Benefits of antihypertensive drug treatment in elderly patients with isolated systolic hypertension

Isolated systolic hypertension affects over 15% of all people older than 60 years. In the elderly, systolic hypertension is a major modifiable cardiovascular risk factor. Systolic blood pressure is associated with higher risk of an adverse outcome, whereas diastolic blood pressure is inversely correlated with total mortality, independent of systolic blood pressure, highlighting the role of pulse pressure as risk factor. Three placebo-controlled outcome trials on antihypertensive drug treatment in older patients with isolated systolic hypertension have been published: the Systolic Hypertension in the Elderly Program (SHEP), the Systolic Hypertension in Europe (Syst-Eur) Trial and the Systolic Hypertension in China (Syst-China) Trial. These three trials demonstrated the benefit of antihypertensive drug treatment. A meta-analysis was performed by pooling the patients from these three trials with a subset of patients with isolated systolic hypertension from five other trials in the elderly. Antihypertensive treatment based on a calcium-channel blocker may provide additional benefits in diabetic patients and in the prevention of dementia and renal dysfunction. The pooled results of 15693 older patients with isolated systolic hypertension prove that antihypertensive drug treatment is justified if on repeated clinic measurements systolic blood pressure is 160 mmHg or higher.     

Relationships of heart rate and heart rate variability with conventional and ambulatory blood pressure in the population

BACKGROUND: Most studies on relationships between blood pressure and autonomic nervous function, assessed by power spectral analysis of heart rate variability, have used conventional or clinic blood pressure measurements in selected subjects, which may have influenced the results. OBJECTIVE: We aimed to investigate, in a population-based approach, associations of heart rate and heart rate variability, assessed in basal resting conditions and in response to standing, with conventional blood pressure measured by an investigator, and with ambulatory blood pressure monitored outside the laboratory. METHODS: RR interval and respiration were registered in 614 men and women, ages 25-89 years. After exclusion of subjects with myocardial infarction or diabetes and elimination of unsatisfactory recordings, 549 subjects remained for analyses at supine rest and 515 of these to assess the orthostatic responses. Hypertension was present in 39% of the subjects. The low-frequency (LF) and high-frequency (HF) components of heart rate variability were quantified by use of autoregressive modelling and expressed in absolute and normalized units. RESULTS: At supine rest, indices of heart rate variability were not independently related to 24 h systolic blood pressure, whereas some indices showed weak associations with diastolic 24 h pressure; the relationships were in general stronger for conventional blood pressure. For example, partial correlation coefficients of the relationships of the LF: HF ratio with systolic pressure were 0.12 (P < or = 0.01) for conventional pressure and 0.02 (NS) for 24 h pressure; these coefficients amounted to 0.20 (P < or = 0.001) and 0.11 (P < or = 0.01) for the diastolic pressures. The decrease of HF power and the increase of the LF:HF ratio on standing were significantly blunted at higher blood pressure, both when measured conventionally and by ambulatory monitoring (P < or = 0.001 for the LF: HF ratio). CONCLUSIONS: Relationships between autonomic nervous function at rest, assessed by use of power spectral analysis of heart rate variability, and conventional blood pressure, can at least partly be ascribed to the influence of the measurement conditions, whereas the orthostatic autonomic responses appear to be influenced by blood pressure per se.     

Follow-up of renal function in treated and untreated older patients with isolated systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators

BACKGROUND: In the outcome trials that provided information on renal function in older hypertensive patients, diuretics and beta-blockers were mostly used as first-line drugs. The long-term renal effects of calcium-channel blockers remain unclear. OBJECTIVE: To compare the changes in renal function in 2,258 treated and 2,148 untreated patients with isolated systolic hypertension, of whom 455 had diabetes mellitus and 390 had proteinuria. METHODS: We performed a post-hoc analysis of the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial. Active treatment was initiated with nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), or both, titrated or combined to reduce the sitting systolic blood pressure by at least 20 mmHg, to less than 150 mmHg. The main outcome measures were serum creatinine concentration and creatinine clearance calculated by the formula of Cockroft and Gault. RESULTS: Serum creatinine concentration at the time when participants were randomly allocated to study groups was less than 176.8 micromol/l (2.0 mg/dl), averaging 88 micromol/l. At the time of the last serum creatinine measurement, the blood pressure difference (P< 0.001) between the two groups was 11.6/4.1 mmHg. In the intention-to-treat analysis (11,427 patient-years), serum creatinine and the calculated creatinine clearance were not influenced by active treatment. However, in the patients assigned randomly to receive active treatment, the incidence of mild renal dysfunction (serum creatinine at least 176.8 mmol/l) decreased by 64% (P= 0.04) and that of proteinuria by 33% (P= 0.03). Active treatment reduced the risk of proteinuria more in diabetic than in non-diabetic patients: by 71%, compared with 20% (P= 0.04). In non-proteinuric patients, active treatment did not influence serum creatinine, whereas in patients with proteinuria at entry to the study, serum creatinine decreased on active treatment (P< 0.001). Furthermore, in on-randomized treatment comparison stratified for risk at baseline, serum creatinine concentration did not change (P= 0.98) in patients continuing to receive monotherapy with nitrendipine, whereas it increased by 6.73 mmol/l (P < 0.001) in patients who received hydrochlorothiazide alone or in combination with other study medication (P < 0.001 for difference in trends). CONCLUSIONS: In older patients with isolated systolic hypertension, antihypertensive treatment starting with the dihydropyridine calcium-channel blocker, nitrendipine, did not decrease blood pressure at the expense of renal function and prevented the development of proteinuria, especially in diabetic patients.     

