G. Leonetti

MORTALITY AND MORBIDITY RESULTS FROM THE EUROPEAN WORKING PARTY ON HIGH BLOOD PRESSURE IN THE ELDERLY TRIAL

The latter was due to a reduction in cardiac mortality (−38%, p=0.036) and a nonsignificant decrease in cerebrovascular mortality (−32%, p=0.16). In the double-blind part of the trial, the total mortality rate was not significantly reduced (−26%, p=0.077). However, cardiovascular mortality was reduced in the actively treated group (−38%, p=0.023), owing to a reduction in cardiac deaths (−47%, p=0.048) and a non-significant decrease in cerebrovascular mortality (−43%, p=0.15). Deaths from myocardial infarction were reduced (−60%, p=0.043), and study-terminating morbid cardiovascular events were significantly reduced by active treatment (−60%, p=0.0064). Non-terminating cerebrovascular events were reduced (−52%, p=0.026), but the non-terminating cardiac events were not (+ 3%, p=0.98). In the patients randomised to active treatment there were 29 fewer cardiovascular events and 14 fewer cardiovascular deaths per 1000 patient years during the double-blind part of the trial.

EFFICACY OF ANTIHYPERTENSIVE DRUG TREATMENT ACCORDING TO AGE, SEX, BLOOD PRESSURE, AND PREVIOUS CARDIOVASCULAR DISEASE IN PATIENTS OVER THE AGE OF 60

Results of the European Working Party on High Blood Pressure in the Elderly (EWPHE) trial have been analysed in relation to age, sex, blood pressure, and previous cardiovascular disease. Cardiovascular mortality and the cardiovascular study-terminating events were significantly and independently related to treatment, age, cardiovascular complications at randomisation, and systolic but not diastolic blood pressure. The benefits of treatment observed in the trial seemed to be independent of entry blood pressure and the presence or absence of cardiovascular complications at entry. There was some evidence that treatment effect decreases with advancing age. Little or no benefit from treatment could be demonstrated in patients over the age of 80 years, the great majority of whom were women.

Metabolic syndrome and target organ damage in untreated essential hypertensives

Background The prevalence and the relationship between metabolic syndrome, and target organ damage (TOD) in essential hypertensive patients has not been fully explored to date. Objective To investigate the association between metabolic syndrome, as defined by the ATP III report, and cardiac and extracardiac TOD, as defined by the 2003 ESH–ESC guidelines for management of hypertension, in a large population of never-treated essential hypertensives. Methods A total of 447 grade 1 and 2 hypertensive patients (mean age 46 ± 12 years) who were attending a hypertension hospital outpatient clinic for the first time underwent the following procedures: (i) physical examination and repeated clinic blood pressure measurements; (ii) routine examinations; (iii) 24-h urine collection for microalbuminuria; (iv) 24-h ambulatory blood pressure monitoring; (v) echocardiography; and (vi) carotid ultrasonography. Metabolic syndrome was defined as involving at least three of the following alterations: increased waist circumference, increased triglycerides, decreased high-density lipoprotein cholesterol, increased blood pressure, or high fasting glucose. Left ventricular hypertrophy (LVH) was defined according to two different criteria: (i) 125 g/m2 in men and 110 g/m2 in women; (ii) 51 g/h2.7 in men and 47 g/h2.7 in women. Results The 135 patients with metabolic syndrome (group I) were similar for age, sex distribution, known duration of hypertension and average 24-h, daytime and night-time ambulatory blood pressure to the 312 patients without it (group II).The prevalence of altered left ventricular patterns (LVH and left ventricular concentric remodelling) was significantly higher in group I (criterion a = 30%, criterion b = 42%) than in group II (criterion a = 23%, criterion b = 30%, P < 0.05 and P < 0.01, respectively). A greater urinary albumin excretion (17 ± 35 versus 11 ± 23 mg/24 h, P = 0.04) was also found in group I compared to group II. There were no significant differences between the two groups in the prevalence of carotid intima–media thickening and plaques. Conclusions These results from a representative sample of untreated middle-aged hypertensives show that: (i) the metabolic syndrome is highly prevalent in this setting and (ii) despite similar ambulatory blood pressure values, patients with metabolic syndrome have a more pronounced cardiac and extracardiac involvement than those without it.

