Comparative effectiveness of antihypertensive drugs in nondiabetic patients with hypertension: A population-based study.

The authors compared the effectiveness of thiazide diuretic (TD), angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), and calcium channel blocker (CCB) monotherapies for the treatment of nondiabetic hypertension using MarketScan Databases 2010-2014. Multivariable Cox regression models assessed whether the addition of a new antihypertensive drug, treatment discontinuation, or switch and major cardiovascular or cerebrovascular events varied across groups. A total of 565 009 patients started monotherapy with ACEIs (43.6%), CCBs (23.6%), TDs (18.8%), or ARBs (14.0%). Patients who took TDs had a higher risk for either drug addition or discontinuation than patients who took ACEIs (hazard ratio [HR], 0.69 [95% CI, 0.68-0.70] vs HR, 0.81 [95% CI, 0.80-0.81]), ARBs (HR, 0.67 [95% CI, 0.66-0.68] vs HR, 0.66 [95% CI, 0.65-0.67]), and CCBs (HR, 0.85 [95% CI, 0.84-0.87] vs HR, 0.94 [95% CI, 0.93-0.95]). Conversely, patients who took TDs experienced a lower risk of clinical events compared with patients who took ACEIs (HR, 1.24 [95% CI, 1.15-1.33]), ARBs (HR, 1.28 [95% CI, 1.18-1.39]), and CCBs (HR, 1.35 [95% CI, 1.25-1.46]). Our results provide a strong rationale for choosing TDs as first-line monotherapy for the control of hypertension.

Clinical features, outcome and cost of hyponatremia-associated admission and hospitalization in elderly and very elderly patients: a single-center experience in Turkey.

PURPOSE: Hyponatremia is a common electrolyte disorder in hospitalized patients. Clinical features, outcome and cost of hyponatremia-associated admission and hospitalization in elderly and very elderly patients are not well known. METHODS: Elderly (>64 years) patients admitted to the emergency department (ED) and hospitalized between January 1, 2010, and December 31, 2010, were evaluated. Hyponatremia was defined as serum sodium level below 135 mmol/L. Hyponatremic patients were divided into two groups: group 1 (n = 150, 65-74 years old) and group 2 (n = 103, >74 years old). RESULTS: A total of 4,960 patients above 65 years of age admitted to ED and hospitalized were included. Prevalence of ED in group 1 and group 2 was 4.1 % (150/3,651) and 7.8 % (103/1,309), respectively (p < 0.001). Vomiting and diarrhea were the most important complaints. A total of 111 (43.8 %) patients were being treated with renin-angiotensin system (RAS) blockers. Mortality, morbidity and hospital cost increased in parallel to decrease in serum Na(+) level and increase in age. Group 2 subjects had not only higher intensive care need (p < 0.01) and mortality rates (p < 0.01), but also higher hospital cost burden (p < 0.05) compared to group 1. Alzheimer's disease was one of the most common co-morbidity in patients, particularly in group 2 (5.3 % vs. 21.3 %, p < 0.001). CONCLUSION: Hyponatremia-associated hospitalization is an important and potentially lethal condition in elderly and very elderly patients. Clinicians should be careful when prescribing RAS blockers and diuretics in elderly patients.

Thiazide diuretics in advanced chronic kidney disease.

Chronic kidney disease (CKD) is prevalent in 3%-4% of the adult population in the United States, and the vast majority of these people are hypertensive. Compared with those with essential hypertension, hypertension in CKD remains poorly controlled despite the use of multiple antihypertensive drugs. Hypervolemia is thought to be a major cause of hypertension, and diuretics are useful to improve blood pressure control in CKD. Non-osmotic storage of sodium in the skin and muscle may be a novel mechanism by which sodium may modulate hypertension; further work is need to study this novel phenomenon with diuretics. Among people with stage 4 CKD, loop diuretics are recommended over thiazides. Thiazide diuretics are deemed ineffective in people with stage 4 CKD. Review of the literature suggests that thiazides may be useful even among people with advanced CKD. They cause a negative sodium balance, increasing sodium excretion by 10%-15% and weight loss by 1-2 kg in observational studies. Observational data show improvement in seated clinic blood pressure of about 10-15 mm Hg systolic and 5-10 mm Hg diastolic, whereas randomized trials show about 15 mm Hg improvement in mean arterial pressure. Volume depletion, hyponatremia, hypokalemia, hypercalcemia, and acute kidney injury are adverse effects that should be closely monitored. Our review suggests that adequately powered randomized trials are needed before the use of thiazide diuretics can be firmly recommended in those with advanced CKD.

