle Medic One Program and the Seattle-King County Health Department Emergency Medical Services Division for their cooperation.

Source Information

From the Cardiovascular Health Research Unit, the Departments of Medicine (D.S.S., B.M.P., T.D.K., K.G.W., L.C., M.K.C.), Epidemiology (D.S.S., B.M.P., T.D.K.), Biostatistics (T.E.R., X.L.), and Health Services (B.M.P., T.D.K., E.H.W.), University of Washington, Seattle; the Epicore Centre, Division of Cardiology, University of Alberta, Edmonton, Alta., Canada (P.M.R.); and the Center for Health Studies, Group Health Cooperative of Puget Sound, Seattle (E.H.W.). Presented in part at the 33rd annual scientific meeting of the Council on Epidemiology and Prevention of the American Heart Association, Sante Fe, N.M., March 18, 1993.

Address reprint requests to Dr. Siscovick at the Cardiovascular Health Research Unit, Metropolitan Park 2 Bldg., Suite 1360, 1730 Minor Ave., Seattle, WA 98101.

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Related Letters:

Diuretic Therapy and the Risk of Cardiac Arrest
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