Although, on average, cognition declines with age, cognition in older adults is a dynamic process. Hypertension is associated with greater decline in cognition with age, but whether treatment of hypertension affects this is uncertain. Here, we modelled dynamics of cognition in relation to the treatment of hypertension, to see if treatment effects might better be discerned by a model that included baseline measures of cognition and consequent mortality
This is a secondary analysis of the Hypertension in the Very Elderly Trial (HYVET), a double blind, placebo controlled trial of indapamide, with or without perindopril, in people aged 80+ years at enrollment. Cognitive states were defined in relation to errors on the Mini-Mental State Examination, with more errors signifying worse cognition. Change in cognitive state was evaluated using a dynamic model of cognitive transition. In the model, the probabilities of transitions between cognitive states is represented by a Poisson distribution, with the Poisson mean dependent on the baseline cognitive state.
The dynamic model of cognitive transition was good (R2 = 0.74) both for those on placebo and (0.86) for those on active treatment. The probability of maintaining cognitive function, based on baseline function, was slightly higher in the actively treated group (e.g., for those with the fewest baseline errors, the chance of staying in that state was 63% for those on treatment, compared with 60% for those on placebo). Outcomes at two and four years could be predicted based on the initial state and treatment.
A dynamic model of cognition that allows all outcomes (cognitive worsening, stability improvement or death) to be categorized simultaneously detected small but consistent differences between treatment and control groups (in favour of treatment) amongst very elderly people treated for hypertension. The model showed good fit, and suggests that most change in cognition in very elderly people is small, and depends on their baseline state and on treatment. Additional work is needed to understand whether this modelling approach is well suited to the valuation of small effects, especially in the face of mortality differences between treatment groups.
This analysis shows the economic benefit of antihypertensive treatment in patients 80 years of age or older from the perspective of the Swiss healthcare system. The cost-effectiveness analysis of antihypertensive treatment in the elderly was carried out applying the results of the Hypertension in the Very Elderly Trial study to the Swiss healthcare system. The analysis shows that hypertension treatment provides, compared with placebo, an additional life expectancy of 0.0457 years per patient, over a follow-up period of 2 years. The medication cost was covered by the reduction of costs related to the treatment of strokes, myocardial infarctions and heart failure: the total cost per patient in the active group resulted in a dominant strategy of savings compared with the placebo group. Sensitivity analysis yielded a stable estimate after varying the costs of medication, stroke, myocardial infarction, heart failure and life expectancy, confirming the robustness of these results. Moreover, considering that antihypertensive treatment also positively affects the incidence of dementia, those net benefits might even be underestimated.
cost-effectiveness; net benefit; Hypertension in the Very Elderly Trial; years of life saved
Indapamide, an indoline-containing diuretic drug, has recently been evaluated in a large Phase III clinical trial (ADVANCE) with a fixed-dose combination of an angiotension converting enzyme inhibitor, perindopril, and demonstrated to significantly reduce the risks of major vascular toxicities in type 2 diabetics. The original metabolic studies of indapamide reported that the indoline functional group was aromatized to indole through a dehydrogenation pathway by cytochrome P450s. However, the enzymatic efficiency of indapamide dehydrogenation was not elucidated. A consequence of indoline aromatization is that the product indoles might have dramatically different therapeutic potencies. Thus, studies that characterize dehydrogenation of the functional indoline of indapamide were needed. Here we identified several indapamide metabolic pathways in vitro with human liver microsomes and recombinant CYP3A4 that include the dehydrogenation of indapamide to its corresponding indole form, and also hydroxylation and epoxidation metabolites, as characterized by LC/MS. Indapamide dehydrogenation efficiency (Vmax/Km = 204 min−1•mM−1) by CYP3A4 was approximately 10-fold greater than that of indoline dehydrogenation. In silico molecular docking of indapamide into two CYP3A4 crystal structures, to evaluate the active site parameters that control dehydrogenation, produced conflicting results about the interactions of Arg 212 with indapamide in the active site. These conflicting theories were addressed by functional studies with a CYP3A4R212A mutant enzyme, which showed that Arg 212 does not appear to facilitate positioning of indapamide for dehydrogenation. However, the metabolites of indapamide were precisely consistent with in silico predictions of binding orientations, using three diverse computer methods to predict drug metabolism pathways.
