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.

Systolic blood pressure variability as a risk factor for stroke and cardiovascular mortality in the elderly hypertensive population.

OBJECTIVE: To investigate whether baseline systolic blood pressure variability was a risk factor for stroke, cardiovascular mortality or cardiac events during the Syst-Eur trial. DESIGN: The Syst-Eur study was a randomized, double-blind, placebo-controlled trial, powered to detect differences in stroke rate between participants on active antihypertensive treatment and placebo. Systolic blood pressure variability measurements were made on 744 participants at the start of the trial. Systolic blood pressure variability was calculated over three time frames: 24 h, daytime and night-time. The placebo and active treatment subgroups were analysed separately using an intention-to-treat principle, adjusting for confounding factors using a multiple Cox regression model. PARTICIPANTS: An elderly hypertensive European population. MAIN OUTCOME MEASURES: Stroke, cardiac events (fatal and non-fatal heart failure, fatal and non-fatal myocardial infarction and sudden death) and cardiovascular mortality (death attributed to stroke, heart failure, myocardial infarction, sudden death, pulmonary embolus, peripheral vascular disease and aortic dissection). RESULTS: The risk of stroke increased by 80% (95% confidence interval: 17-176%) for every 5 mmHg increase in night-time systolic blood pressure variability in the placebo group. Risk of cardiovascular mortality and cardiac events was not significantly altered. Daytime variability readings did not predict outcome. Antihypertensive treatment did not affect systolic blood pressure variability over the median 4.4-year follow-up. CONCLUSION: In the placebo group, but not the active treatment group, increased night-time systolic blood pressure variability on admission to the Syst-Eur trial was an independent risk factor for stroke during the trial.

Results of the pilot study for the Hypertension in the Very Elderly Trial.

BACKGROUND: The risks and benefits of treating hypertension in individuals older than 80 years are uncertain. A meta-analysis has suggested that a reduction in stroke events of 36% may have to be balanced against a 14% increase in total mortality. OBJECTIVES: To report the results of the pilot study of the Hypertension in the Very Elderly Trial (HYVET), which is in progress to address these issues. METHODS: The HYVET-Pilot was a multicentre international open pilot trial. In 10 European countries, 1283 patients older than 80 years and with a sustained blood pressure of 160-219/90-109 mmHg were allocated randomly to one of three treatments: a diuretic-based regimen (usually bendroflumethiazide; n = 426), an angiotensin-converting enzyme inhibitor regimen (usually lisinopril; n = 431) or no treatment (n = 426). The procedure permitted doses of the drug to be titrated and diltiazem slow-release to be added to active treatment. Target blood pressure was < 150/80 mmHg and mean follow-up was 13 months. RESULTS: In the combined actively treated groups, the reduction in stroke events relative hazard rate (RHR) was 0.47 [95% confidence interval (CI) 0.24 to 0.93] and the reduction in stroke mortality RHR was 0.57 (95% CI 0.25 to 1.32). However, the estimate of total mortality supported the possibility of excess deaths with active treatment (RHR 1.23, 95% CI 0.75 to 2.01). CONCLUSIONS: The preliminary results support the need for the continuing main HYVET trial. It is possible that treatment of 1000 patients for 1 year may reduce stroke events by 19 (nine non-fatal), but may be associated with 20 extra non-stroke deaths.

Copper-homocysteine complexes and potential physiological actions.

During the last 2 decades it was proposed that atherogenesis was closely related to the homeostasis of homocysteine (hCys) and/or copper. We hypothesized that the physiological action of hCys may be connected with its ability to form complexes with Cu. Our results showed the presence of two different Cu-hCys complexes. At a molar ratio Cu:hCys 1:1, a blue complex most probably consistent with a tentative dimeric Cu(II)(2)(hCys)(2)(H(2)O)(2) formula was formed, with tetrahedral Cu coordination and anti-ferromagnetic properties. The redox processes between Cu(II) and hCys, in a molar ratio > or =1:3 led to formation of a second yellow Cu(I)hCys complex. Both Cu-hCys complexes affected the metabolism of extracellular thiols more than hCys alone and inhibited glutathione peroxidase-1 activity and mRNA abundance. The biological action of hCys and Cu-hCys complexes involved remodeling and phosphorylation of focal adhesion complexes and paxillin. The adhesive interactions of monocytes with an endothelial monolayer led to the redistribution of both paxillin and F-actin after all treatments, but the diapedesis of monocytes through endothelial cell monolayer was both greater and faster in the presence of the tentative Cu(II)(2)(hCys)(2)(H(2)O)(2) complex. Together, these observations suggest that Cu-hCys complexes actively participate in the biochemical responses of endothelial cells that are involved in the aethiopathogenesis of atherosclerosis.

Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension.

