LINICAL HARMACOLOGY HERAPEUTICS | ‘TH! 39 NUMBER 3 MARCH 1986 COMMENTARY The cardiovascular risks of thiazide diuretics Edward D. Freis, M.D. Washington, D. C. It is not surprising that a discipline as rapidly growing and changing as the management of hypertension should engender a number of controversies. These dis- agreements may have considerable medical, economic, and public health impact simply because there are so many millions of patients with hypertension involved. The purpose of this discussion is to present what some would consider controversial points of view concerning the safety of thiazide diuretics. DOSE, VOLUME CHANGE, AND BLOOD PRESSURE REDUCTION WITH DIURETICS There is a close association between volume reduc- tion and the antihypertensive response to diuretics. Chlorothiazide causes a fall of approximately 10% in extracellular volume and 15% in plasma volume,'? which incidentally is the same as the reduction asso- ciated with severe dietary restriction of sodium.*“ The reduction in extracellular fluid volume is re- From the Veterans Administration Medical Center and the George- town University Medical Center. Submitted for publication Aug. 5, 1985; accepted Oct. 22, 1985. Reprint requests to: Edward D. Freis, M.D., Senior Medical Inves- tigator, Hypertension Research (151E), Veterans Administration Medical Center, 50 Irving St. N.W., Washington, DC 20422. flected in a loss of body weight of approximately | to 2 kg.?° If weight loss does not occur, it is uncertain whether any reduction of blood pressure (BP) can be ascribed to the effects of the diuretic. MacGregor et al.° did not observe any reduction in body weight with small doses of hydrochlorothiazide, 12.5 and 25 mg/day, but there was a weight reduction with doses of 50 mg/day. Although some patients respond to 25 mg with a fall in BP, in other patients doses <50 mg/ day would not be sufficient to lower volume and, pos- sibly, BP effectively. Ina Veterans Administration Cooperative study,’ 340 patients with mild hypertension received a dose of hy- drochlorothiazide, 25 mg twice a day, initially that was increased as needed to 50 and then 100 mg twice a day. Fifty percent of those who achieved a diastolic BP <90 mm Hg did so with 25 mg twice a day (50 mg/day), 30% of these responders required 100 mg/day, and the remaining 20% of these responders needed 200 mg/ day. Thus many of these patients required doses far in excess of 12.5 or 25 mg/day. Other studies have also found that the dose-response curve of hydrochlorothi- azide does not remain flat in the small dose range, and considerably higher doses such as 100 mg/day are re- quired in many patients.*” 239 240 Freis Administering a diuretic plus a step 2 drug (similar to studies that claimed effectiveness of small doses of hydrochlorothiazide,®'*'' Magee and Freis'* tested na- dolol, 80 mg/day, plus various doses of hydrochloro- thiazide, including 12.5, 25, and 50 mg/day. Each dose was given for 3 weeks with an intervening diuretic placebo period of 2 to 4 weeks. As compared with placebo, there was no reduction in BP with the 12.5 mg dose of hydrochlorothiazide. The 25 mg dose low- ered systolic but not diastolic BP significantly, whereas the 50 mg dose lowered both significantly. Thus there were many patients whose diastolic BP was not well controlled with small doses <50 mg/day. HYPOKALEMIA, EXTRACELLULAR AND INTRACELLULAR One of the most widely held dogmas concerning the treatment of hypertension is that diuretic-induced hy- pokalemia must be avoided. As a result, sales of po- tassium salts and potassium-sparing diuretics have to- talled over 250 million dollars per year.'? Also, some investigators have reduced the doses of diuretics to very low levels, such as 6.25 or 12.5 mg hydrochlorothiazide per day.'0!! The extracellular hypokalemia caused by diuretics is not associated with a similar reduction in intracellular potassium. A review of the literature indicates that, with few exceptions, most investigators found that only min- imal reductions (average 5% to 7%) in total body po- tassium stores occur after thiazides.'* In contrast, the fall in extracellular potassium levels is much greater, averaging 20% below the pretreatment control level."* The large concentration gradient between extracellular and intracellular potassium is maintained by several active transport mechanisms, the most important of which is the sodium-potassium metabolic pump.’ Be- cause of these active transport mechanisms, extracel- lular hypokalemia can exist with little change in intra- cellular potassium concentrations. In the presence of heart disease and especially in patients with congestive heart failure, there may be a reduction in myocardial intracellular potassium con- centrations.'® However, in the great majority of patients with hypertension who do not have overt heart disease there is no evidence that intracellular potassium levels are significantly reduced.'