Angiotensin-converting enzyme inhibitors (ACEI) have a well-established role in the prevention of cardiovascular events in hypertension, left ventricular dysfunction, and heart failure. More recently, ACEI have been shown to prevent cardiovascular events in individuals with increased cardiovascular risk, where hypertension, left ventricular dysfunction, or heart failure was not the primary indication for ACEI therapy.
To review studies of the effects of the ACEI perindopril on cardiovascular events.
The EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery Disease Study), PROGRESS (Perindopril Protection Against Recurrent Stroke Study), and ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm) trials are reviewed.
Perindopril alone reduced cardiovascular events in subjects with stable coronary heart disease. Perindopril in combination with indapamide reduced cardiovascular events in subjects with cerebrovascular disease. Perindopril in combination with amlodipine reduced cardiovascular events in subjects with hypertension.
Perindopril reduced cardiovascular events. The reduction of cardiovascular events by perindopril was in large part associated with reduction of blood pressure, and greater reduction in cardiovascular events was associated with greater reduction of blood pressure. Perindopril may need to be combined with other antihypertensive agents to maximize reduction of cardiovascular events.
Angiotensin-converting enzyme inhibitor; hypertension; coronary heart disease; stroke; myocardial infarction; heart failure
Background. The incidence of hypertension in the Western countries is continuously increasing in the elderly population and remains the leading cause of cardiovascular and morbidity. Methods. we analysed some significant clinical trials in order to present the relevant findings on those hypertensive population. Results. Several studies (SYST-EUR, HYVET, CONVINCE, VALUE, etc.) have demonstrated the benefits of treatment (nitrendipine, hydrochrotiazyde, perindopril, indapamide, verapamil, or valsartan) in aged hypertensive patients not only concerning blood pressure values but also the other important risk factors. Conclusion. Hypertension is the most prevalent cardiovascular disorder in the Western countries, and the relevance of receiving pharmacological treatment of hypertension in aged patients is crucial; in addition, the results suggest that combination therapy—nitrendipine plus enalapril—could have more benefits than those observed with the use of nitrendipine alone.
In the 1980s a change occurred in hydrochlorothiazide prescribing practices for hypertension from high-dose (50 mg/day) to low-dose (12.5–25 mg/day) therapy. However, randomized controlled trials (RCT) for prevention of calcium-containing kidney stones (CCKS) employed only high doses (≥50 mg/day). We hypothesized that these practices have resulted in underdosing of hydrochlorothiazide for prevention of CCKS. Patients with a filled prescription for thiazide diuretics that underwent a 24-h urine stone risk factor analysis were eligible. Those with evidence that thiazide was prescribed for CCKS were further analyzed. Of 107 patients, 102 were treated with hydrochlorothiazide, 4 with indapamide, and one with chlorthalidone. Only 35% of hydrochlorothiazide-treated patients received 50 mg/day; a dose previously shown to reduce stone recurrence. Fifty-two percent were prescribed 25 mg and 13% 12.5 mg daily, doses that were not studied in RCT. Evidence-based hydrochlorothiazide use was suboptimal regardless of where the patient received care (Nephrology or Endocrinology clinic). In a small subset of patients (n = 6) with 24-h urinary calcium excretion measured at baseline and after 2 hydrochlorothiazide doses (25 and ≥50 mg), there was a trend toward decreased urinary calcium excretion as the dose was increased from 25 to ≥50 mg/day (p = 0.051). Low-dose hydrochlorothiazide was often used for prevention of CCKS despite the fact that there is no evidence that it is effective in this setting. This may have resulted from a practice pattern of using lower doses for hypertension therapy or a lack of knowledge of RCT results in treatment of CCKS.
Nephrolithiasis; Thiazide diuretics; Thiazide-like diuretics; Prescribing practices; Dose–response
Ambulatory blood pressure (BP) is more sensitive than office BP and is highly correlated with the left ventricular mass (LVM) of hypertensive patients with left ventricular hypertrophy (LVH).
