Original Article
Diuretic Therapy for Hypertension and the Risk of Primary Cardiac Arrest
N Engl J Med 1994; 330:1852-1857June 30, 1994
- 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.
Media in This Article
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.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.Article Activity
- Article
Unexpected findings from the Multiple Risk Factor Intervention Trial, a trial of the primary prevention of coronary heart disease, suggested that treating hypertension with high doses of thiazide diuretic drugs might increase the risk of sudden death from cardiac causes1-4. Meta-analyses of clinical trials evaluating the treatment of hypertensive patients with high doses of a thiazide suggest a reduction of 8 to 12 percent in mortality from coronary heart disease -- substantially less than the reduction of 20 to 25 percent predicted in epidemiologic studies5,6. In recent clinical trials, in contrast, the treatment of hypertensive patients with lower doses of thiazide drugs was associated with reductions of 20 to 25 percent in mortality from coronary heart disease7-9.
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 drugs10-18. 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), β-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), α-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 1Table 1
Risk Factors for Primary Cardiac Arrest among the Case and Control Patients Treated with Drugs for Hypertension.). 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.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 2Table 2
Thiazide Diuretic Therapy and the Risk of Primary Cardiac Arrest in Patients with Hypertension, According to the Number of Antihypertensive Drugs.). 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.There was little evidence of a significant modification of the effect by age, sex, ECG abnormalities, or current smoking (Figure 1Figure 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.). 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.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 3Table 3
Daily Dose of Thiazide Therapy and the Risk of Primary Cardiac Arrest in Patients with Hypertension, According to the Number of Antihypertensive Drugs.). 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.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 4Table 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.). 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.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 β-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 β-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 β-adrenergic-antagonist drugs were used as the reference group (Figure 2Figure 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.). 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 β-adrenergic-antagonist therapy.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 β-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 drug25-27. 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 results27-29. 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 trials5-9. 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 disease7-9.
Our findings related to the addition of a potassium-sparing drug to a thiazide may also explain differences in the outcomes of several recent trials7,8. 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 β-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 β-adrenergic-antagonist drug as the initial drug therapy for patients with hypertension31. Our findings and those of recent clinical trials7-9 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.
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.
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.).
Address reprint requests to Dr. Siscovick at the Cardiovascular Health Research Unit, Metropolitan Park 2 Bldg., Suite 1360, 1730 Minor Ave., Seattle, WA 98101.
- References
References
1
