Prescribing patterns of diuretics in multi-drug antihypertensive regimens

Recent literature suggests that most hypertensives will require two or more drugs to achieve target blood pressure. Our objective was to estimate the proportion of patients receiving diuretics, including thiazides, for blood pressure control among those receiving two or more drugs. We studied 25,052 hypertensives in a tertiary care Veterans Affairs facility and identified individuals taking any thiazide or loop diuretic among patients receiving two, three, four, or more drugs. Rates of any diuretic use were 50%, 73%, and 89%, and decreased to 39.0%, 59.0%, and 72.5% for thiazide use, respectively. Rates of thiazide use were statistically significantly higher among African Americans compared with the general study population, but did not differ significantly in the elderly. Though overall diuretic use seems to be increasing as compared with previous studies, there is room for improvement in the use of thiazides in multi-drug hypertension regimens.     

Beta-blockers and diuretics: to use or not to use

The present review scrutinizes the recommendations of many guidelines to use beta-blockers and diuretics as first-line therapy in hypertension. These recommendations were ostensibly based on multiple prospective randomized trials attesting to a reduction of morbidity and mortality with both beta-blockers and diuretics in monotherapy as well as in combination. Although diuretic-based therapy has been shown to prevent strokes (and, to a lesser extent, heart attacks, and cardiovascular and all-cause mortality), no such data are available for beta-blockers. To the contrary, a recent metaanalysis documented that although blood pressure was lowered significantly by beta-blockers, this drug class was ineffective in preventing coronary heart disease, and cardiovascular and all-cause mortality (odds ratio 1.01, 0.98, and 1.05, respectively). Patients who received a combination of beta-blockers and diuretics fared consistently worse than those taking diuretics alone. Although diuretics have an unparalleled track record of safety and efficacy, the recent findings suggesting that long-term use increased the risk for renal cell carcinoma (RCC) is of concern. Over the past decade, an association between RCC and diuretic therapy has been documented in nine case control studies (odds ratio 1.55, confidence interval [CI] 1.42-1.71). In three cohort studies, diuretic therapy was associated with a greater than twofold increased risk of RCC. The risk of RCC increased with cumulative diuretic doses. In the elderly, a low-dose diuretic probably remains a good choice for antihypertensive therapy; however, in middle-aged patients, particularly in women, diuretics should be avoided for the long-term treatment of hypertension. Sweeping recommendations for the use of beta-blockers and diuretics as preferred therapeutic strategies are inappropriate and a more sophisticated drug therapy regimen is often needed.     

Diuretic Use and Risk of Vertebral Fracture in Women

Background

Vertebral fracture is the most common type of osteoporotic fracture. While thiazide diuretics, which are commonly prescribed for the treatment of hypertension, decrease calciuria, they may also induce hyponatremia, which has been associated with increased vertebral fracture risk. Loop diuretics increase calciuria, which would reduce bone mineral density and increase vertebral fracture risk, but they rarely cause hyponatremia. Recent studies on diuretics and fractures did not include or specifically examine vertebral fracture. The few studies of diuretics and vertebral fracture have been limited by cases defined by self-report or administrative data, relatively small number of cases, study design that was not prospective, and lack of long-term follow-up with updated information on diuretic use.

Methods

We conducted a prospective cohort study of thiazide diuretic use, loop diuretic use, and risk of incident clinical vertebral fracture in 55,780 women, 55-82 years of age, participating in the Nurses' Health Study, without a prior history of any fracture. Diuretic use was assessed by questionnaire every 4 years. Self-reported vertebral fracture was confirmed by medical record review. Cox proportional-hazards models were used to simultaneously adjust for potential confounders.

Results

Our analysis included 420 incident vertebral fracture cases documented between 2002 and 2012. The multivariate-adjusted relative risk of clinical vertebral fracture for women taking thiazides compared with women not taking thiazides was 1.47 (95% confidence interval, 1.18-1.85). The multivariate adjusted relative risk of vertebral fracture for women taking loop diuretics compared with women not taking loop diuretics was 1.59 (95% confidence interval, 1.12-2.25).

Conclusion

Thiazide diuretics and loop diuretics are each independently associated with increased risk of vertebral fracture in women.     