In this prospectively designed ancillary study of the PICXEL trial, the effects of first-line combination perindopril/indapamide on ambulatory BP were compared with those of monotherapy with enalapril in 127 patients. Hypertensive patients with LVH received once daily either perindopril 2 mg/indapamide 0.625 mg (n = 65) or enalapril 10 mg (n = 62) for 52 weeks. Dose adjustments were allowed for uncontrolled BP. Twenty-four-hour ambulatory BP and echocardiographic parameters were measured at baseline, week 24, and week 52.
At study end, both treatments significantly improved ambulatory BP compared with baseline (p ≤ 0.01). Perindopril/indapamide treatment reduced 24-hour and daytime systolic BP (SBP) and pulse pressure (PP) significantly more than enalapril treatment (p < 0.01). No significant between-group differences were noted for diastolic BP (DBP) or for night-time measurements. Trough/peak ratios were higher with perindopril/indapamide than with enalapril (88.5 vs 65.8 for SBP and 86.7 vs 63.9 for DBP, respectively). The global smoothness index was higher with perindopril/indapamide than with enalapril (6.6 vs 5.2 for SBP and 5.6 vs 4.9 for DBP, respectively). With perindopril/indapamide treatment, LVM index was significantly reduced (−9.1 g/m2 from baseline; p vs baseline <0.001). More patients required dose increases with enalapril (87%) than with perindopril/indapamide (71%). No unusual safety elements were noted.
First-line perindopril/indapamide combination decreased ambulatory SBP and PP, and LVM more effectively than enalapril.
left ventricular hypertrophy; ambulatory blood pressure monitoring; perindopril; indapamide; enalapril
To determine if the fixed-dose perindopril/indapamide combination (Per/Ind) normalizes blood pressure (BP) in the same fraction of hypertensive patients when treated in everyday practice or in controlled trials.
In this prospective trial, 17 938 hypertensive patients were treated with Per 2 mg/Ind 0.625 mg for 3–6 months. In Group 1 Per/Ind was initiated in newly diagnosed patients (n = 7032); in Group 2 Per/Ind replaced previous therapy in patients already treated but having either their BP still uncontrolled or experiencing side-effects (n = 7423); in Group 3 Per/Ind was added to previous treatment in patients with persistently high BP (n = 3483). BP was considered normalized when ≤ 140/90 mm Hg. A multivariate analysis for predictors of BP normalization was performed.
Subjects were on average 62 years old and had a baseline BP of 162.3/93.6 mm Hg. After treatment with Per/Ind, BP normalization was reached in 69.6% of patients in the Initiation group, 67.5% in the Replacement Group, and 67.4% in the Add-on Group (where patients were more frequently at risk, diabetic, or with target organ damage). Mean decreases in systolic BP of 22.8 mm Hg and in diastolic BP of 12.4 mm Hg were recorded.
This trial was established to reflect everyday clinical practice, and a treatment strategy based on the Per/Ind combination, administered as initial, replacement, or add-on therapy, led to normalization rates that were superior to those observed in Europe in routine practice. These results support recent hypertension guidelines which encourage the use of combination therapy in the management of arterial hypertension.
perindopril; indapamide; blood pressure normalization; risk factors; combination therapy
The importance of thiazide-induced hyponatremia (TIH) is reemerging because thiazide diuretic prescription seems to be increasing after the guidelines recommending thiazides as first-line treatment of essential hypertension have been introduced. Thiazide diuretics act by inhibiting reabsorption of Na+ and Cl- from the distal convoluted tubule by blocking the thiazide-sensitive Na+/Cl- cotransporter. Thus, they inhibit electrolyte transport in the diluting segment and may impair urinary dilution in some vulnerable groups. Risk factors predisposing to TIH are old age, women, reduced body masses, and concurrent use of other medications that impair water excretion. While taking thiazides, the elderly may have a greater defect in water excretion after a water load compared with young subjects. Hyponatremia is usually induced within 2 weeks of starting the thiazide diuretic, but it can occur any time during thiazide therapy when subsequent contributory factors are complicated, such as reduction of renal function with aging, ingestion of other drugs that affect free water clearance, or changes in water or sodium intake. While some patients are volume depleted on presentation, most appear euvolemic. Notably serum levels of uric acid, creatinine and urea nitrogen are usually normal or low, suggestive of syndrome of inappropriate secretion of antidiuretic hormone. Despite numerous studies, the pathophysiological mechanisms underlying TIH are unclear. Although the traditional view is that diuretic-induced sodium or volume loss results in vasopressin-induced water retention, the following 3 main factors are implicated in TIH: stimulation of vasopressin secretion, reduced free-water clearance, and increased water intake. These factors will be discussed in this review.