Multiple Risk Factor Intervention Trial Research Group
CrossRef | Web of Science2
Multiple Risk Factor Intervention Trial Research Group
CrossRef | Web of Science | Medline3
Kuller LH ,Hulley SB ,Cohen JD ,Neaton J . Unexpected effects of treating hypertension in men with electrocardiographic abnormalities: a critical analysis. Circulation 1986;73:114-123
CrossRef | Web of Science | Medline4
Kuller L ,Farrier N ,Caggiula A ,Borhani N ,Dunkle S . Relationship of diuretic therapy and serum magnesium levels among participants in the Multiple Risk Factor Intervention Trial. Am J Epidemiol 1985;122:1045-1059
Web of Science | Medline5
MacMahon SW ,Cutler JA ,Furberg CD ,Payne GH . The effects of drug treatment for hypertension on morbidity and mortality from cardiovascular disease: a review of randomized controlled trials. Prog Cardiovasc Dis 1986;29:Suppl 1:99-118
CrossRef | Web of Science | Medline6
Collins R ,Peto R ,MacMahon S , et al. Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiologic context. Lancet 1990;335:827-838
CrossRef | Web of Science | Medline7
SHEP Cooperative Research Group
CrossRef | Web of Science8
Dahlof B ,Lindholm LH ,Hansson L ,Schersten B ,Ekbom T ,Wester P-O . Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991;338:1281-1285
CrossRef | Web of Science | Medline9
MRC Working PartyMedical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992;304:405-412
CrossRef | Web of Science10
Elmfeldt D ,Berglund G ,Wedel H ,Wilhelmsen L . Incidence and importance of metabolic side-effects during antihypertensive therapy. Acta Med Scand Suppl 1983;672:79-83
Medline11
Medical Research Council Working Party on Mild to Moderate Hypertension
CrossRef | Web of Science12
Fisch CH . Relation of electrolyte disturbances to cardiac arrhythmias. Circulation 1973;47:408-419
Web of Science | Medline13
Carlsen JE ,Kober L ,Torp-Pedersen C ,Johansen P . Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. BMJ 1990;300:975-978
CrossRef | Web of Science | Medline14
Dorup I ,Skajaa K ,Clausen T ,Kjeldsen K . Reduced concentrations of potassium, magnesium, and sodium-potassium pumps in human skeletal muscle during treatment with diuretics. BMJ 1988;296:455-458
CrossRef | Web of Science | Medline15
Siegel D ,Hulley SB ,Black DM , et al. Diuretics, serum and intracellular electrolyte levels, and ventricular arrhythmias in hypertensive men. JAMA 1992;267:1083-1089
CrossRef | Web of Science | Medline16
Hollifield JW . Potassium and magnesium abnormalities: diuretics and arrhythmias in hypertension. Am J Med 1984;77:Suppl 5A:28-32
CrossRef | Web of Science | Medline17
Hollifield JW . Electrolyte disarray and cardiovascular disease. Am J Cardiol 1989;63:21B-26B
CrossRef | Web of Science | Medline18
Martin BJ ,Milligan K . Diuretic-associated hypomagnesemia in the elderly. Arch Intern Med 1987;147:1768-1771
CrossRef | Web of Science | Medline19
Nomenclature and criteria for diagnosis of ischemic heart disease: Report of the Joint International Society and Federation of Cardiology/World Health Organization Task Force on Standardization of Clinical Nomenclature
Web of Science | Medline20
Siscovick DS . Challenges in cardiac arrest research: data collection to assess outcomes. Ann Emerg Med 1993;22:92-98
CrossRef | Web of Science | Medline21
Psaty BM ,Koepsell TD ,LoGerfo JP ,Wagner EH ,Inui TS . β-Blockers and primary prevention of coronary heart disease in patients with high blood pressure. JAMA 1989;261:2087-2094
CrossRef | Web of Science | Medline22
Blackburn H ,Keys A ,Simonson E ,Rautaharju P ,Punsar S . The electrocardiogram in population studies: a classification system. Circulation 1960;21:1160-1175
Web of Science | Medline23
Rautaharju PM ,Warren JW ,Jain U ,Wolf HK ,Nielsen CL . Cardiac infarction injury score: an electrocardiographic coding scheme for ischemic heart disease. Circulation 1981;64:249-256
CrossRef | Web of Science | Medline24
Little RJ, Rubin DB. Statistical analysis with missing data. New York: John Wiley, 1987.