OBJECTIVE: To examine the association of clinic and ambulatory heart rate with total, cardiovascular, and noncardiovascular death in a cohort of elderly subjects with isolated systolic hypertension from the Systolic Hypertension in Europe Trial. METHODS: A total of 4682 patients participated, whose untreated blood pressure on conventional measurement at baseline was 160 to 219 mm Hg systolic and lower than 95 mm Hg diastolic. Clinic heart rate was the mean of 6 readings during 3 visits. Ambulatory heart rate was recorded with a portable intermittent technique in 807 subjects. RESULTS: Raised baseline clinic heart rate was positively associated with a worse prognosis for total, cardiovascular, and noncardiovascular mortality among the 2293 men and women taking placebo. Subjects with heart rates higher than 79 beats/min (bpm) (top quintile) had a 1.89 times greater risk of mortality than subjects with heart rate lower than or equal to 79 bpm (95% confidence interval, 1.33-2.68 bpm). In a Cox regression analysis, predictors of time to death were heart rate (P<.001), age (P<.001), serum creatinine level (P =.001), presence of diabetes (P =.002), previous cardiovascular disease (P =.01), triglyceride readings (P =.02), smoking (P =.04), and elevated systolic blood pressure (P =.05), while total cholesterol level was found to be nonsignificant in the model. In the ambulatory monitoring subgroup, clinic and ambulatory heart rates predicted noncardiovascular but not cardiovascular mortality. However, in a Cox regression analysis in which clinic and ambulatory heart rates were included, a significant association with noncardiovascular mortality was found only for clinic heart rate (P =.004). In the active treatment group, the weak predictive power of clinic heart rate for mortality disappeared after adjustment for confounders. CONCLUSIONS: In untreated older patients with isolated systolic hypertension, a clinic heart rate greater than 79 bpm was a significant predictor of all-cause, cardiovascular, and noncardiovascular mortality. Ambulatory heart rate did not add prognostic information to that provided by clinic heart rate.

Ambulatory pulse pressure as predictor of outcome in older patients with systolic hypertension.

We enrolled 808 older patients with isolated systolic hypertension (160 to 219/71 <95 mm Hg) to investigate whether ambulatory measurement of pulse pressure and mean pressure can refine risk stratification. The patients (> or =60 years) were randomized to nitrendipine (10 to 40 mg/day) with the possible addition of enalapril (5 to 20 mg/day) or hydrochlorothiazide (12.5 to 25 mg/day) or to matching placebos. At baseline, pulse pressure and mean pressure were determined from six conventional blood pressure (BP) readings and from 24-h ambulatory recordings. With adjustment for significant covariables, we computed mutually adjusted relative hazard rates associated with 10 mm Hg increases in pulse pressure or mean pressure. In the placebo group, the 24-h and nighttime pulse pressures consistently predicted total and cardiovascular mortality, all cardiovascular events, stroke, and cardiac events. Daytime pulse pressure predicted cardiovascular mortality, all cardiovascular end points, and stroke. The hazard rates for 10 mm Hg increases in pulse pressure ranged from 1.25 to 1.68. Conventionally measured pulse pressure predicted only cardiovascular mortality with a hazard rate of 1.35. In the active treatment group compared with the placebo patients, the relation between outcome and ambulatory pulse pressure was attenuated to a nonsignificant level. Mean pressure determined from ambulatory or conventional BP measurements was not associated with poorer prognosis. In conclusion, in older patients with isolated systolic hypertension higher pulse pressure estimated by 24-h ambulatory monitoring was a better predictor of adverse outcomes than conventional pulse pressure, whereas conventional and ambulatory mean pressures were not correlated with a worse outcome.

Quality control of the blood pressure phenotype in the European Project on Genes in Hypertension.

OBJECTIVES: In the European Project on Genes in Hypertension (EPOGH) standardized epidemiological methods were used to determine complex phenotypes consisting of blood pressure (BP) in combination with other traits. In this report, we present the quality control of one of the BP phenotypes. METHODS: In seven European countries eight different research groups recruited random samples of nuclear families. Trained observers measured the BP five times consecutively with the participants in the seated position at each of two separate home visits, 1 to 3 weeks apart, according to the guidelines of the British Hypertension Society. Quality assurance and quality control of this BP phenotype were implemented according to detailed instructions defined in the protocol of the EPOGH study. RESULTS: On 31 August 2001, BP measurements of 2476 subjects were available for analysis. Fewer BP readings than the five planned per visit occurred in one of the eight centres, but only in 0.4% of the home visits. Across centres the relative frequency of identical consecutive readings for systolic or diastolic blood pressure varied from 0 to 6%. The occurrence of odd readings ranged from 0 to 0.1%. Of the 49,488 systolic and diastolic BP readings, 24.0% ended on a zero (expected 20%). In most EPOGH centres there was a progressive decline in the BP from the first to the second home visit. Overall, these decreases averaged 2.36 mmHg [95% confidence interval (CI): 1.98-2.74, P < 0.001] for systolic BP and 1.74 mmHg (95% CI: 1.46-2.02, P < 0.001) for diastolic BP. CONCLUSIONS: Quality assurance and control should be planned at the design stage of a project involving BP measurement and implemented from its very beginnings until the end. The procedures of quality assurance set up in the EPOGH study for the BP measurements resulted in a well-defined BP phenotype, which was consistent across centres.