hyponatremia; thiazides; water; diuretics; vasopressins
Available information regarding the relation among atherosclerosis, low-density lipoproteins, markers of thrombosis, inflammation and endothelial dysfunction has accumulated, but is still very limited, making only minimal contributions to clinical decision-making. Many more clinical trials are needed, but unless there is a relationship between atherosclerosis prevention, specific markers and a pharmaceutical product, financial support for such trials will be difficult to obtain. The anti-inflammatory effect of statins is well established. Angiotensin-converting enzyme inhibitors are generally not thought of as having anti-inflammatory effects, but the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) study observed extensive RR reduction with perindopril. It was explained not simply by control of hypertension, but by reduced activity of multiple factors, supported by specific substudies. The ‘cardiovascular continuum’ is an excellent unifying term to explain atherosclerosis mechanisms, relate mechanisms to clinical understanding, and assist the clinician in selecting the appropriate prevention and control therapies. This so-called continuum actually describes a relationship among different biochemical, enzymatic and hormonal factors that affect the cardiovascular system. It can be seen in the downregulation of the angiotensin II receptor type 1 by statins, which contributes to hypertension control while lowering low-density lipoproteins. Peroxisome proliferator activator receptor-gamma also demonstrates the cardiovascular continuum with activation of the receptor by glitazones. The glitazones increase insulin sensitivity for diabetes control. Activation of the peroxisome proliferator activator receptor-gamma inhibits inflammation, which is possibly related to atherosclerosis, normalization of endothelial function, suppression of metalloproteinases and a decrease in smooth muscle cell migration. All of these effects may decrease atherosclerosis production while improving control of diabetes mellitus, a key disease in the cardiovascular continuum for development of atherosclerosis. Consideration of such interrelationships is just scratching the surface. Nevertheless, it can be seen that the complicated process of atherosclerosis development has a multifaceted explanation that has been minimally defined, but holds the key to prevention and control of this major medical problem faced in modern society.
Angiotensin-converting enzyme inhibitors; Angiotensin receptor blockers; Cardiovascular continuum; Coronary artery disease; Dysmetabolic syndrome; Endothelial dysfunction; Glitazones; Inflammation; Statins
Purpose of review
1. To review the current controversies related to the use of thiazide diuretics as first-line treatment of hypertension
2. To discuss the causal roles for hyperuricemia and hypokalemia on the adverse consequences of thiazide usage
Thiazides significantly reduce morbidity and mortality in hypertensive subjects. However, there remains debate about thiazide usage as first line treatment of hypertension. This negative impact of thiazides may be partially attributed to the ability of thiazides to exacerbate features of metabolic syndrome and/or increase the risk for developing diabetes. Several clinical trials suggest that thiazide-induced hyperuricemia and hypokalemia may account for some of these negative effects. Thiazide treatment is also associated with a decline of renal function in spite of a lowering blood pressure. In this review, we discuss the clinical and experimental evidence supporting a potential role of hyperuricemia and hypokalemia on the development of renal injury and worsening of the metabolic syndrome..
Hyperuricemia and hypokalemia may have pivotal roles in the exacerbation of the metabolic syndrome in response to thiazides. We propose that controlling serum uric acid and serum potassium could improve thiazide efficacy and also reduce its risk for inducing metabolic syndrome or diabetes.