Evaluations of hospitalizations associated with thiazide-associated hyponatremia.

The prevalence of hypertension in the United States has grown dramatically in recent years. Thiazide diuretics have played a major role in the rising rate of blood pressure (BP) control. Accompanying this has been the appearance of adverse drug events, including hospitalizations associated with thiazide-associated hyponatremia (HTAH). Hyponatremia is a common yet often overlooked side effect of this drug class. Identification of HTAH risk factors may aid in creating strategies to prevent hospitalizations. This is a retrospective, case-controlled study of 10,805 patients (1802 cases, 9003 controls) examining HTAH risk factors within a group-model integrated-care organization. Multivariate analysis revealed that age (odds ratio [OR], 1.75; 95% confidence interval [CI], 1.58-1.93), angiotensin-converting enzyme (ACE) inhibitor use (OR, 1.53; 95% CI, 1.16-2.00), and hypokalemia (OR, 40.94; 95% CI, 26.46-66.33) were most associated with HTAH. Urinary tract infection (UTI), type 2 diabetes, hyperlipidemia, and gastroesophageal reflux disease (GERD) were also found to be HTAH risk factors. Potassium supplements (OR, 0.60; 95% CI, 0.44-0.83) and weight (OR, 0.91; 95% CI, 0.88-0.93) had protective effects. A predictive model was developed to determine overall HTAH risk given the presence of individual risk factors. Age, weight, hypokalemia, GERD, type 2 diabetes, UTI, and ACE inhibitor use independently correlated with an increased risk of HTAH. This model may be applied in clinical practice to guide thiazide prescribing.

Thiazide and loop diuretics.

KEY POINTS AND PRACTICAL RECOMMENDATIONS: • Although chlorthalidone and hydrochlorothiazide are structurally similar, they are very different pharmacokinetically, with chlorthalidone having both an extremely long half-life (approximately 40 to 60 hours) and a large volume of distribution, with gradual elimination from the plasma compartment by tubular secretion. • Furosemide usage, the most widely used diuretic in the loop diuretic class, can be complicated by extremely erratic absorption, with a bioavailability range of 12% to 112%. • Chlorthalidone, at a dose of 25 mg, is comparatively more potent than 50 mg of hydrochlorothiazide, particularly as related to overnight blood pressure reduction. • In ALLHAT, there was no difference among chlorthalidone, amlodipine, lisinopril, and doxazosin for the primary outcome or mortality. • Secondary outcomes were similar except for a 38% higher rate of heart failure with amlodipine; a 10% higher rate of combined cardiovascular disease, a 15% higher rate of stroke, and a 19% higher rate of heart failure with lisinopril; and a 20% higher rate of cardiovascular disease, a 20% higher rate of stroke (40% higher rate in blacks), and an 80% higher rate of heart failure with doxazosin, compared with chlorthalidone. • The ACCOMPLISH study may affect future practice guidelines as a result of its findings favoring the amlodipine/benazepril combination; however, the generalizability to patient populations with a lesser cardiovascular risk profile remains in question and the dose of hydrochlorothiazide was only 12.5 mg to 25 mg daily, which was a dose lower than that used in placebo-controlled trials using hydrochlorothiazide. • Certain low-renin patient groups (eg, blacks, the elderly, and diabetics) as well as those who manifest the metabolic syndrome are commonly more responsive to thiazide-type diuretic therapy. • Diuretics can be successfully combined with ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, centrally acting agents, and even calcium channel blockers. • Although thiazide-type diuretics are among the best-tolerated antihypertensive agents in terms of symptomatic adverse effects, diuretic-related adverse side effects include those with established mechanisms (eg, such as electrolyte changes and/or metabolic abnormalities) and other side effects, which are less well understood mechanistically (eg, impotence), although the latter is not universally accepted as a diuretic-related side effect. • Thiazide-induced hypokalemia is associated with increased blood glucose, and treatment of thiazide-induced hypokalemia may reverse glucose intolerance and possibly prevent diabetes. • Thiazide-induced hyperuricemia occurs as a result of volume contraction and competition with uric acid for renal tubular secretion, but does not necessarily contraindicate using a thiazide, especially if a uric acid-lowering drug such as allopurinol is being used. • Adverse interactions include the blunting of thiazide effects by nonsteroidal anti-inflammatory drugs and the potential to increase fatigue, lethargy, and increase in glucose when combined with ß-blockers. • Thiazide-type diuretics are useful first-line agents in the treatment of hypertension because they have been proven to reduce cardiovascular mortality and morbidity in systolic and diastolic forms of hypertension and do so at low cost. • Loop diuretics should not be used as first-line therapy in hypertension since there are no outcome data with them. They should be reserved for conditions of clinically significant fluid overload (eg, heart failure and significant fluid retention with vasodilator drugs, such as minoxidil) or with advanced renal failure and can be combined with thiazide-type diuretics.