25
Spence JD ,Wong DG ,Lindsay RM . Effects of triamterene and amiloride on urinary sediment in hypertensive patients taking hydrochlorothiazide. Lancet 1985;2:73-75
CrossRef | Web of Science | Medline26
Widmann L ,Dyckner T ,Wester P-O . Effects of triamterene on serum and skeletal muscle electrolytes in diuretic-treated patients. Eur J Clin Pharmacol 1988;33:577-579
CrossRef | Web of Science | Medline27
Andersson P-O ,H-Andersen H ,Hagman A ,Henning R . Potassium sparing by amiloride during thiazide therapy in hypertension. Clin Pharmacol Ther 1984;36:197-200
CrossRef | Web of Science | Medline28
Farnett L ,Mulrow CD ,Linn WD ,Lucey CR ,Tuley MR . The J-curve phenomenon and the treatment of hypertension: is there a point beyond which pressure reduction is dangerous? JAMA 1991;265:489-495
CrossRef | Web of Science | Medline29
McCloskey LW ,Psaty BM ,Koepsell TD ,Aagaard GN . Level of blood pressure and risk of myocardial infarction among treated hypertensive patients. Arch Intern Med 1992;152:513-520
CrossRef | Web of Science | Medline30
Dyckner T . Serum magnesium in acute myocardial infarction: relation to arrhythmias. Acta Med Scand 1980;207:59-66
CrossRef | Web of Science | Medline31
The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V)
CrossRef | Web of Science | Medline
- Citing Articles (98)
Citing Articles
1
Clive Rosendorff. (2011) Why Are We Still Using Hydrochlorothiazide?. The Journal of Clinical Hypertensionno-no
CrossRef2
Cooper, William O., Habel, Laurel A., Sox, Colin M., Chan, K. Arnold, Arbogast, Patrick G., Cheetham, T. Craig, Murray, Katherine T., Quinn, Virginia P., Stein, C. Michael, Callahan, S. Todd, Fireman, Bruce H., Fish, Frank A., Kirshner, Howard S., O'Duffy, Anne, Connell, Frederick A., Ray, Wayne A., . (2011) ADHD Drugs and Serious Cardiovascular Events in Children and Young Adults. New England Journal of Medicine 365:20, 1896-1904
Full Text3
Biff F. Palmer. (2011) Metabolic Complications Associated With Use of Diuretics. Seminars in Nephrology 31:6, 542-552
CrossRef4
Franz H. Messerli, Sripal Bangalore. (2011) Half a Century of Hydrochlorothiazide: Facts, Fads, Fiction, and Follies. The American Journal of Medicine 124:10, 896-899
CrossRef5
Won Ho Kim, Jong Hwan Lee, Justin Sangwook Ko, Tae Soo Hahm, Sangmin M. Lee, Hyun Sung Cho. (2011) The effect of patient-controlled intravenous analgesia on postoperative hypokalemia in patients undergoing laparoscopic cholecystectomy. Journal of Anesthesia 25:5, 685-691
CrossRef6
Firas J. Al Badarin, Mohammad A. Abuannadi, Carl J. Lavie, James H. O'Keefe. (2011) Evidence-Based Diuretic Therapy for Improving Cardiovascular Prognosis in Systemic Hypertension. The American Journal of Cardiology 107:8, 1178-1184
CrossRef7
Alan H. Gradman, Jan N. Basile, Barry L. Carter, George L. Bakris, . (2011) Combination Therapy in Hypertension. The Journal of Clinical Hypertension 13:3, 146-154
CrossRef8
Richard E. Katholi, Daniel M. Couri. (2011) Left Ventricular Hypertrophy: Major Risk Factor in Patients with Hypertension: Update and Practical Clinical Applications. International Journal of Hypertension 2011, 1-10
CrossRef9
Oleg E. Osadchii. (2010) Mechanisms of hypokalemia-induced ventricular arrhythmogenicity. Fundamental & Clinical Pharmacology 24:5, 547-559
CrossRef10
C. Nordin. (2010) The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence. Diabetologia 53:8, 1552-1561
CrossRef11
Philip A. Kithas, Mark A. Supiano. (2010) Spironolactone and Hydrochlorothiazide Decrease Vascular Stiffness and Blood Pressure in Geriatric Hypertension. Journal of the American Geriatrics Society 58:7, 1327-1332
CrossRef12
Cecilia P. Chung, Katherine T. Murray, C. Michael Stein, Kathi Hall, Wayne A. Ray. (2010) A computer case definition for sudden cardiac death. Pharmacoepidemiology and Drug Safety 19:6, 563-572
CrossRef13