Thiazides; metabolic syndrome; endothelial dysfunction; renal injury; hypokalemia; hyperuricemia
Hypertension in the elderly is associated with increased occurrence rates of sodium sensitivity, isolated systolic hypertension, and ‘white coat effect’. Arterial stiffness and endothelial dysfunction also increase with age. These factors should be considered in selecting antihypertensive therapy. The prime objective of this therapy is to prevent stroke. The findings of controlled trials show that there should be no cut-off age for treatment. A holistic program for controlling cardiovascular risks should be fully discussed with the patient, including evaluation to exclude underlying causes of secondary hypertension, and implementation of lifestyle measures. The choice of antihypertensive drug therapy is influenced by concomitant disease and previous medication history, but will typically include a thiazide diuretic as the first-line agent; to this will be added an angiotensin inhibitor and/or a calcium channel blocker. Beta blockers are not generally recommended, in part because they do not combat the effects of increased arterial stiffness. The hypertension–hypotension syndrome requires case-specific management. Drug-resistant hypertension is important to differentiate from faulty compliance with medication. Patients resistant to third-line drug therapy may benefit from treatment with extended-release isosorbide mononitrate. A trial of spironolactone may also be worthwhile.
hypertension; elderly; antihypertensive treatment; patient management
To assess the magnitude and independence of the effects of routine blood pressure lowering and intensive glucose control on clinical outcomes in patients with long-standing type 2 diabetes.
RESEARCH DESIGN AND METHODS
This was a multicenter, factorial randomized trial of perindopril-indapamide versus placebo (double-blind comparison) and intensive glucose control with a gliclazide MR–based regimen (target A1C ≤6.5%) versus standard glucose control (open comparison) in 11,140 participants with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. Annual event rates and risks of major macrovascular and microvascular events considered jointly and separately, renal events, and death during an average 4.3 years of follow-up were assessed, using Cox proportional hazards models.
There was no interaction between the effects of routine blood pressure lowering and intensive glucose control for any of the prespecified clinical outcomes (all P > 0.1): the separate effects of the two interventions for the renal outcomes and death appeared to be additive on the log scale. Compared with neither intervention, combination treatment reduced the risk of new or worsening nephropathy by 33% (95% CI 12–50%, P = 0.005), new onset of macroalbuminuria by 54% (35–68%, P < 0.0001), and new onset of microalbuminuria by 26% (17–34%). Combination treatment was associated with an 18% reduction in the risk of all-cause death (1–32%, P = 0.04).
The effects of routine blood pressure lowering and intensive glucose control were independent of one another. When combined, they produced additional reductions in clinically relevant outcomes.
Only a few randomized controlled trials investigating antiosteoporotic agents with fracture endpoints have included participants over the age of 80 years. The pivotal trial with alendronic acid had an upper age range of 80 years, although a separate trial that showed a significant reduction in nonvertebral fractures included some participants up to age of 84 years. Risedronate and zoledronic acid are the only bisphosphonates to show a significant reduction in new vertebral, hip and nonvertebral fractures during a 3-year period in those over 80 years of age. In addition, zoledronic acid was associated with a reduction in the rate of new clinical fractures and improved survival in elderly subjects after hip fracture. More recently, denosumab was found to significantly reduce the risk of new radiographic vertebral, hip and nonvertebral fractures in women up to the age of 89 years with osteoporosis. Strontium ranelate and teriparatide have shown fracture reductions in populations that have included subjects over the age of 80 years. There has been evidence to show that a combination of calcium and vitamin D reduces nonvertebral fracture in older populations. The role of vitamin D alone is less clear, although there is the suggestion that it may be effective at higher doses. The burden of osteoporosis is unquestionably rising within our ageing population. More emphasis is therefore required on researching the benefits of these pharmacological agents in very elderly people.
bisphosphonates; calcium; denosumab; elderly; fracture; fracture prevention; osteoporosis; strontium ranelate; teriparatide; vitamin D
Thiazide diuretics are used, worldwide, as the first-choice drug for patients with uncomplicated hypertension. In addition to their anti-hypertensive actions, they increase bone mineral density and reduce the prevalence of fractures, indicating that thiazides may have a role in the management of postmenopausal osteoporosis. Traditionally, the bone-protective effects of thiazides have been attributed to an increase in renal calcium reabsorption, secondary to the inhibition of the sodium chloride cotransporter, NCC, expressed in the kidney distal tubule. Whether thiazides exert a direct osteoanabolic effect independently of their renal action is controversial. Here we demonstrate that freshly frozen sections of human and rat bone express NCC, principally in bone-forming cells, the osteoblasts. In primary and established culture models of osteoblasts, fetal rat calvarial (FRC) and human MG63 cells, NCC protein is virtually absent in proliferating cells while its expression is dramatically increased during differentiation. Thiazides directly stimulate the production of osteoblast markers, runt-related transcription factor 2 (runx2) and osteopontin, in the absence of a proliferative effect. Using overexpression/knockdown studies in FRC cells, we show that thiazides, but not loop diuretics, increase mineralized nodule formation acting on NCC. Overall, our study demonstrates that thiazides stimulate osteoblast differentiation and bone mineral formation independently of their renal actions. In addition to their use as part of a therapeutic treatment plan for elderly, hypertensive individuals, our discovery opens up the possibility that bone-specific drug targeting by thiazides may be developed for the prevention and treatment of osteoporosis in the patient population as a whole.