The assessment and treatment of water imbalance in patients with psychosis.

Polydipsia and episodic life-threatening water intoxication remain important clinical problems for a significant portion of persons with schizophrenia. The disorders are associated with increased morbidity and mortality from a number of causes. With a basic understanding of the pathophysiology, one can easily diagnose and assess the clinical conditions. We review here the scope and pathophysiology of disordered water imbalance, including both primary and secondary polydipsia and hyponatremia. Reversible factors and possible interventions are reviewed. Treatment options for preventing water intoxication have expanded from discontinuation of offending agents, targeted fluid restriction, and clozapine therapy to the addition of oral vasopressin antagonists. The latter, however, are extremely potent and must be carefully monitored.

Thiazide diuretics in the management of hypertension.

Hypertension is highly prevalent in Canada, affecting more than 20% of all adults. Thiazide diuretics have been shown in numerous studies to be effective agents for controlling blood pressure and reducing cardiovascular disease and death in hypertensive patients. Thiazide diuretics are recommended as initial first line therapy for uncomplicated hypertension in the 2003 Canadian Hypertension recommendations. However, these agents are underutilized and in Canada, the proportion of persons with hypertension treated with diuretics is declining. To improve understanding of thiazide diuretic use, this document outlines the clinical pharmacology of thiazide diuretics, evidence for effectiveness in treating hypertension, as well as the side effects and controversies surrounding their use.

ALLHAT: a critical assessment.

The ALLHAT study has attracted considerable attention in the media and in the research community, partly due to the study's unexpected and controversial conclusions. However, the study has several serious shortcomings. The primary end-points in ALLHAT were negative and the conclusions are based entirely on secondary end-points and subgroup analyses. Moreover, there is good reason for skepticism concerning the findings on heart failure in ALLHAT, because of ambiguity in the diagnosis, lack of information on blood pressure and absence of a "washout" period. The study design was severely flawed and does not reflect clinical reality. Also, blood pressure differences between groups severely complicate interpretation. From a patient perspective in ALLHAT, there are drug safety concerns with the thiazides, as there was evidence of excess diabetes development. The ALLHAT results are difficult to generalize and have limited relevance in European settings. Thus, the ALLHAT study suffers from several major shortcomings and there is a huge body of evidence that contradicts the ALLHAT interpretations.

[Are the newer antihypertensive agents better and more effective than diuretics?]. / Er de nyere antihypertensive medikamentene bedre og mer effektive enn diuretika?