Daniel Mines. (2010) Commentary on the validation studies of sudden cardiac death and ventricular arrhythmia by Hennessy et al. and Chung et al.. Pharmacoepidemiology and Drug Safety 19:6, 573-575
CrossRef14
O. James Ekundayo, Chris Adamopoulos, Mustafa I. Ahmed, Bertram Pitt, James B. Young, Jerome L. Fleg, Thomas E. Love, Xuemei Sui, Gilbert J. Perry, David S. Siscovick, George Bakris, Ali Ahmed. (2010) Oral potassium supplement use and outcomes in chronic heart failure: A propensity-matched study. International Journal of Cardiology 141:2, 167-174
CrossRef15
Sverre E. Kjeldsen, Roland E. Schmieder, Thomas Unger, Giuseppe Mancia. (2010) Telmisartan and hydrochlorothiazide combination therapy for the treatment of hypertension. Current Medical Research and Opinion 26:4, 879-887
CrossRef16
J Blacher, A Evans, D Arveiler, P Amouyel, J Ferrières, A Bingham, J Yarnell, B Haas, M Montaye, J-B Ruidavets, P Ducimetière. (2010) Residual cardiovascular risk in treated hypertension and hyperlipidaemia: the PRIME Study. Journal of Human Hypertension 24:1, 19-26
CrossRef17
Kimberly M. Neff, James J. Nawarskas. (2010) Hydrochlorothiazide Versus Chlorthalidone in the Management of Hypertension. Cardiology in Review 18:1, 51-56
CrossRef18
Roland E Schmieder, Thomas Philipp, Javier Guerediaga, Manuel Gorostidi, Christopher Bush, Deborah L Keefe. (2009) Aliskiren-based therapy lowers blood pressure more effectively than hydrochlorothiazide-based therapy in obese patients with hypertension: sub-analysis of a 52-week, randomized, double-blind trial. Journal of Hypertension 27:7, 1493-1501
CrossRef19
Min Bokyung, C. Michael White. (2009) A Review of Critical Differences Among Loop, Thiazide, and Thiazide-Like Diuretics. Hospital Pharmacy 44:2, 129-149
CrossRef20
Ray, Wayne A., Chung, Cecilia P., Murray, Katherine T., Hall, Kathi, Stein, C. Michael, . (2009) Atypical Antipsychotic Drugs and the Risk of Sudden Cardiac Death. New England Journal of Medicine 360:3, 225-235
Full Text21
Naoki NAGO. (2009) Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics 40:3, 117S-118S
CrossRef22
Arshad Khuroo, Sanjeev Mishra, Onkar Singh, Saurabh Saxena, Tausif Monif. (2008) Simultaneous Determination of Atenolol and Chlorthalidone by LC–MS–MS in Human Plasma. Chromatographia 68:9-10, 721-729
CrossRef23
Claudio Ferri, Paolo Pasqualetti, Sergio Tiberti, Davide Grassi. (2008) Electrophysiological effects of short-term antihypertensive therapy. Expert Review of Cardiovascular Therapy 6:10, 1343-1346
CrossRef24
Sirirat Reungjui, Thongchai Pratipanawatr, Richard J Johnson, Takahiko Nakagawa. (2008) Do thiazides worsen metabolic syndrome and renal disease? The pivotal roles for hyperuricemia and hypokalemia. Current Opinion in Nephrology and Hypertension 17:5, 470-476
CrossRef25
Patricia R. Hebert, Christopher S. Coffey, Daniel W. Byrne, Theresa A. Scott, Robert H. Fagard, Jeffrey N. Rottman, Katherine T. Murray, John A. Oates. (2008) Treatment of elderly hypertensive patients with epithelial sodium channel inhibitors combined with a thiazide diuretic reduces coronary mortality and sudden cardiac death. Journal of the American Society of Hypertension 2:5, 355-365.e2
CrossRef26
Feng J. He, Graham A. MacGregor. (2008) Beneficial effects of potassium on human health. Physiologia Plantarum 133:4, 725-735
CrossRef27
K-H Yiu, H-F Tse. (2008) Hypertension and cardiac arrhythmias: a review of the epidemiology, pathophysiology and clinical implications. Journal of Human Hypertension 22:6, 380-388
CrossRef28
Jean-Jacques Mourad, Nicolas Danchin, Jacques Puel, Hervé Gallois, Jérôme Msihid, Michel E. Safar, Hirofumi Tanaka. (2008) Cardiovascular impact of exercise and drug therapy in older hypertensives with coronary heart disease: PREHACOR study. Heart and Vessels 23:1, 20-25
CrossRef29
Andrew Hall, Hamish Dobbie, Giovambattista Capasso, Robert Unwin. 2008. Diuretics and β-Blockers. , 591-600.
