Diuretics, -Blockers, and the Risk for Sudden Cardiac Death in Hypertensive Patients

The efficacy of diuretics, particularly thiazides, in hypertensive patients has been assessed in many randomized, controlled trials since the early 1970s. These trials have provided clear evidence that diuretics reduce the incidence of fatal and nonfatal stroke [1]. In contrast, the effect of these drugs on the development of coronary heart disease has been less than expected [2]. This has led to much speculation on potentially fatal adverse effects of non-potassium-sparing diuretics. Findings from the Multiple Risk Factor Intervention Trial indicating that non-potassium-sparing diuretics may increase the risk for sudden cardiac death in hypertensive patients [3] have been presented as evidence for fatal complications related to diuretic use [4]. However, this view has been challenged by others [5]. Diuretic-induced hypokalemia or hypomagnesemia leading to cardiac arrhythmias has been proposed as the mechanism underlying the putative association between non-potassium-sparing diuretics and sudden death [6]. -Blockers have been reported to decrease the risk for sudden cardiac death [7, 8], but evidence from the Medical Research Council trial in older hypertensive patients suggests that -blockers could be ineffective in preventing coronary events in these patients [9]. Moreover, in a recent study of patients with hypertension [10], -blocker use was associated with an increased risk for sudden death. We did a casecontrol study among patients receiving drug therapy for hypertension to determine whether recipients of non-potassium-sparing diuretics have an increased risk for sudden cardiac death. We also assessed the risk for sudden death among persons receiving -blockers. Methods Case-Patients and Controls Eligible case-patients were all residents of Rotterdam, the Netherlands, with a sudden cardiac death between 21 November 1988 and 21 November 1990 who had been receiving drug therapy for hypertension on the date of death. Sudden death was defined as death occurring within 1 hour of the onset of symptoms or as unwitnessed death [11, 12]. The death was considered to be of cardiac origin unless, according to the attending physician, evidence from hospital or autopsy records suggested a noncardiac cause [13]. The age- and sex-matched controls were also receiving drug treatment for hypertension on the day the corresponding case-patient died but were alive on that date. The study was approved by the ethics committee of the Academic Hospital Dijkzigt/Erasmus University, Rotterdam. Selection of Case-Patients and Controls For 2 years, municipal authorities prospectively provided information on all persons aged 20 years or older who died in Rotterdam. The physicians who signed the death certificate were mailed a questionnaire comprising three brief questions on the period between the onset of symptoms and the occurrence of death, the possibility of a noncardiac cause, and the name and address of the patient's general practitioner. If the patient met the criteria for sudden cardiac death, the general practitioner was asked by mailed questionnaire whether the patient was receiving antihypertensive medication on the date of death and, if so, whether hypertension was the indication for the prescription and not another condition such as congestive heart failure or arrhythmias. We sent a questionnaire to physicians of 10 649 patients who were reported to have died of natural causes during the study period. A total of 8314 questionnaires was returned (a response rate of 78%), and 7834 (74%) contained adequate information on the circumstances of death. Responding physicians reported 1847 deaths as sudden cardiac deaths; 272 (15%) of these patients were receiving drugs for hypertension on the date of death. Fifteen patients (5%) were excluded because general practitioners refused to cooperate or because evidence of antihypertensive drug treatment on the date of death was missing from the files. Thus, we identified 257 cases of sudden cardiac death. When a case-patient was identified, a general practitioner practicing in Rotterdam was randomly selected and visited at his or her office. The first patient of the same sex as and born within 2.5 years of the birth of the corresponding case-patient was selected from the alphabetically ordered patient registry. The general practitioner was subsequently asked the same questions asked of the case-patient's general practitioner on the use of antihypertensive medication and whether hypertension was the indication for treatment. The first randomly selected patient who met the criteria was selected as the control. Ascertainment of the Use of Antihypertensive Medications All information on case-patients and controls, available at the general practitioner's office, was thoroughly examined by one of the investigators (AWH). This information was obtained from patient charts, correspondence from medical specialists, laboratory results, and electrocardiograms. Only