BACKGROUND: In recent years, the expenses for medical antihypertensive therapy have increased considerably, the main reason being the switchover to newer and more expensive antihypertensive drugs. RESULTS: Several recent studies which have compared the efficacy of the older, conventional drugs (thiazid diuretics and beta-blockers) with the newer agents (calcium blockers, angiotensin-converting enzyme (ACE) inhibitors), have shown that they are almost equipotent with regard to effects on blood pressure, morbidity and mortality. At lower doses, the metabolic effects of thiazide diuretics are minimal and probably without clinical significance, and the risk of developing diabetes mellitus type 2 does not seem to be increased. INTERPRETATION: The cheaper thiazide diuretics are still valuable drugs in the treatment of hypertension. If more than one agent is necessary to reduce blood pressure to the desired level, they can be combined with other antihypertensive agents.

Choosing a first-line drug in the management of elevated blood pressure: what is the evidence? 1: Thiazide diuretics.

Elevated blood pressure is associated with an increased risk of cardiovascular illness and death. Efforts to reduce that risk have led to recommendations for a wide array of nondrug and drug therapies. Choosing the optimal first-line drug for hypertensive patients should address a hierarchy of treatment goals: decrease in morbidity and mortality associated with hypertension, decrease in blood pressure, lack of effect on patients' quality of life, dosing convenience and low cost. This article examines the evidence for thiazide diuretics as a class of first-line antihypertensive drugs in light of these treatment goals. The evidence indicates that low-dose thiazides are preferable to high-dose thiazides and that low-dose thiazides are better than or equivalent to other antihypertensive drugs for each of the goals of therapy.

Choosing a first-line drug in the management of elevated blood pressure: what is the evidence? 2: Beta-blockers.

Elevated blood pressure is associated with an increased risk of cardiovascular illness and death. Efforts to reduce that risk have led to recommendations for a wide array of nondrug and drug therapies. Choosing the optimal first-line drug for hypertensive patients should address a hierarchy of treatment goals: decrease in morbidity and mortality associated with hypertension, decrease in blood pressure, good tolerance, dosing convenience and low cost. This article examines the evidence for beta-blockers as a class of first-line antihypertensive drugs in light of these treatment goals. The evidence indicates that beta-blockers are probably not as effective in reducing morbidity and mortality as low-dose thiazide diuretics and that there may be significant differences in effectiveness among various beta-blockers.

Thiazide diuretics and the initiation of anti-gout therapy.

While physiologic and epidemiologic evidence link diuretic therapy with hyperuricemia, no previous study has quantified the risk for initiation of treatment specific for hyperuricemia or gout among elderly patients taking thiazide diuretics. We performed a retrospective cohort study of 9249 enrollees aged 65 or older in the New Jersey Medicaid program who were newly started on an antihypertensive medication from November 1981 through February 1989 and who had no prior use of anti-gout therapy (allopurinol, colchicine, or a uricosutic) during the preceding one-year period. We used Cox proportional hazards analysis to determine the risk for the initiation of anti-gout therapy in patients using various antihypertensive treatment regimens relative to no antihypertensive exposure. Patient follow-up extended for up to two years. Antihypertensive exposure was characterized over the entire period of follow-up according to the following categories: thiazide diuretic therapy alone; non-thiazide antihypertensive therapy; thiazide diuretic therapy in combination with any non-thiazide antihypertensive agent(s); and no antihypertensive use. Antihypertensive exposure was entered into the model as a time-varying covariate. Estimates of risk were adjusted for age, sex, race, nursing home residence, number of prescriptions filled, intensity of physician use, hospitalization history, and year of antihypertensive treatment initiation. The adjusted relative risk for the initiation of anti-gout therapy was 1.00 (95% CI, 0.65-1.53) for non-thiazide antihypertensive therapy alone, 1.99 (95%, CI, 1.21-3.26) for thiazide diuretic therapy, and 2.29 (95% CI, 1.55-3.37) for thiazide diuretic therapy in combination with any non-thiazide agent(s). Risk for anti-gout therapy was significantly increased for thiazide doses of > or = 25 mg/day (in hydrochlorothiazide equivalents); no significant increase in risk was seen for lower doses. We conclude that use of thiazide diuretics in doses of 25 mg/day or higher is associated with a significantly increased risk for initiation of anti-gout therapy. Such treatment may reflect the occurrence of clinical sequelae of diuretic-induced hyperuricemia or the inappropriate treatment of asymptomatic hyperuricemia.