CrossRef30
Barry L Carter, Domenic A Sica. (2007) Strategies to improve the cardiovascular risk profile of thiazide-type diuretics as used in the management of hypertension. Expert Opinion on Drug Safety 6:5, 583-594
CrossRef31
W. Zidek. (2007) Behandlung der arteriellen Hypertonie. Der Internist 48:6, 613-624
CrossRef32
Poorna R. Karuparthi, Preethi Yerram, Guido Lastra, Melvin R. Hayden, James R. Sowers. (2007) Understanding essential hypertension from the perspective of the cardiometabolic syndrome. Journal of the American Society of Hypertension 1:2, 120-134
CrossRef33
Anne Miternique-Grosse, Christophe Griffon, Luz Siegel, Agnès Neuville, Denis Weltin, Dominique Stephan. (2006) Antiangiogenic effects of spironolactone and other potassium-sparing diuretics in human umbilical vein endothelial cells and in fibrin gel chambers implanted in rats. Journal of Hypertension 24:11, 2207-2213
CrossRef34
Steen Neldam. (2006) Telmisartan/hydrochlorothiazide in the treatment of hypertension. Aging Health 2:3, 395-408
CrossRef35
2006. Diuretics. , 1152-1169.
CrossRef36
Domenic A. Sica. (2006) Antihypertensive Therapy and Its Effects on Potassium Homeostasis. The Journal of Clinical Hypertension 8:1, 67-73
CrossRef37
Michio FUKUDA, Genjiro KIMURA. (2006) Pathophysiology of Antihypertensive Therapy with Diuretics. Hypertension Research 29:9, 645-653
CrossRef38
Franz H. Messerli, Ehud Grossman. (2005) Therapeutic Controversies in Hypertension. Seminars in Nephrology 25:4, 227-235
CrossRef39
Ariel J. Reyes, William P. Leary, Giuseppe Crippa, Mário F.C. Maranhão, Rafael Hernández-Hernández. (2005) The aldosterone antagonist and facultative diuretic eplerenone: A critical review. European Journal of Internal Medicine 16:3, 145-153
CrossRef40
Robert A. Phillips. (2005) Diuretics Should Continue to Be One of the Preferred Initial Therapies in the Management of Hypertension. The Journal of Clinical Hypertension 7:2, 111-116
CrossRef41
Steven G. Coca, Mark A. Perazella, Gregory K. Buller. (2005) The cardiovascular implications of hypokalemia. American Journal of Kidney Diseases 45:2, 233-247
CrossRef42
Martin von Planta. (2005) Scientific Basis of Cardio-Pulmonary Resuscitation, an Evidence-Based Review. Heart Drug 5:4, 205-213
CrossRef43
Roland E Schmieder. (2004) Telmisartan/hydrochlorothiazide combination therapy in the treatment of essential hypertension. Expert Opinion on Pharmacotherapy 5:11, 2303-2310
CrossRef44
Ray, Wayne A., Murray, Katherine T., Meredith, Sarah, Narasimhulu, Sukumar Suguna, Hall, Kathi, Stein, C. Michael, . (2004) Oral Erythromycin and the Risk of Sudden Death from Cardiac Causes. New England Journal of Medicine 351:11, 1089-1096
Full Text45
Domenic A. Sica. (2004) Diuretic-Related Side Effects: Development and Treatment. The Journal of Clinical Hypertension 6:9, 532-540
CrossRef46
Lionel H Opie, R Schall. (2004) Old antihypertensives and new diabetes. Journal of Hypertension 22:8, 1453-1458
CrossRef47
John L Lin, Doris Armour. (2004) Selected medical management of the older rehabilitative patient. Archives of Physical Medicine and Rehabilitation 85, 76-82
CrossRef48