printed or handwritten (that is, reproducible) information was used. From these sources, the specific antihypertensive medication use on the index date (the day the case-patient died), the duration of use, and the dosage were assessed. We first categorized the prescribed antihypertensive medication into three groups: non-potassium-sparing diuretics (predominantly hydrochlorothiazide, chlorthalidone, and furosemide) regardless of concomitant use of -blockers; -blockers (predominantly atenolol and metoprolol) regardless of concomitant use of non-potassium-sparing diuretics; and antihypertensive medication without either non-potassium-sparing diuretics or -blockers. The latter category served as the reference group. We chose this categorization to assess the risk for sudden death among persons receiving non-potassium-sparing diuretics or -blockers, regardless of the concomitant use of the other antihypertensive drugs. We also decided in advance to categorize the antihypertensive medication into four mutually exclusive medication groups: 1) non-potassium-sparing diuretic therapy without -blocking agents; 2) -blocking agents without non-potassium-sparing diuretic therapy; 3) non-potassium-sparing diuretics and -blockers used concomitantly; and 4) antihypertensive medication without either non-potassium-sparing diuretics or -blockers. Accordingly, category 4 included antihypertensive drugs that have not been recommended for first-choice therapy in most published national guidelines on hypertension therapy [14, 15]. In all analyses, this category was the reference group, and it primarily included potassium-sparing diuretics (used by 65% of the patients in this group), calcium antagonists, and angiotensin-converting enzyme inhibitors. The concomitant use of a non-potassium-sparing diuretic and either a potassium-sparing diuretic or an angiotensin-converting enzyme inhibitor was considered to be a potassium-sparing combination and was thus placed in category 4. Assessment of Comparability of Patient Groups Given the nonexperimental approach taken in this study, it was important to ascertain that patients who died suddenly had not received non-potassium-sparing diuretics or -blockers for medical reasons that eventually led to their death. We had to determine whether clinical variables were present, such as indications or contraindications, that were related both to the use of non-potassium-sparing diuretics or -blockers and to the patient's propensity to sudden cardiac death. We obtained data on the following potential confounders from the general practitioners' records: 1. History of cardiovascular disease, including previous myocardial infarction, heart failure, angina pectoris, stroke, intermittent claudication, atrial fibrillation, and other cardiac arrhythmias (tachycardia, bradycardia, and atrioventricular blocks). These diseases were considered to be present when the diagnosis was explicitly mentioned in the patient file. 2. Cardiovascular risk indicators, including smoking habits, last available plasma cholesterol concentration, body weight, and left ventricular hypertrophy (measured by electrocardiography). 3. Use of digitalis. 4. Comorbid conditions, such as diabetes mellitus (that is, a diagnosis of diabetes recorded in the patient file), kidney dysfunction (the last measured serum creatinine level more than 100 mol/L), and chronic obstructive pulmonary disease (categorized into two groups: a diagnosis of asthma, chronic bronchitis, or emphysema without current use of pulmonary medication and current use of -agonists, oral corticosteroids, or theophylline). We also recorded information on the severity of hypertension, including blood pressure at the initiation of therapy, the mean pressure during the last 5 years, the last available blood pressure, and the number of antihypertensive drugs currently used. Validation of Data Collection Because investigators could not be blinded to the vital status of the patient when collecting the data, efforts were made to check the validity of the data collection. First, the use of antihypertensive and concomitant medications on the index date as collected from the general practitioner's files was compared with data obtained from computerized pharmacy databases. For logistic reasons, medication histories from pharmacies were available for 28% of the case-patients and for 46% of the controls. These different proportions primarily resulted from the fact that persons enrolled in the mandatory collective insurance (most of the Rotterdam population) are usually deleted from the computerized pharmacy databases within 1 to 2 months of their death. We found only a few discrepancies between the findings recorded in the general practitioner's office and the pharmacy data. To further check the validity of the data collected from the patient files, a physician who was unaware of the specific research question and was blinded to the vital status of the patient reexamined the files of a random sample of 10% of both t