thiazide diuretics; osteoblast; thiazide-sensitive Na+:Cl- cotransporter, NCC; fetal rat calvaria; osteoporosis
Fourteen patients with untreated mild to moderate essential hypertension had on average an abnormally high cardiovascular reactivity to exogenous noradrenaline and angiotension II, while plasma noradrenaline, renin activity, exchangeable body sodium, and blood volume were normal. Treatment with a low dose of indapamide (2.5 mg/day) for six weeks decreased blood pressure by 10% in these hypertensive patients but not in 13 normal control subjects. Plasma or blood volume and exchangeable sodium were not changed significantly; nevertheless, the latter, and body weight, tended to be decreased slightly. Though a mild reduction in extracellular sodium in both normal and hypertensive subjects appears possible, it may not per se fully explain indapamide's blood pressure-lowering effect in essential hypertension. Indapamide induced a mild decrease in angiotensin II pressor responsiveness in normal or hypertensive subjects, but a possible depressor influence from this change was probably antagonised by a concomitant pronounced increase in plasma renin activity. In hypertensive patients, the abnormally high noradrenaline reactivity was corrected by indapamide without an accompanying increase in endogenous plasma noradrenaline levels. Indapamide-induced changes in blood pressure correlated with those in noradrenaline pressor dose. It was concluded, therefore, that indapamide may decrease blood pressure in essential hypertension at least in part by lowering an abnormally high cardiovascular noradrenaline reactivity without causing an equivalent increase in adrenergic nervous activity.
Hypertension is one of the main risk factors for the development of cardiovascular diseases and the search for new therapeutic strategies aimed at optimizing its control remains an ongoing research and clinical challenge. In recent years, there has been a marked increase in the use of combinations of antihypertensive drugs with complementary mechanisms of action, with the aims of reducing blood pressure levels more rapidly and vigorously than strategies employing monotherapy and improving treatment compliance and adhesion. Therefore, as recommended by the 2009 reappraisal of the European Society of Hypertension/European Society of Cardiology Guidelines, the use of a triple combination that combines a calcium channel blocker, an angiotensin II receptor blocker and a thiazide diuretic seems a reasonable and efficacious combination for the management of hypertensive patients with moderate, high or very high risk. This article reviews the clinical trials carried out with the fixed combination of amlodipine/valsartan/hydrochlorothiazide at the doses recommended for each drug in monotherapy. The data show that this combination achieved greater reductions in mean sitting diastolic and systolic blood pressure than amlodipine, valsartan or hydrochlorothiazide in monotherapy, with favorable pharmacodynamic and pharmacokinetic profiles. The triple combination at high single doses should be used with caution in elderly patients and those with renal or liver failure. Although the tolerability and safety of the triple combination are good, the most-frequently reported adverse effects were peripheral edema, headache and dizziness. Analytical alterations were consistent with the already-known biochemical effects of amlodipine, valsartan or hydrochlorothiazide in monotherapy. In summary, triple-therapy with amlodipine/valsartan/hydrochlorothiazide in a single pill contributes additional advantages to fixed -combinations of two drugs, achieving a greater and more rapid reduction in blood pressure levels in a safe, well-tolerated manner.