° Hypomagnesemia also may occur after diuretic therapy,’’ although there is little evidence to implicate this biochemical change as a ma- jor cause of arrhythmias. ECG MONITORING Through the use of 24- or 48-hour continuous mon- itoring of the ECG, recent studies in patients with un- CLIN PHARMACOL THER MARCH 1986 complicated hypertension carried out by Papademetriou et al.'® in our laboratory found no association between hypokalemia and ventricular arrhythmias. Monitoring was carried out before and after 4 weeks of therapy with hydrochlorothiazide, 50 mg twice a day, in 24 patients, 15 of whom became hypokalemic. In the hy- pokalemic group the mean plasma potassium level fell from 4.0 to 3.0 mEq/L. Before diuretic therapy pre- mature ventricular beats (PVBs) averaged 7.1 per hour. Five patients had multifocal PVBs, one had couplets, and one had a four-beat run of ventricular tachycardia. After diuretic therapy the PVBs averaged 8.3 per hour. Three patients had multifocal PVBs and three had cou- plets, while none had ventricular tachycardia. Thus there was no essential difference in the incidence of arrhythmias before or after the induction of hypokale- mia. Two other independent investigators have con- firmed this finding.'*”° For example, Lief et al.'° con- ducted 48-hour continuous ECG monitoring in 13 pa- tients with uncomplicated hypertension. Treatment with 100 mg hydrochlorothiazide per day for 1 to 6 months lowered plasma potassium levels to the range of 2.5 to 3.2 mEq/L. When monitoring was repeated at the end of the 6 months, the ECG did not reveal either increased or dangerous ectopy such as couplets or ventricular tachycardia. The increase in serum potassium to normal levels in patients with overt hypokalemia that resulted from potassium supplements or potassium-sparing di- uretics also had no effect on ventricular arrhythmic activity.” Two older studies” did report an association be- tween cardiac arrhythmias and hypokalemia secondary to thiazides. Holland et al.”? used 24-hour monitoring of the ECG before and after hydrochlorothiazide, 100 mg/day, but did not take into account that in the same individual the frequency of PVBs can vary over a wide range from one day to the next.** By including only patients with <6 PVBs per hour at baseline, Holland et al. increased the likelihood of finding increased ar- rhythmias on the second or hypokalemic recording by chance alone. The negative findings of Papademetriou et al.'*?! and Leif et al.!? were not based on the ex- clusion of patients with more than minimal PVBs. Although similarly designed to the study of Holland et al., the study of Madias et al.” did not confirm his results. Hollifield and Slaton,*? who also found an association between hypokalemia and cardiac arrhythmias after hy- drochlorothiazide, 100 mg/day, did not use 24-hour monitoring but instead recorded the ECG during rela- tively short periods of exercise. These findings have not yet been confirmed. The Medical Research Council of Great Britain trial VOLUME 39 NUMBER 3 reported two contradictory studies.” An increased in- cidence of ventricular ectopy was noted in one subgroup of patients receiving long-term therapy with thiazides. However, these patients had no predose baseline re- cordings. In a second study patients were monitored both before and after therapy. Results indicated no in- crease in arrhythmias after thiazides. There was also no correlation between serum potassium levels and the frequency of ventricular arrhythmias in these patients without overt heart disease. HYPOKALEMIA AND SUDDEN DEATH The large Multiple Risk Factor Intervention Trial (MRFIT)*°”’ was a primary prevention trial intended to test the effects of a multifactorial intervention program, that included antihypertensive drugs, on death resulting from coronary heart disease. After 7 years morbidity did not differ significantly in the special intervention group who received drug therapy for hypertension (in- cluding 50 to 100 mg hydrochlorothiazide or chloro- thalidone per day) and those who were referred to com- munity health facilities where they received no or un- known therapy. A subgroup of intensive care patients who had minor ECG abnormalities had higher death rates from coronary heart disease than did the referred- care group with similar characteristics. This observa- tion has been widely quoted as evidence that thiazides increase the incidence of fatal arrhythmias in a subgroup of patients with minor ECG abnormalities. The evi- dence is questionable, however, for several reasons. The most important reason is that the relationship between coronary deaths and thiazide diuretics was not an initial objective of the study, but was rather a part of a ret- rospective search for associations between