β-blockers and diuretics: to use or not to use

The present review scrutinizes the recommendations of many guidelines to use β-blockers and diuretics as first-line therapy in hypertension. These recommendations were ostensibly based on multiple prospective randomized trials attesting to a reduction of morbidity and mortality with both β-blockers and diuretics in monotherapy as well as in combination. Although diuretic-based therapy has been shown to prevent strokes (and, to a lesser extent, heart attacks, and cardiovascular and all-cause mortality), no such data are available for β-blockers. To the contrary, a recent metaanalysis documented that although blood pressure was lowered significantly by β-blockers, this drug class was ineffective in preventing coronary heart disease, and cardiovascular and all-cause mortality (odds ratio 1.01, 0.98, and 1.05, respectively). Patients who received a combination of β-blockers and diuretics fared consistently worse than those taking diuretics alone. Although diuretics have an unparalleled track record of safety and efficacy, the recent findings suggesting that long-term use increased the risk for renal cell carcinoma (RCC) is of concern. Over the past decade, an association between RCC and diuretic therapy has been documented in nine case control studies (odds ratio 1.55, confidence interval [CI] 1.42–1.71). In three cohort studies, diuretic therapy was associated with a greater than twofold increased risk of RCC. The risk of RCC increased with cumulative diuretic doses. In the elderly, a low-dose diuretic probably remains a good choice for antihypertensive therapy; however, in middle-aged patients, particularly in women, diuretics should be avoided for the long-term treatment of hypertension. Sweeping recommendations for the use of β-blockers and diuretics as preferred therapeutic strategies are inappropriate and a more sophisticated drug therapy regimen is often needed.     

Indapamide: a diuretic of choice for the treatment of hypertension?

In recent years, the therapeutic approach to mild hypertension has evolved from a stepped care approach to one including varied, initial monotherapies, with the selection of drug based on factors present in an individual patient, followed by combination therapy. The greatest cumulative experience of the value of antihypertensive therapy has been obtained with diuretics. The reduction in risk of cardiovascular disease with successful antihypertensive therapy using conventional agents, including diuretics, is not as great as might have been anticipated by the magnitude of change in blood pressure. This could be due to antecedent cardiovascular injury prior to therapy or to risk factors induced by therapy. The recent introduction of a new generation of drugs with combined diuretic and hypotensive effects that reduce blood pressure without inducing the biochemical changes associated with thiazides, offers an opportunity to evaluate this question. Indapamide is the first of this new generation to be released. Its pharmacologic characteristics show that it has the prerequisites to be considered a first-line drug for use in hypertension. It meets the requirements of a Phase II or second generation drug in that it has similar efficacy, but less short term toxicity than first generation drugs. It has been introduced at a cost that is competitive with thiazides and potassium-sparing combination drugs and is cheaper than many other classes of antihypertensive drugs. The major caution in promoting its use is that its long term effect on morbidity and mortality in hypertensive disease has not yet been evaluated. In summary, this is a promising new drug that has the potential to replace first generation thiazides in the routine management of hypertension.     

Loop diuretic use and increased rates of hip bone loss in older men: the Osteoporotic Fractures in Men Study

BACKGROUND: Older adults commonly use loop diuretics, which can increase urinary calcium excretion, leading to potential bone loss. Studies examining the association between loop diuretics and bone mineral density (BMD) are lacking, particularly those involving men. METHODS: In this cohort study, we ascertained medication use (interviewer-administered questionnaire verified with inspection of medication containers) and measured the BMD of the total hip and 2 subregions (by dual-energy x-ray absorptiometry) at baseline and at a second visit an average of 4.6 years later among 3269 men aged 65 years and older. RESULTS: Eighty-four men were categorized as continuous users of loop diuretics, 181 as intermittent users of loop diuretics, and 3004 men as nonusers of loop diuretics. After adjustment for age, baseline BMD, body mass index, weight change from baseline, physical activity,clinic site, perceived health status, cigarette smoking status, diabetes mellitus, chronic obstructive pulmonary disease, congestive heart failure, hypertension, and statin use, the average annual rate of decline in total hip BMD steadily increased from -0.33% (95% confidence interval [CI], -0.36% to -0.31%) for nonusers,to -0.58% (95% CI, -0.69% to -0.47%) for intermittent users, and to -0.78% (95% CI, -0.96% to -0.60%)for continuous users. Findings were similar for change in BMD at the femoral neck and trochanter. CONCLUSIONS: We conclude that loop diuretic use in older men is associated with increased rates of hip bone loss. These results suggest that the potential for bone loss should be considered when loop diuretics are prescribed to older patients in clinical practice.     

Moderne Differenzialtherapie mit Diuretika

Diuretics block different electrolyte transporters in renal tubular cells. Their predominant action is inhibition of renal sodium chloride reabsorption, however, and achievement of a negative body sodium balance is the principal goal of diuretic therapy in patients with hypertension and edema. Several classes of diuretics can be distinguished with respect to the sites of sodium reabsorption along the nephron, but loop diuretics and distal-tubular diuretics (incl. thiazides) are the most widely used. The latter have a less potent natriuretic effect than loop diuretics, but their long duration of action predispose them for treatment of patients with uncomplicated hypertension. In conditions of gross edema, e.g. heart and/or renal failure, distal-tubular diuretics lose their efficacy and must be replaced by or combined with loop diuretics ("sequential nephron blockade"). Aldosterone antagonists are unique among diuretics because they improve survival in patients with heart failure independently of their effect on sodium metabolism.     