Prognostic significance of renal function in elderly patients with isolated systolic hypertension: results from the Syst-Eur trial.

Several reports suggest that markers of renal function such as serum creatinine, serum uric acid, and urinary excretion of protein may be related to cardiovascular complications and mortality. This study analyzed the data from the Syst-Eur trial, which was a randomized, placebo-controlled, double-blind intervention trial in elderly patients with isolated systolic hypertension. The purpose was to evaluate whether serum levels of creatinine and uric acid and urinary protein excretion at entry are related to subsequent morbidity and mortality. Incidence rates of total mortality, cardiovascular mortality, stroke (fatal as well as nonfatal), coronary events, and all cardiovascular endpoints were calculated for each quintile of serum creatinine or serum uric acid or for each category of protein excretion (none, trace, and overt). Crude and adjusted relative hazard rates were also determined for each 20 micro M increase in serum creatinine, each 50 micro M increase in serum uric acid, and for each protein excretion category. Even when adjusted for age, gender, and various other covariates, serum creatinine was significantly associated with a worse prognosis. There was an U-shaped relationship between serum uric acid and total mortality, but otherwise no obvious relationships were detected between serum uric acid levels and complications when appropriate adjustments were made for confounding variables. Proteinuria at entry was a significant predictor of total mortality and all cardiovascular endpoints. It is concluded that higher levels of serum creatinine and trace or overt proteinuria are associated with an increased number of cardiovascular events and with a higher mortality in patients with isolated systolic hypertension.

Withdrawal from treatment in the Syst-Eur Trial.

OBJECTIVE: To investigate the reasons for withdrawal from double-blind randomized trials, and the reasons for changing treatment within a randomized therapeutic group. DESIGN: The Syst-Eur trial, in which 4695 older patients with systolic hypertension were randomized to active or placebo treatment. METHODS: The reasons for withdrawal from the trial were examined, both for patient-initiated and investigator-initiated withdrawals. In addition, the reasons for stopping the first-line treatment (nitrendipine), the second-line treatments (enalapril and hydrochlorothiazide) and the corresponding placebos, were determined. RESULTS: A total of 135 patients (6%) were withdrawn by the investigators from placebo treatment because their blood pressure was too high, and, similarly, 36 (1.6%) through patient initiation. The corresponding results for the actively treated patients were 14 (0.6%) and 7 (0.3%). Very few patients were withdrawn from the trial because of the adverse effects of treatment. However, 39 (4%) stopped taking active nitrendipine because of ankle oedema, compared with 4 (0.5%) on placebo. Similarly, 28 versus three stopped due to flushing. Forty-one (10%) stopped taking enalapril because of cough, against eight (2%) for enalapril placebo. In all, 15.0% stopped active nitrendipine, 20.2% enalapril and 6.3% hydrochlorothiazide, versus placebo 7.1, 9.1 and 5.1%. CONCLUSIONS: The numbers withdrawn from the trial for adverse treatment consequences were small in comparison to the cardiovascular benefits. Nevertheless the numbers stopping individual treatments were higher than expected.

How well can blood pressure be controlled? Progress report on the Systolic Hypertension in Europe Follow-Up Study (Syst-Eur 2).

BACKGROUND: The randomised, double-blind, placebo-controlled Systolic Hypertension in Europe trial (Syst-Eur 1) proved that blood pressure (BP) lowering therapy starting with nitrendipine reduces the risk of cardiovascular complications in elderly patients with isolated systolic hypertension. In an attempt to confirm the safety of long-term antihypertensive therapy based on a dihydropyridine, the Syst-Eur patients remained in open follow-up after the end of Syst-Eur 1. This paper presents the second progress report of this follow-up study (Syst-Eur 2). It describes BP control and adherence to study medications. METHODS: After the end of Syst-Eur 1 all patients, treated either actively or with placebo, were invited either to continue or to start antihypertensive treatment with the same drugs as previously used in the active treatment arm. In order to reach the target BP (sitting SBP <150 mmHg), the first line agent, nitrendipine, could be associated with enalapril and/or hydrochlorothiazide. RESULTS: Of the 3787 eligible patients, 3516 (93%) entered Syst-Eur 2. At the last available visit, 72% of the patients were taking nitrendipine. SBP/DBP at entry in Syst-Eur 2 averaged 160/83 mmHg in the former placebo group and 151/80 mmHg in the former active-treatment group. At the last follow-up visit SBP/DBP in the patients previously randomised to placebo or active treatment had decreased by 16/5 mmHg and 7/5 mmHg, respectively. The target BP was reached by 74% of the patients. CONCLUSION: Substantial reductions in systolic BP may be achieved in older patients with isolated systolic hypertension with a treatment strategy starting with the dihydropyridine calcium-channel blocker, nitrendipine, with the possible addition of enalapril and/or hydrochlorothiazide.