On-treatment diastolic blood pressure and prognosis in systolic hypertension.

BACKGROUND: It has been suggested that low diastolic blood pressure (BP) while receiving antihypertensive treatment (hereinafter called on-treatment BP) is harmful in older patients with systolic hypertension. We examined the association between on-treatment diastolic BP, mortality, and cardiovascular events in the prospective placebo-controlled Systolic Hypertension in Europe Trial. METHODS: Elderly patients with systolic hypertension were randomized into the double-blind first phase of the trial, after which all patients received active study drugs (phase 2). We assessed the relationship between outcome and on-treatment diastolic BP by use of multivariate Cox regression analysis during receipt of placebo (phase 1) and during active treatment (phases 1 and 2). RESULTS: Rates of noncardiovascular mortality, cardiovascular mortality, and cardiovascular events were 11.1, 12.0, and 29.4, respectively, per 1000 patient-years with active treatment (n = 2358) and 11.9, 12.6, and 39.0, respectively, with placebo (n = 2225). Noncardiovascular mortality, but not cardiovascular mortality, increased with low diastolic BP with active treatment (P < .005) and with placebo (P < .05); for example, hazard ratios for lower diastolic BP, that is, 65 to 60 mm Hg, were, respectively, 1.15 (95% confidence interval, 1.00-1.31) and 1.28 (95% confidence interval, 1.03-1.59). Low diastolic BP with active treatment was associated with increased risk of cardiovascular events, but only in patients with coronary heart disease at baseline (P < .02; hazard ratio for BP 65-60 mm Hg, 1.17; 95% confidence interval, 0.98-1.38). CONCLUSIONS: These findings support the hypothesis that antihypertensive treatment can be intensified to prevent cardiovascular events when systolic BP is not under control in older patients with systolic hypertension, at least until diastolic BP reaches 55 mm Hg. However, a prudent approach is warranted in patients with concomitant coronary heart disease, in whom diastolic BP should probably not be lowered to less than 70 mm Hg.

[What's new in postmenopausal osteoporosis].

The ability of bone to resist fracture is the best indicator of bone quality and is potentially related to several bone properties, including quality, turnover rate, microarchitecture, geometry, and mineralization. The U.S. Preventive Services Task Force recommends routine osteoporosis screening (by DXA) beginning at age 65 years for all women, and beginning at age 60 years for those at high risk. These recommendations are controversial, because no randomized trial results have shown that screening ultimately prevents fractures. Additional radiologic procedures may be helpful, particularly to define bone fractures. Several serum and urine biochemical tests are now available that provide an index of the overall rate of bone turnover and are usually characterized as those related primarily to bone formation or bone resorption. The results of clinical trials have shown that antiresorptive agents reduce fracture risk to varying degrees and that the magnitude of the reduction in fracture risk is proportional to the magnitude of changes in bone turnover and bone mineral density (BMD). The bisphosphonates are currently the preferred agents for the prevention and treatment of osteoporosis with the goal of reducing the risk of both vertebral and nonvertebral fractures. They are retained over time in the skeleton and may exert long-term effects. A 10-year course is safe and effective in women with high risk for fractures. A temporary stop may be considered after 5 years of treatment in less severe cases, on an individual basis. Calcitonin and raloxifene have no significant effect on the risk of hip and other nonvertebral fractures. Teriparatide, a synthetic 1-34 parathormone stimulates new bone formation, repairing architectural defects and reducing the risk of vertebral and all nonvertebral (but not hip) fractures in severe postmenopausal osteoporosis. Its administration is limited by time (no more than 2 years) and cost. The effect of vitamin D and calcium on the fracture's risk is controversial and its administration as the sole treatment is recommended mainly for elderly and other populations with Vitamin D deficiency. It is mandatory to supply the recommended vitamin D and calcium to the whole population independent of the need for therapy. Strontium ranelate appears to stimulate bone formation and reduce resorption and has been shown to reduce moderately vertebral and non-vertebral fractures in postmenopausal women with established osteoporosis. New medications are in development, including antiresorptive and bone formation stimulating agents.

[Is there a future for COX-2 inhibitors?].

The two cyclooxygenase isoforms (COX-1 and COX-2--coxibs) have overlapping functions and both are involved in the regulation of homeostatic and inflammatory processes in the various tissues. Treatment with highly selective COX-2 inhibitors is associated with significantly fewer serious adverse gastrointestinal events than is treatment with the dual inhibitors--the non-selective NSAIDs. Of the two coxibs, rofecoxib was shown to be much more selective than celecoxib and with less interaction with other drugs. Various clinical studies have demonstrated that the coxibs are equivalent, in anti-inflammatory, analgesic and antipyretic efficacy to comparator non-selective NSAIDs in osteoarthritis, rheumatoid arthritis, post surgery pain and dysmenorrhea. Perioperative use of coxibs reduces pain, opioid consumption and the risk of bleeding caused by the non-selective NSAIDs. The coxibs show similar tolerability for renal, liver and cardiothrombotic events as compared to the non-selective NSAIDs. Coxibs are contraindicated in pregnancy, in nursing mothers and pediatric patients and should be used with caution in patients with asthma. The impact of the coxibs on the cardiovascular system is controversial. However, coxibs should be used in caution and at the lowest recommended dose in patients with hypertension, ischemic heart disease and heart failure. These drugs do not interfere with the aspirin anti-platelet aggregation activity. Emerging evidence suggest that the coxibs may also find potential use as supportive therapy in various malignant tumors and intestinal polyps where COX-2 is overly expressed.