Fadi A. El-Atat, Samy I. McFarlane, James R. Sowers, J. Thomas Bigger. (2004) Sudden cardiac death in patients with diabetes. Current Diabetes Reports 4:3, 187-193
CrossRef49
(2004) References. American Journal of Kidney Diseases 43, 268-290
CrossRef50
Marvin Moser, John Setaro. (2004) Continued importance of diuretics and β-adrenergic blockers in the management of hypertension. Medical Clinics of North America 88:1, 167-187
CrossRef51
John E. Macdonald, Allan D. Struthers. (2004) What is the optimal serum potassium level in cardiovascular patients?. Journal of the American College of Cardiology 43:2, 155-161
CrossRef52
Giuseppe Mancia, Guido Grassi. (2004) The Hypertension Guidelines of the Seventh Joint National Committee. High Blood Pressure & Cardiovascular Prevention 11:2, 55-59
CrossRef53
Munemichi INABA, Yuichi NOGUCHI, Taro YAMAMOTO, Tomihiko IMAI, Masako HATANO, Shinji YAGI, Shigehiro KATAYAMA. (2004) Effects of a Low Dose of Indapamide, a Diuretic, Given Daily or Every-Other-Day on Blood Pressure and Metabolic Parameters. Hypertension Research 27:3, 141-145
CrossRef54
Bernard Waeber. (2003) Trials in isolated systolic hypertension: An update. Current Cardiology Reports 5:6, 427-434
CrossRef55
Renke Maas, Rainer H Böger. (2003) Antihypertensive therapy: special focus on drug interactions. Expert Opinion on Drug Safety 2:6, 549-579
CrossRef56
Bernard Waeber. (2003) Trials in isolated systolic hypertension: An update. Current Hypertension Reports 5:4, 329-336
CrossRef57
Care California Healthcare FoundationAme. (2003) Guidelines for Improving the Care of the Older Person with Diabetes Mellitus. Journal of the American Geriatrics Society 51:5s, 265-280
CrossRef58
Flávio D Fuchs. (2003) Diuretics: drugs of choice for the initial management of patients with hypertension. Expert Review of Cardiovascular Therapy 1:1, 35-41
CrossRef59
M Galinier, A Pathak, V Fallouh, C Baixas, L Schmutz, J Roncalli, S Boveda, J.M Fauvel. (2002) Intérêt du holter ECG dans la surveillance de la cardiopathie hypertensive. Annales de Cardiologie et d'Angéiologie 51:6, 336-340
CrossRef60
Lwin Lwin Tin, D. Gareth Beevers, Gregory Y. H. Lip. (2002) Hypertension, left ventricular hypertrophy, and sudden death. Current Cardiology Reports 4:6, 449-457
CrossRef61
Alan H. Gradman, Celso Acevedo. (2002) Evolving strategies for the use of combination therapy in hypertension. Current Hypertension Reports 4:5, 343-349
CrossRef62
EDWARD D. FROHLICH. (2002) Clinical Management of the Obese Hypertensive Patient. Cardiology in Review 10:3, 127-138
CrossRef63
Domenic A. Sica. (2002) Rationale for Fixed-Dose Combinations in the Treatment of Hypertension. Drugs 62:3, 443-462
CrossRef64
Prakash C Deedwania, Yangheng Fu. (2001) Pharmacotherapy of hypertension in patients with diabetes mellitus. Expert Opinion on Pharmacotherapy 2:11, 1805-1816
CrossRef65
D.George Wyse, Peter L Friedman, Michael A Brodsky, Karen J Beckman, Mark D Carlson, Anne B Curtis, Alfred P Hallstrom, Merritt H Raitt, Bruce L Wilkoff, H.Leon Greene. (2001) Life-threatening ventricular arrhythmias due to transient or correctable causes: high risk for death in follow-up. Journal of the American College of Cardiology 38:6, 1718-1724