Low-dose thiazides in the treatment of hypertension: benefits and risks in perspective.

Diuretics in low doses are very effective agents for controlling hypertension either where used alone or in combination. They have a marked cardioprotective effect, are the best tolerated of any anti-hypertensives and are at the same time the least expensive.

Treating hypertension and cardiovascular risk: are there trade-offs?

Numerous studies have demonstrated that antihypertensive agents differentially affect blood lipids. Thiazide diuretics increase total cholesterol, low-density lipoprotein, and triglycerides and cause a slight reduction in high-density lipoprotein (HDL). Most beta-blockers are associated with large increases in triglycerides and substantial reductions in HDL. Conversely, alpha 1-inhibitors, such as prazosin, doxazosin, and terazosin, lower total cholesterol, increases HDL, and favorably alter the HDL/total cholesterol ratio. Results of major clinical trials have demonstrated that lowering total cholesterol or low-density lipoprotein and increasing HDL reduces the risk of coronary heart disease. Therefore concerns have increased that the lipid effects of thiazides and some beta-blockers may totally or partly negate the beneficial reduction on coronary heart disease afforded by blood pressure reduction. Trial data can be used to estimate the potential secondary costs of disease outcomes that would be associated with lipid differences. Because there are presumably no secondary costs with alpha 1-inhibitors as a result of their favorable effects on lipids and because there are substantial secondary costs associated with thiazides, the cost of long-term treatment would be similar for the two agents.

ACE inhibitors compared with thiazide diuretics as first-step antihypertensive therapy.

While ACE inhibitors are considerably more expensive than thiazide diuretics, they are slightly more effective antihypertensive agents in white patients and have fewer side effects. They can be regarded as suitable first-line therapy in diabetic hypertensives. It is probable that as new drugs in this class are marketed, the price differential will lessen and they will be regarded as acceptable and useful first-line drugs in an increasingly large number of patients.

The decision to treat: profiling benefit.

The decision to treat a hypertensive patient is usually based on the level of the blood pressure and some consideration of epidemiological risk factors. The implicit assumption is that all patients derive the same benefit from a particular type of drug. Recent evidence suggests that benefits are influenced by many factors, both positive and negative, which include age, sex, race, tobacco smoking and many diseases that can be provoked or aggravated by commonly used drugs, e.g. asthma, claudication, diabetes and gout. Risk factor analysis no longer seems the most appropriate technique on which to base treatment decisions. Analysis of potential benefits from different treatment strategies in an individual patient seems a better way.

Economics of antihypertensive therapy.

Antihypertensive therapy has come a long way in the past 40 years. With the wide range of drugs now available, cost has become an additional consideration in selection of therapy. However, precise figures for comparison of drugs within and between classes can be difficult and time-consuming to gather. The unit-cost tables in this article are presented with the hope that they will simplify the selection process. Of course, unit cost is not the sole criterion to be considered; potency and frequency of administration also influence the overall cost of therapy.

Diuretic therapy for mild hypertension: the "real" cost of treatment.

The benefit of any medical intervention, particularly drug therapy, must be weighed against its cost. These costs are not only dollar expenditures but effects on lifestyle and overall health. Diuretic therapy for hypertension has been in use long enough to allow long-term clinical evaluation. It is clear from the numerous prospective drug intervention trials involving hypertensive patients that diuretic therapy is not free of "costs." Aside from the fact that 15 to 20% of diuretic-treated patients reportedly drop out of trials because of side effects, including exertional dyspnea, fatigability, lethargy and impotence, numerous metabolic derangements have been reported with these drugs, i.e., potassium, uric acid, lipid, sodium, glucose and magnesium alterations. Perhaps most important are the changes in lipid fractions, which may be responsible for the failure of antihypertensive therapy to decrease the risk of coronary heart disease. Thus, although diuretics are somewhat less expensive than other antihypertensive drugs in terms of dollars, their overall costs are high. The major alternatives, such as the alpha-blocker prazosin or the central nervous system agent clonidine, are preferable, do not impair a patient's lifestyle and are recommended to be used along with changes in diet and an exercise program for control of mild to moderate hypertension.