hypertension treatment; antihypertensive fixed-dose triple-therapy; blood pressure control
OBJECTIVES: About 20% of elderly people use long-term diuretic medication, but there is doubt whether prolonged diuretic medication on such a large scale is necessary. We performed a study to assess what proportion may successfully be withdrawn from diuretic therapy. DESIGN: Double blind randomised controlled trial with six month follow up. SETTING: General practice. SUBJECTS: 202 patients taking long-term diuretics without manifest heart failure or hypertension. INTERVENTIONS: Patients were allocated to either placebo (withdrawal group, n = 102) or continuation of diuretic treatment (control group, n = 100). MAIN OUTCOME MEASURE: Occurrence of clinical conditions requiring diuretic therapy based on fixed criteria. RESULTS: During follow up diuretic therapy was required in 50 patients in the withdrawal group and 13 in the control group (risk difference 36%; 95% confidence interval 22% to 50%). Heart failure was the most frequent cause of prescribing diuretic therapy (n = 25). Cessation of diuretic therapy caused a mean increase in systolic blood pressure of 13.5 (9.2 to 17.8) mm Hg and in diastolic pressure of 4.6 (1.9 to 7.3) mm Hg. CONCLUSION: Withdrawal of long-term diuretic treatment in elderly patients leads to symptoms of heart failure or increase in blood pressure to hypertensive values in most cases. Any attempt to withdraw diuretic therapy requires careful monitoring conditions, notably during the initial four weeks.
OBJECTIVE--To determine the effect of thiazide diuretic drugs on rates of bone mineral loss. DESIGN--Longitudinal, observational study with a mean follow up of five years. SETTING--Hawaii Osteoporosis Center, Honolulu. SUBJECTS--1017 Japanese-American men born between 1900 and 1920, of whom 378 were treated for hypertension (study group) and 639 did not have hypertension (control group). INTERVENTION--Thiazide diuretics were taken by 325 men for a mean of 11.9 years; 53 men took antihypertensive drugs other than thiazides. MAIN OUTCOME MEASURE--Rate of bone loss estimated from serial photon absorptiometric scanning at three skeletal sites (calcaneus, distal radius, and proximal radius). RESULTS--Rates of bone loss at all three sites were significantly reduced among thiazide users when compared with controls. The reductions in loss rate ranged from 28.8% (p = 0.02) (distal radius) to 49.2% (p = 0.0005) (calcaneus) relative to the controls. At all three sites the men taking other antihypertensive drugs had faster loss rates (22.6-43.1%) than those of the controls but the difference was significant only for the distal radius. CONCLUSION--Thiazide diuretics slow the rate of bone loss in elderly men.
Nephrolithiasis remains a formidable health problem in the United States and worldwide. A very important but underaddressed area in nephrolithiasis is the accompanying bone disease. Epidemiologic studies have shown that osteoporotic fractures occur more frequently in patients with nephrolithiasis than in the general population. Decreased bone mineral density and defects in bone remodeling are commonly encountered in patients with calcium nephrolithiasis. The pathophysiologic connection of bone defects to kidney stones is unknown. Hypercalciuria and hypocitraturia are two important risk factors for stone disease, and treatments with thiazide diuretics and alkali, respectively, have been shown to be useful in preventing stone recurrence in small prospective trials. However, no studies have examined the efficacy of these agents or other therapies in preventing continued bone loss in calcium stone formers. This manuscript reviews the epidemiology, pathophysiology, and potential treatments of bone disease in patients with nephrolithiasis.
bone disease; citrate; kidney stone; nephrolithiasis; thiazide
Osteoporosis is a growing health concern as the number of senior adults continues to increase worldwide. Falls and fractures are very common among frail older adults requiring home health and long-term care. Preventative strategies for reducing falls have been identified and many therapies (both prescription and non-prescription) with proven efficacy for reducing fracture risk are available. However, many practitioners overlook the fact that a fragility fracture is diagnostic for osteoporosis even without knowledge of bone mineral density testing. As a result, osteoporosis is infrequently diagnosed and treated in the elderly after a fracture. Based on existing literature, we have developed an algorithm for the assessment and treatment of osteoporosis among persons with known prior fracture(s) living in long-term care facilities or receiving home health care.