Pearls and pitfalls in the use and abuse of diuretics for chronic congestive heart failure

The main purpose of using diuretics is usually lost sight of, i.e. it is for the relief of dyspnea by using the least amount of a diuretic. The production of a low output state and hypercoagulation in an attempt to achieve dry weight by lowering blood volume excessively are among the hazards of using more diuretic than is absolutely necessary to achieve the goal of relieving dyspnea. The use of jugular venous pressure measurement and the status of dyspnea should have precedence over body weight in determining diuretic dose adjustment. Often forgotten in using diuretics is that potassium without magnesium will not enter cells and that the almost universal preference for furosemide over thiazides threatens to increase the incidence of osteoporosis. Also, the tendency to ignore loss of the water-soluble vitamins thiamine and ascorbic acid may result in refractory edema and the inability to manage the stresses of congestive heart failure.     

The value of serum magnesium determination in hypertensive patients receiving diuretics

Some clinicians contend that hypomagnesemia is a common problem in patients receiving diuretic therapy and that routine serum magnesium determinations may be indicated in such patients. We determined serum magnesium (Mg++) levels in 354 patients with uncomplicated hypertension. No significant difference was observed in the mean Mg++ between the 245 diuretic-treated patients and the 109 patients not receiving diuretics, 0.965 vs 0.97 mmol/L (1.93 vs 1.94 mEq/L). When analyzed by type of diuretic, there were statistically significant differences in the mean serum Mg++ concentrations between those receiving thiazides, 0.94 mmol/L (1.87 mEq/L); those receiving no diuretics, 0.97 mmol/L (1.94 mEq/L); and those receiving triamterene-containing diuretics, 1.01 mmol/L (2.01 mEq/L). These absolute differences, however, were clinically quite small, and hypomagnesemia was uncommon. Neither patient age, the duration of diuretic use, nor the serum potassium level correlated with Mg++. With respect to dose, those receiving 100 mg/d of hydrochlorothiazide had the lowest Mg++ concentrations and the greatest prevalence of hypomagnesemia (12%), defined as Mg++ less than 0.75 mmol/L (1.5 mEq/L). Serum Mg++ need not routinely be determined in patients with uncomplicated hypertension who are receiving triamterene-containing diuretics or low-dose (50 mg/d or less) hydrochlorothiazide.     

Older age and in-hospital development of hypokalemia from loop diuretics: results from a multicenter survey. GIFA Investigators. Multicenter Italian Pharmacoepidemiologic Study Group

BACKGROUND: Hypokalemia is a common finding among older patients taking diuretic medications. However, it is not known whether older age per se carries an increased risk of hypokalemia, particularly during a patient's treatment with loop diuretics. METHODS: The association between age and incident hypokalemia was examined in 18,872 patients with normal baseline serum potassium enrolled during three yearly multicenter surveys; 4,035 patients started receiving loop diuretics during their hospital stay. Demographic variables, comorbid conditions, medications, and objective tests that were associated with incident hypokalemia in separate age- and sex-adjusted logistic regression models were examined as potential confounders. RESULTS: Among patients with normal baseline serum potassium, the factors of age, presence of coronary disease or diabetes, comorbidity, the use of ACE inhibitors, loop diuretics, digitalis, corticosteroids, or insulin, and baseline serum potassium were associated with incident hypokalemia in initial models. After these variables were adjusted for, age (for each decade, odds ratio = 1.30; 95% confidence interval = 1.17-1.46; p < .0001) was associated with incident hypokalemia. The use of parenteral (2.30; 1.53-3.46; p < .0001) but not oral (1.16; 0.79-1.69; p = .44) loop diuretics was associated with hypokalemia. Eventually, age was associated with hypokalemia when the summary regression model was analyzed in patients taking loop diuretics (1.33; 1.03-1.71; p = .027), as well as in those taking intravenous loop diuretics only (1.84; 1.25-2.70; p = .002). CONCLUSIONS: Older age is independently associated with the in-hospital development of hypokalemia, particularly among patients taking loop diuretics. Monitoring of serum potassium levels is therefore advisable when older patients are treated with these agents.     

Predicting acute gout in diuretic-treated hypertensive patients

Factors predisposing to diuretic-induced acute gout were investigated in a case-control study. Seventy hypertensive patients with acute gout occurring during diuretic treatment were identified and matched for age and sex to 140 hypertensive controls who took diuretics but did not develop gout. Gout was related more strongly to the use of loop diuretics than thiazides, with 30% of cases taking a loop diuretic compared to 14% of controls (P less than 0.01). In a sub-group of men who took a thiazide and no other diuretic, gout was significantly associated with obesity (odds ratio 3.7, 95% confidence interval 1.4, 9.1) and high alcohol intake (odds ratio 3.3, 95% confidence interval 1.1, 9.8). In these patients, 23% of gout was attributable to obesity and 16% to high alcohol consumption. Approximately 40% of acute gout might have been prevented by avoiding thiazides in those 20% of men who weighed more than 90 kg and/or consumed more than 56 units of alcohol per week.