Prognostic significance of electrocardiographic voltages and their serial changes in elderly with systolic hypertension.

The aim of the present study was to assess the prognostic value of ECG voltages at baseline and their serial changes during follow-up in a large prospective study with standardized follow-up and strictly defined end points. Patients who were 60 years old or older, with systolic blood pressure of 160 to 219 mm Hg and diastolic pressure <95 mm Hg, were randomized into the double-blind placebo-controlled Systolic Hypertension in Europe trial. Active treatment consisted of nitrendipine, which could be combined with or replaced by enalapril, hydrochlorothiazide, or both. At the end of the double-blind part of the trial (median follow-up, 2.0 years), follow-up was extended and all patients received active study drugs (median total follow-up, 6.1 years). Electrocardiography was performed at baseline and yearly thereafter. Electrocardiographic left ventricular mass was prospectively defined as the sum of 3 voltages (RaVL+SV1+RV5), which averaged 3.1+/-1.0 mV. The adjusted relative hazard rate, associated with a 1 mV higher sum at baseline, amounted to 1.10 and 1.15 for all-cause and cardiovascular mortality and to 1.21 and 1.18 for strokes and cardiac events, respectively (P< or =0.01 for all). A 1-mV decrease in electrocardiographic voltages during follow-up independently predicted a lower incidence of cardiac events (relative hazard rate: 0.86; P< or =0.05), but not of stroke or mortality. In conclusion, electrocardiographic voltages at baseline and their serial changes during follow-up predict subsequent events in older patients with systolic hypertension.

Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial.

BACKGROUND: To assess the impact of immediate versus delayed antihypertensive treatment on the outcome of older patients with isolated systolic hypertension, we extended the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial by an open-label follow-up study lasting 4 years. METHODS: The Syst-Eur trial included 4695 randomized patients with minimum age of 60 years and an untreated blood pressure of 160-219 mmHg systolic and below 95 mmHg diastolic. The double-blind trial ended after a median follow-up of 2.0 years (range 1-97 months). Of 4409 patients still alive, 3517 received open-label treatment consisting of nitrendipine (10-40 mg daily) with the possible addition of enalapril (5-20 mg daily), hydrochlorothiazide (12.5-25 mg daily), or both add-on drugs. Non-participants (n = 892) were also followed up. RESULTS: Median follow-up increased to 6.1 years. Systolic pressure decreased to below 150 mmHg (target level) in 2628 participants (75.0%). During the 4-year open-label follow-up, stroke and cardiovascular complications occurred at similar frequencies in patients formerly randomized to placebo and those continuing active treatment. These rates were similar to those previously observed in the active-treatment group during the double-blind trial. Considering the total follow-up of 4695 randomized patients, immediate compared with delayed antihypertensive treatment reduced the occurrence of stroke and cardiovascular complications by 28% (P = 0.01) and 15% (P = 0.03), respectively, with a similar tendency for total mortality (13%, P = 0.09). In 492 diabetic patients, the corresponding estimates of long-term benefit (P < 0.02) were 60, 51 and 38%, respectively. CONCLUSIONS: Antihypertensive treatment can achieve blood pressure control in most older patients with isolated systolic hypertension. Immediate compared with delayed treatment prevented 17 strokes or 25 major cardiovascular events per 1000 patients followed up for 6 years. These findings underscore the necessity of early treatment of isolated systolic hypertension.

The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study.

BACKGROUND: After the double-blind, placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial ended in February 1997, randomized patients were offered active study medication for a further period of observation. OBJECTIVE: To refine the estimates of the long-term effects of antihypertensive therapy on the incidence of dementia. METHODS: Eligible patients had no dementia and were at least 60 years old. Their systolic blood pressure at entry was 160 to 219 mm Hg, with diastolic blood pressure below 95 mm Hg. Antihypertensive therapy was started immediately after randomization in the active treatment group, but only after termination of the double-blind trial in the control patients. Treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d), hydrochlorothiazide (12.5-25 mg/d), or both add-on drugs. RESULTS: Median follow-up increased from 2.0 years in the double-blind trial to 3.9 years overall. The incidence of dementia doubled from 32 to 64 cases, 41 of whom had Alzheimer disease. Throughout follow-up, systolic/diastolic blood pressure was 7.0/3.2 mm Hg higher in the 1417 control patients than in the 1485 subjects randomized to active treatment. At the last examination, the blood pressure difference was still 4.2/2.9 mm Hg; 48.1%, 26.4%, and 11.4% of the control patients were taking nitrendipine, enalapril, and/or hydrochlorothiazide, whereas in the active treatment group these proportions were 70.2%, 35.4%, and 18.4%, respectively. Compared with the controls, long-term antihypertensive therapy reduced the risk of dementia by 55%, from 7.4 to 3.3 cases per 1000 patient-years (43 vs 21 cases, P<.001). After adjustment for sex, age, education, and entry blood pressure, the relative hazard rate associated with the use of nitrendipine was 0.38 (95% confidence interval, 0.23-0.64; P<.001). Treatment of 1000 patients for 5 years can prevent 20 cases of dementia (95% confidence interval, 7-33). CONCLUSION: The extended follow-up of Syst-Eur patients reinforces the evidence that blood pressure-lowering therapy initiated with a long-acting dihydropyridine protects against dementia in older patients with systolic hypertension.