CrossRef66
Hillel W. Cohen, Shantha Madhavan, Michael H. Alderman. (2001) High and low serum potassium associated with cardiovascular events in diuretic-treated patients. Journal of Hypertension 19:7, 1315-1323
CrossRef67
Edward D. Frohlich. (2001) Hypertension. Current Treatment Options in Cardiovascular Medicine 3:4, 333-345
CrossRef68
John I.S. Robertson. (2001) A critique of hypertension treatment trials and of their evaluation. Journal of Evaluation in Clinical Practice 7:2, 149-164
CrossRef69
Pitt O. Lim, William F. Young, Thomas M. MacDonald. (2001) A review of the medical treatment of primary aldosteronism. Journal of Hypertension 19:3, 353-361
CrossRef70
Jing Fang, Shantha Madhavan, Hillel Cohen, Michael H. Alderman. (2000) Serum Potassium and Cardiovascular Mortality. Journal of General Internal Medicine 15:12, 885-890
CrossRef71
Akihiko Hirata, Masahiko Igarashi, Hiroshi Yamaguchi, Akira Suwabe, Makoto Daimon, Takeo Kato, Makoto Tominaga. (2000) Nifedipine suppresses neointimal thickening by its inhibitory effect on vascular smooth muscle cell growth via a MEK-ERK pathway coupling with Pyk2. British Journal of Pharmacology 131:8, 1521-1530
CrossRef72
(2000) Part 6: Advanced Cardiovascular Life Support. Resuscitation 46:1-3, 127-134
CrossRef73
Morris J Brown, Christopher R Palmer, Alain Castaigne, Peter W de Leeuw, Giuseppe Mancia, Talma Rosenthal, Luis M Ruilope. (2000) Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). The Lancet 356:9227, 366-372
CrossRef74
Asim Hameedi, Hal L. Chadow. (2000) The promise of selective aldosterone receptor antagonists for the treatment of hypertension and congestive heart failure. Current Hypertension Reports 2:4, 378-383
CrossRef75
Norman M. Kaplan. (2000) Diuretics as a Basis of Antihypertensive Therapy. Drugs 59:Supplement 2, 21-25
CrossRef76
Arthur Greenberg. (2000) Diuretic Complications. The American Journal of the Medical Sciences 319:1, 10
CrossRef77
Jules B. Puschett. (2000) Diuretics and the Therapy of Hypertension. The American Journal of the Medical Sciences 319:1, 1
CrossRef78
Kishore J. Harjai, Homeyar K. Dinshaw, Eduardo Nunez, Mehul Shah, Hilary Thompson, Tansel Turgut, Hector O. Ventura. (1999) The prognostic implications of outpatient diuretic dose in heart failure. International Journal of Cardiology 71:3, 219-225
CrossRef79
Edward D Frohlich. (1999) The necessity for recognition and treatment of patients with “mild” hypertension. Journal of the American College of Cardiology 34:5, 1369-1377
CrossRef80
Michael J. Domanski, Derek V. Exner, Craig B. Borkowf, Nancy L. Geller, Yves Rosenberg, Marc A. Pfeffer. (1999) Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. Journal of the American College of Cardiology 33:3, 598-604
CrossRef81
(1999) 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. Journal of Hypertension 17:2, 151???183
CrossRef82
Lawrence E. Ramsay. (1999) Thiazide Diuretics in Hypertension. Clinical and Experimental Hypertension 21:5-6, 805-814
CrossRef83