a number of subgroups. As the authors of MRFIT report themselves state, evidence derived from such retrospective corre- lations can only be regarded as hypotheses that must be supported by other well-designed trials.” Such confirmatory reports have not been forthcom- ing. For example, the Hypertension Detection and Fol- low-up Program (HDFP) included 1963 participants who had diastolic BP between 90 and 104 mm Hg and resting ECG abnormalities similar to the group with increased sudden death in the MRFIT. They found that rates for the major cardiovascular diseases were lower in the groups who received chlorthalidone, 50 mg/day. They concluded: ‘‘These HDFP findings, therefore, of- fer no support for the hypothesis raised in MRFIT that intensive diuretic therapy may increase the mortality rate of hypertensive patients with resting ECG abnor- malities.’’** There was also no correlation in the MRFIT between either diuretic dosage or serum potassium levels and deaths from coronary heart disease.” Cardiovascular risks of thiazides 241 The evidence cited above is against the view that, in patients without heart disease, thiazide-induced hypo- kalemia causes increased cardiac arrhythmias including sudden death. Because of the fear of fatal arrhythmias, potassium replacement therapy may be overdone’ and possibly could lead to serious consequences.” HYPOKALEMIA AND ACUTE MYOCARDIAL INFARCTION Many physicians are concerned that in the presence of acute myocardial infarction, fatal arrhythmias are more likely to develop if the patient had been receiving a thiazide diuretic. Not only is there a fall in plasma potassium levels after thiazide dosing, there is also a reduction resulting from the production of catechol- amines that occurs in response to the stress associated with the acute event.*' The resulting hypokalemia in the presence of increased susceptibility to arrhythmias secondary to the acute infarct could set the stage for ventricular fibrillation. If such were the case, however, one would expect a higher percentage of fatal myocar- dial infarctions and sudden death in patients receiving thiazide diuretics before the infarct than in those who do not receive diuretics. As indicated above, an increase in sudden death and myocardial infarction was found in a subgroup in the MRFIT. An insignificant increase also was found in the patients who received thiazides in the Oslo trial. Despite the higher coronary artery disease death rate in one subgroup, the MRFIT reported a 7% lower death rate for myocardial infarction in the total special in- tervention group. More importantly, most of the other therapeutic trials that have used thiazide diuretics as the basic therapy did not find an increase in sudden death or fatal myocardial infarction among the patients receiving the drug as compared with the control group. In fact, fatal myocardial infarction and sudden death was less frequent in the patients receiving thiazides than in the controls in most of the trials. Such was the ex- perience of the Veterans Administration Study,” the Australian trial,** and the HDFP.” In each of these studies the ratio of the percentages of fatal infarcts to total infarcts was lower in the patients who received the drug than in the control patients, opposite to what one would expect if diuretics caused fatal arrhythmias in patients with acute myocardial infarction. If there is an increased susceptibility to arrhythmias induced by diuretics, as suggested by the MRFIT,”® it is confined to only one subgroup of patients with minor ECG ab- normalities. However, as has been shown by the HDFP data,= even these subgroup findings could not be confirmed. As indicated above, except for one subgroup of the 242 = Freis MRFIT and an insignificant increase among the patients who received active drug in the Oslo trial, the other studies failed to indicate a rise in the number of deaths from coronary artery disease associated with thiazide diuretics. Thus the burden of evidence from the clinical trials indicates that thiazide diuretics do not increase the number of deaths in patients with hypertension who develop an acute myocardial infarction. There have been some reports of patients presenting at hospitals in whom there was an association between hypokalemia and malignant arrhythmias in the presence of acute myocardial infarction. Such reports were not well doc- umented, however.! There was inadequate monitoring and lack of serum potassium level measurements im- mediately before the event. In fact, some levels were measured after the patients were resuscitated, which in itself could cause severe hypokalemia. Finally, patients taking digitalis were included in the studies even though digitalis is known to be associated with arrhythmias in the presence of hypokalemia. Nordrehaug*® recently reported on the relationship between