Task Force II: blood pressure measurement and cardiovascular outcome

OBJECTIVE: To reach a consensus on the prognostic significance of new techniques of automated blood pressure measurement. METHODS: A Task Force on the prognostic significance of ambulatory blood pressure monitoring wrote this review in preparation for the Eighth International Consensus Conference (28-31 October 2001, Sendai, Japan). This synopsis was amended to account for opinions aired at the conference and to reflect the common ground reached in the discussions. POINTS OF CONSENSUS: (1) Prospective studies in treated and untreated hypertensive patients and in the general population have demonstrated that, even after adjusting for established risk factors, the incidence of cardiovascular events is correlated with blood pressure on conventional as well as ambulatory measurement. Ambulatory monitoring, however, significantly refines the prediction already provided by conventional blood pressure measurement. (2) White-coat hypertension is usually defined as an elevated clinic blood pressure in the presence of a normal daytime ambulatory blood pressure. Event-based studies in hypertensive patients have convincingly demonstrated that the risk of cardiovascular disease is less in patients with white-coat hypertension than in those with higher ambulatory blood pressure levels even after controlling for concomitant risk factors. Based on prognostic evidence, white-coat hypertension can now be defined as a conventional blood pressure that is persistently equal to or greater than 140/90 mmHg with an average daytime ambulatory blood pressure of below 135/85 mmHg. The issue of whether or not white-coat hypertension predisposes to sustained hypertension needs further research. (3) There is a growing body of evidence showing that a decreased nocturnal fall in blood pressure (<10% of the daytime level) is associated with a worse prognosis, irrespective of whether night-time dipping is studied as a continuous or a class variable. (4) Intermittent techniques of ambulatory blood pressure monitoring are limited in terms of quantifying short-term blood pressure variability. Proven cardiovascular risk factors such as old age, a higher than usual blood pressure and diabetes mellitus are often associated with greater short-term blood pressure variability. After adjusting for these risk factors, some - but not all - studies have nevertheless reported an independent and positive relationship between cardiovascular outcome and measures of variability of daytime and night-time blood pressure, for example standard deviation. (5) Reference values for ambulatory blood pressure measurement in children are currently based on statistical parameters of blood pressure distribution. In children and adolescents, functional rather than distribution-based definitions of ambulatory hypertension have yet to be developed. (6) Several studies of gestational hypertension have shown that, compared with office measurement, ambulatory blood pressure monitoring is a better predictor of maternal and fetal complications. Pregnancy is a special indication for ambulatory monitoring so that the white-coat effect can be measured and pregnant women are not given antihypertensive drugs unnecessarily. (7) Ambulatory pulse pressure and the QKD interval are measurements obtained by ambulatory monitoring that to some extent reflect the functional characteristics of the large arteries. The QKD interval is correlated with left ventricular mass, and ambulatory pulse pressure is a strong predictor of cardiovascular outcome. (8) Under standardized conditions, the self-measurement of blood pressure is equally as effective as ambulatory blood pressure monitoring in identifying the white-coat effect, but further studies are required to elucidate fully the prognostic accuracy of self-measured blood pressure in comparison with conventional and ambulatory blood pressure measurement. CONCLUSIONS: Ambulatory blood pressure measurement refines the prognostic information provided by conventional blood pressure readings obtained in the clinic or the doctor's office. Longitudinal studies of patients with white-coat hypertension should clarify the transient, persistent or progressive nature of this condition, particularly in paediatric patients, in whom white-coat hypertension may be a harbinger of sustained hypertension and target-organ damage in adulthood. Finally, the applicability, cost-effectiveness and long-term prognostic accuracy of the self-measurement of blood pressure should be evaluated in relation to conventional blood pressure measurement and ambulatory monitoring.     