Thiazide diuretics cause changes in calcium metabolism. Clinically, these changes include a decreased excretion of calcium, and in some instances, this results in a corresponding increase in bone mineral. The study of mineral metabolism in bone is difficult because of the slow turnover rate of bone. For this reason, the rat fracture model was used to study bone mineral metabolism in animals given thiazide diuretics. Fifty rats were divided into four groups: group 1 received a fracture of the right tibia and thiazide diuretics, group 2 received thiazide and no fracture, group 3 received no drugs and a fracture, and group 4 received no drugs and no fracture. At the end of 35 days postinjury, all animals were sacrificed. Biochemical and biomechanical results were analyzed, and revealed that animals that received thiazide diuretics and a fracture had the highest bone mineral content.
To investigate the role of drugs in the rising incidence of fractures of the femoral neck in the elderly a case-control study inquiring about the use of prescribed drugs was carried out. The drug histories of 102 patients with femoral neck fractures were obtained from general practice records and compared with those of 204 controls matched for age and sex from the same practices. At the time of fracture 41 patients with fractures and 126 controls were receiving at least one prescription (relative risk of fracture of the femoral neck in patients taking drugs = 0.42, p = 0.0006). For all types of prescribed drugs except antibiotics the risk of fracture of the femoral neck was less in patients taking drugs than in those not doing so, and this was true at all times in the year before fracture. Six patients with fractures were receiving thiazide diuretics compared with 37 controls (relative risk 0.28, p = 0.004). These results indicate that, contrary to popular belief, drugs that sedate or that impair postural control are not important factors in fractures of the femoral neck. The results are consistent with the hypothesis that the hypocalciuria induced by thiazides protects against fracture, but the degree of protection is not significantly greater than that associated with other drugs.
Objective To determine the value of monitoring blood pressure by quantifying the probability that observed changes in blood pressure reflect true changes.
Design Analysis of blood pressure measurements of patients in the perindopril protection against recurrent stroke study (PROGRESS).
Setting Randomised placebo controlled trial carried out in 172 centres in Asia, Australasia, and Europe.
Participants 1709 patients with history of stroke or transient ischaemic attack randomised to fixed doses of perindopril and indapamide.
Measurements Mean of two blood pressure measurements in patients receiving treatment recorded to the nearest 2 mm Hg with a standard mercury sphygmomanometer at baseline and then at three months, six months, nine months, and 15 months and then every six months to 33 months.
Results There was no change in the mean blood pressure of the cohort during the 33 month follow-up. Six months after blood pressure was stabilised on treatment, if systolic blood pressure was measured as having increased by >10 mm Hg, six of those measurements would be false positives for every true increase of ≥10 mm Hg. The corresponding value for an increase of 20 mm Hg was over 200. Values for 5 mm Hg and 10 mm Hg increases in diastolic blood pressure were 3.5 and 39, respectively. The likelihood that observed increases in blood pressure reflected true increases rose with the time between measurements such that the ratio of true positives to false positives reached parity at 21 months.
Conclusions Usual clinical approaches to the monitoring of patients taking drugs to lower blood pressure have a low probability of yielding reliable information about true changes in blood pressure. Evidence based guidelines for monitoring treatment response are urgently required to guide clinical practice.
Trial registration Australia and New Zealand Clinical Trial Registry.
There is limited evidence to support the efficacy of current pharmaceutical agents in reducing the risk of hip fracture in older postmenopausal women with established osteoporosis.
To clarify the efficacy of risedronate in reducing the risk of hip fracture in elderly postmenopausal women aged ≥ 70 years with established osteoporosis, i.e., those with bone mineral density-defined osteoporosis and a prevalent vertebral fracture.
Post hoc analysis of the Hip Intervention Program (HIP) study, a randomized controlled trial comparing risedronate with placebo for reducing the risk of hip fracture in elderly women. Women aged 70 to 100 years with established osteoporosis (baseline femoral neck T-score ≤ −2.5 and ≥1 prior vertebral fracture) were included. The main outcome measure was 3-year hip fracture incidence in the risedronate and placebo groups.
A total of 1656 women met the inclusion criteria. After 3 years, hip fracture had occurred in 3.8% of risedronate-treated patients and 7.4% of placebo-treated patients (relative risk 0.54; 95% confidence interval 0.32–0.91; P = 0.019).
Risedronate significantly reduced the risk of hip fracture in women aged up to 100 years with established osteoporosis.
osteoporosis; postmenopausal; hip fracture; risedronate