hypokalemia, arrhythmias, and the early prog- nosis in 289 women and 785 men hospitalized with acute myocardial infarction. All patients had serum po- tassium levels determined on admission and the ECG was monitored continuously for the first 2 days. The study showed no significant increase in complete heart block, bundle branch block, grade 2 atrioventricular block, atrial fibrillation, PVBs, or ventricular tachy- cardia in patients with hypokalemia on admission to the hospital as compared with those who did not have hypokalemia. It should be noted that the patients re- ceived their drug therapy in a coronary care unit. If a causal relationship between hypokalemia and arrhyth- mias were to be accepted, it is possible that the hy- pokalemia might have affected the outcome differently if the patients were managed under less ideal circum- stances. Also, hypokalemia on admission did not pre- dict prognosis during the first 3 months after the infarct. Thus there was no correlation between either death or the incidence of arrhythmias and the presence of hy- pokalemia, with one exception of ventricular fibrilla- tion.*° As previously discussed, intracellular potassium levels may be decreased in the myocardium of patients with heart disease,'® and this reduction may be further aggravated by diuretics. This relationship is controver- sial, however, as there may be other causes of ventric- ular fibrillation as indicated below. In addition to diuretics, excess circulating catechol- amines can also cause hypokalemia.*' The excess of catecholamines usually occurs during the early stages of an acute myocardial infarction. In addition, cate- CLIN PHARMACOL THER MARCH 1986 cholamines are known to induce arrhythmias indepen- dent of their hypokalemic effects. It is possible, there- fore, that the hypokalemia in this instance may be only a marker for the presence of excess catecholamines that are producing ventricular fibrillation through some other mechanism. Nordrehaug et al.*’ studied 60 patients who had re- ceived no prior drug therapy, including diuretics, before their acute myocardial infarction. Serum potassium levels correlated negatively with ventricular tachycar- dia. However, blood samples for the determination of potassium levels were drawn early, at an average of 3.8 hours after the onset of the infarct. This was much earlier than in a study* in which no correlation was found between serum potassium levels and ventricular tachycardia. Because in the latter study no patients were receiving a diuretic before the infarct, it seems most likely that hypokalemia was a reflection of the cate- cholamine level, which again could have caused ven- tricular tachycardia from arrhythmogenic effects of cat- echolamines other than their hypokalemic action. Additional evidence against the prognostic impor- tance of hypokalemia in acute myocardial infarction is provided by studies that show that the infusion of glu- cose, insulin, and potassium fail to reduce the incidence of ventricular tachycardia and fibrillation in patients with acute myocardial infarction.*”? DIURETICS AND INCREASED SERUM CHOLESTEROL LEVELS Another concern in the use of diuretics is that ele- vations in serum levels of cholesterol, although slight, might over a long period of time aggravate coronary heart disease. It was postulated that the protective effect of the BP lowering could be cancelled out by the rise in cholesterol levels.*° Serum cholesterol levels do rise modestly after thi- azide diuretic dosing.*°““’ However, the elevation usu- ally reverts back to pretreatment levels during long-term dosing. Except for one study,” serum cholesterol levels measured during the first few months of treatment were no longer elevated | or 2 years later.***’ Other studies documented the initial rise in cholesterol levels followed by the later fall. Alcazar et al.* observed the expected rise in cholesterol levels at 1 and 3 months after the start of hydrochlorothiazide dosing. Cholesterol levels returned to pretreatment levels at 6 months and re- mained there subsequently. The Veterans Administra- tion study on hydrochlorothiazide vs. propranolol“ also found serum cholesterol levels to be slightly elevated after 3 months of dosing, but by 12 months the cho- lesterol level had fallen to slightly below pretreatment VOLUME 39 NUMBER 3 values. Using the data from HDFP, Williams et al.*’ also found a short-term increase followed by a long- term return to baseline. Thus according to practically all of the existing evidence, the elevation in serum cho- lesterol levels is only transient and, therefore, of no importance in the development of atherosclerosis. CONCLUSIONS The claim that diuretic-induced hypokalemia and in- creased serum cholesterol levels may be dangerous is not supported by recent evidence. 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