Benefit of Antihypertensive Treatment in the diabetic patients enrolled in the Systolic Hypertension in Europe (Syst-Eur) Trial

In this review we attempt to determine the role of calcium channel blockers in preventing cardiovascular sequelae in patients with both hypertension and diabetes mellitus. The data have been collected from three sources: post-hoc analyses of subgroups of diabetic patients in placebo-controlled hypertension trials (SHEP, Syst-Eur, Syst-China); stepped-care blood pressure-oriented trials (HOT, UKPDS); and comparative trials focusing primarily on metabolic aspects and intermediate endpoints (ABCD, FACET).On balance, the data seem to indicate that long-acting calcium channel blockers score remarkably well in preventing cardiovascular complications in diabetic hypertensive patients.     

Cerebral complications of hypertension

Ischaemic and degenerative brain diseases are a major health problem leading to a devastating loss of autonomy. Hypertension has been shown to carry an increased risk not only for cerebrovascular morbidity and mortality but also for cognitive impairment and dementia. Although diastolic blood pressure is considered an important risk factor, it is now clear that isolated systolic hypertension and elevated pulse pressure also play an important role in the development of brain complications. Therefore the treatment of these conditions must urgently become a widespread tool of prevention. All the randomised placebo-controlled trials completed for the last 30 years have shown a reduction in fatal and/or non-fatal strokes. In the most recent trials in isolated systolic hypertension in older patients, the benefit was even greater because of the higher risk in these populations. The new classes of drugs, in particular, calcium-channels blockers and angiotensin-converting enzyme inhibitors, have been shown to be as effective as the originally used diuretics and beta-blockers. Active treatment in the Syst-Eur trial based on nitrendipine as first step, possibly associated with enalapril and/or hydrochlorthiazide reduced not only stroke and cardiovascular complications but also the incidence of dementia including Alzheimer's disease. This important finding must be confirmed by further trials specifically focusing on the prevention of dementia. In addition, the importance of pulse pressure as a risk factor, underlines the need for new drugs which could increase aortic distensibility and decrease systolic blood pressure without greatly reducing diastolic pressure. Improving the management of hypertension offers new opportunities to reduce age-related disease in older people and to promote healthy aging.     

Benefits of antihypertensive pharmacologic therapy and blood pressure reduction in outcome trials

In a quantitative overview of published trials, we investigated whether pharmacologic properties of antihypertensive drugs, as opposed to reduction in blood pressure, explain cardiovascular outcomes in hypertensive or high-risk patients. We used meta-regression to investigate the association between the odds ratios of outcome (experimental vs. reference treatment) and the corresponding blood pressure differences between study groups. Thus, we correlated odds ratios with between-group differences in systolic pressure. We then compared odds ratios of benefit observed in recent trials with those predicted by meta-regression on the basis of the differences in systolic pressure between randomized groups. Among nine actively-controlled trials in hypertension, significant differences in systolic pressure (follow-up minus baseline) between randomized groups (experimental minus reference) were observed in the ALLHAT, CAPPP, MIDAS, and NORDIL trials. Furthermore, the differences in achieved systolic and/or diastolic pressure between study groups were also significant in the hypertension trials and studies in high-risk patients, which involved untreated control patients. The differences between the observed odds ratios and those predicted by meta-regression did not reach statistical significance except for NORDIL and the single-drug therapy subgroup of the PROGRESS trial. In NORDIL, the risk of stroke was lower on diltiazem than on the older drug classes despite a 3.1 mm Hg higher systolic pressure on the calcium channel blocker. In PROGRESS, perindopril alone reduced blood pressure by 5/3 mm Hg, but did not affect the incidence of all cardiovascular events or the recurrence of stroke. In conclusion, the finding that in the reviewed trials blood pressure reduction largely accounted for outcome emphasizes the desirability of tight blood pressure control. The hypothesis that blood pressure-lowering medications might influence cardiovascular prognosis over and beyond their antihypertensive effect remains to a large extent unproved.     