Suzanne Oparil. (1999) Long-Term Morbidity and Mortality Trials with Amlodipine. Journal of Cardiovascular Pharmacology 33, S1-S6
CrossRef84
(1999) 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. Clinical and Experimental Hypertension 21:5-6, 1009-1060
CrossRef85
Briegeen Girvin, G Dennis Johnston. (1998) A randomized comparison of a conventional dose, a low dose and alternate-day dosing of bendrofluazide in hypertensive patients. Journal of Hypertension 16:7, 1049-1054
CrossRef86
John A Delyani. (1998) Anti-aldosterone therapy in the treatment of heart failure: new thoughts on an old hormone. Expert Opinion on Investigational Drugs 7:5, 753-759
CrossRef87
Narayan, Man IN'T Veld. (1998) Clinical pharmacology of modern antihypertensive agents and their interaction with alpha-adrenoceptor antagonists. BJU International 81:S1, 6-16
CrossRef88
Michel Galinier, Serban Balanescu, Joelle Fourcade, Maria Dorobantu, Serge Boveda, Pierre Massabuau, Philippe Cabrol, Bruno Dongay, Jean M. Fauvel, Jean P. Bounhoure. (1997) Prognostic value of ventricular arrhythmias in systemic hypertension. Journal of Hypertension 15:12, 1779-1783
CrossRef89
John F. Steiner, Allan V. Prochazka. (1997) The assessment of refill compliance using pharmacy records: Methods, validity, and applications. Journal of Clinical Epidemiology 50:1, 105-116
CrossRef90
Frans H. H. Leenen. (1996) 1,4-Dihydropyridines versus beta-blockers for hypertension: Are either safe for the heart?. Cardiovascular Drugs and Therapy 10:4, 397-402
CrossRef91
Lionel H. Opie. (1996) Calcium channel antagonists should be among the first-line drugs in the management of cardiovascular disease. Cardiovascular Drugs and Therapy 10:4, 455-461
CrossRef92
Franz H. Messerli. (1996) Whatever happened to the calcium antagonist controversy?. Journal of the American College of Cardiology 28:1, 12-13
CrossRef93
David S. Siscovick, T. E. Raghunathan, Bruce M. Psaty, Thomas D. Koepsell, Leonard Cobb, Pentti M. Rautaharju, Edward H. Wagner. (1996) Diastolic blood pressure and the risk of primary cardiac arrest among pharmacologically treated hypertensive patients. Journal of General Internal Medicine 11:6, 350-356
CrossRef94
A. W. Hoes, D. E. Grobbee. (1996) Diuretics and Risk of Sudden Death in Hypertension — Evidence and Potential Implications. Clinical and Experimental Hypertension 18:3-4, 523-535
CrossRef95
Peter Trenkwalder, Michael Plaschke, Richard Aulehner, Helmut Lydtin. (1996) Felodipine or Hydrochlorothiazide/Triamterene for Treatment of Hypertension in the Elderly: Effects on Blood Pressure, Hypertensive Heart Disease, Metabolic and Hormonal Parameters. Blood Pressure 5:3, 154-163
CrossRef96
Ron M.C. Herings, Bruno H.C. Stricker, Anthonius de Boer, Albert Bakker, Ferd Sturmans, Andy Stergachis. (1996) Current use of thiazide diuretics and prevention of femur fractures. Journal of Clinical Epidemiology 49:1, 115-119
CrossRef97
(1994) Diuretic Therapy and the Risk of Cardiac Arrest. New England Journal of Medicine 331:18, 1235-1236
Full Text98
Bigger, J. Thomas Jr., . (1994) Diuretic Therapy, Hypertension, and Cardiac Arrest. New England Journal of Medicine 330:26, 1899-1900
Full Text
- Letters