Clinical applications of arterial stiffness; definitions and reference values

Arterial stiffening is the most important cause of increasing systolic and pulse pressure, and for decreasing diastolic pressure beyond 40 years of age. Stiffening affects predominantly the aorta and proximal elastic arteries, and to a lesser degree the peripheral muscular arteries. While conceptually a Windkessel model is the simplest way to visualize the cushioning function of arteries, this is not useful clinically under changing conditions when effects of wave reflection become prominent. Many measures have been applied to quantify stiffness, but all are approximations only, on account of the nonhomogeneous structure of the arterial wall, its variability in different locations, at different levels of distending pressure, and with changes in smooth muscle tone. This article summarizes the methods and indices used to estimate arterial stiffness, and provides values from a survey of the literature, followed by recommendations of an international group of workers in the field who attended the First Consensus Conference on Arterial Stiffness, which was held in Paris during 2000, under the chairmanship of M.E. Safar and E.D. Frohlich.     

Heritability and intrafamilial aggregation of arterial characteristics

BACKGROUND: We investigated the heritability and familial aggregation of various indexes of arterial stiffness and wave reflection and we partitioned the phenotypic correlation between these traits into shared genetic and environmental components. METHODS: Using a family-based population sample, we recruited 204 parents (mean age, 51.7 years) and 290 offspring (29.4 years) from the population in Cracow, Poland (62 families), Hechtel-Eksel, Belgium (36), and Pilsen, the Czech Republic (50). We measured peripheral pulse pressure (PPp) sphygmomanometrically at the brachial artery; central pulse pressure (PPc), the peripheral augmentation indexes (PAIxs) and central augmentation indexes (CAIxs) by applanation tonometry at the radial artery; and aortic pulse wave velocity (PWV) by tonometry or ultrasound. In multivariate-adjusted analyses, we used the ASSOC and PROC GENMOD procedures as implemented in SAGE and SAS, respectively. RESULTS: We found significant heritability for PAIx, CAIx, PPc and mean arterial pressure ranging from 0.37 to 0.41; P < or = 0.0001. The method of intrafamilial concordance confirmed these results; intrafamilial correlation coefficients were significant for all arterial indexes (r > or = 0.12; P < or = 0.02) with the exception of PPc (r = -0.007; P = 0.90) in parent-offspring pairs. The sib-sib correlations were also significant for CAIx (r = 0.22; P = 0.001). The genetic correlation between PWV and the other arterial indexes were significant (rhoG > or = 0.29; P < 0.0001). The corresponding environmental correlations were only significantly positive for PPp (rhoE = 0.10, P = 0.03). CONCLUSION: The observation of significant intrafamilial concordance and heritability of various indexes of arterial stiffness as well as the genetic correlations among arterial phenotypes strongly support the search for shared genetic determinants underlying these traits.     

Systolic Hypertension in Europe (Syst-Eur) trial phase 2: objectives, protocol, and initial progress. Systolic Hypertension in Europe Investigators

The Systolic Hypertension in Europe (Syst-Eur) trial proved that blood pressure (BP) lowering therapy starting with nitrendipine reduces the risk of cardiovascular complications in older (> or = 60 years) patients with isolated systolic hypertension (systolic BP > or = 160 mm Hg and diastolic BP < 95 mm Hg). After the completion of the Syst-Eur trial on 14 February 1997, 3506 consenting patients (93.0% of those eligible) were enrolled in phase 2 of the Syst-Eur trial. This open follow-up study aims to confirm the safety of long-term antihypertensive therapy based on a dihydropyridine. To lower the sitting systolic BP below 150 mm Hg (target BP), the first-line agent nitrendipine (10-40 mg/day) may be associated with enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), both add-on study drugs, or if required any other antihypertensive agent. On 1 November 1998, 3248 patients were still being followed, 86 patients had proceeded to non-supervised follow-up, and 43 had died. The median follow-up in Syst-Eur 2 was 14.3 months. At the last available visit, systolic/diastolic BP in the patients formerly randomised to placebo (n = 1682) or active treatment (n = 1824), had decreased by 13.2/5.2 mm Hg and by 4.6/1.6 mm Hg, respectively, so that the between-group BP difference was 1.7 mm Hg systolic (95% Ci: 0.8 to 2.6 mm Hg; P < 0.001) and 0.9 mm Hg diastolic (95% Cl: 0.4 to 1.5 mm mm Hg; P < 0.001). At the beginning of Syst-Eur 2, the goal BP was reached by 25.4% and 50.6% of the former placebo and active-treatment groups; at the last visit these proportions were 55.9% and 63.1%, respectively. At that moment, 45.9% of the patients were on monotherapy with nitrendipine, 29.3% took nitrendipine in combination with other study drugs. Until the end of 2001, BP control of the Syst-Eur 2 patients will be further improved. Cardiovascular complications and adverse events, such as cancer or gastro-intestinal bleeding, will be monitored and validated by blinded experts.