Comparison of cardiovascular, renal, and humoral effects of acute administration of two calcium channel blockers in normotensive and hypertensive subjects

The acute effects of two calcium channel blockers, nifedipine and verapamil, were compared in eight normotensive subjects and eight patients with essential hypertension. Nifedipine 10 mg and verapamil 160 mg orally had no effect on blood pressure of normal subjects, but reduced systolic and diastolic pressures of hypertensive patients to the same extent. The blood pressure reduction caused by nifedipine was more prompt and of lesser duration than that caused by verapamil. In both normal subjects and hypertensive patients nifedipine caused a transient rise in heart rate and plasma renin activity, and plasma catecholamines showed a tendency to increase; verapamil did not affect these variables. Nifedipine induced a marked increase in urine volume and renal sodium excretion in hypertensive patients, with a much smaller change in normotensives. Verapamil did not influence water and sodium excretion in either direction. Thus, this study shows similarities and differences between the effects induced by acute oral administration of the most-used vasodilating calcium antagonists.

Effects of Cardiac Rehabilitation and Beta-Blocker Therapy on Heart Rate Variability After First Acute Myocardial Infarction

After acute myocardial infarction (AMI), rehabilitation with physical training increases parasympathetic tone. It is unknown whether such a favorable effect of exercise on the sympathovagal balance interacts with effects of other widespread therapies, such as beta blockers. In 53 patients after a first, uncomplicated AMI, we studied the combined short- and long-term influence on heart rate variability (HRV) of rehabilitation and beta blockade. Patients were divided into 3 groups: group 1 (n = 19) underwent rehabilitation with physical training; group 2 (n = 20) was taking beta blockers and underwent rehabilitation; group 3 (n = 14) was taking beta blockers and did not enter the rehabilitation program for logistic reasons. Patients were similar as to age, site of infarction, ejection fraction, left ventricular diameter, and baseline stress test duration. Measures of HRV (obtained from a 15-minute resting electrocardiogram) were the standard deviation of the mean RR interval (RRSD), the mean squared successive differences (MSSD), the percent of RR intervals differing >50 ms from the preceding one (pNN50), the low-(LF) and high-(HF) frequency components of the autoregressive power spectrum of the RR intervals and their ratio (LF/HF). Four weeks after AMI, there was less sympathetic predominance in groups 2 and 3 (i.e., patients taking beta blockers [p <0.05]). Rehabilitation modified HRV in groups 1 and 2 (p <0.05), with signs of increased parasympathetic tone (group 1: MSSD +25%, pNN50 +69%, LF/HF -40%; group 2: MSSD +41%, pNN50 +48%, LF/HF -39%). These changes persisted in the long term. In group 3, HRV was unchanged over time. Hence, after AMI, the effects of rehabilitation and beta blockers on HRV are not redundant: their association induces a more favorable sympathovagal balance, accelerating the recovery of a normal autonomic profile.

Antihypertensive and renal effects of orally administered verapamil

SummaryIn 12 in-patients with moderate uncomplicated hypertension, maintained on constant sodium intake for 15 days, single-blind oral administration of verapamil 80–160 mg t. i. d. for 10 days had a significant antihypertensive effect: in the supine position systolic blood pressure decreased from 177±5 to 150±3 mmHg, and diastolic pressure from 111±3 to 96±2 mmHg; standing values were similarly lowered from 171±7 to 143±4 mmHg, systolic, and from 118±4 to 97±2 mmHg, diastolic. The heart rate did not show any significant change (from 79±3 to 77±2 beats/min, supine, and from 92±3 to 87±3 beats/min, upright). The antihypertensive effect was uniform throughout the day, being similar 2, 3, 6 and 8 h after administration of a dose. Dynamic exercise (75–100 watts on a cycle-ergometer) caused identical increases in arterial pressure and heart rate on the last day of placebo and again on the last day with verapamil, but the peak levels of systolic pressure reached during exercise were lower after verapamil than with placebo, because of the lower blood pressure before exercise. Reduction of arterial pressure by verapamil was not accompanied by increased plasma renin activity, or by renal retention of sodium and water: there was a small increase in sodium excretion, at least during the first days of verapamil administration (from 107±15 to 113±15 mEq Na+/day), and a slight significant reduction in body weight (from 74.2±3.7 to 73.5±3.7 kg). It is concluded that oral administration of verapamil significantly lowers blood pressure without simultaneously inducing cardiac stimulation, renin secretion or salt and water retention.

Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: Objectives, protocol, and organization

SummaryThe Syst-Eur Trial is a concerted action of the European Community’s Medical and Health Research Programme. The trial is carried out in consultation with the World Health Organization, the International Society of Hypertension, the European Society of Hypertension and the World Hypertension League. This article describes the objectives and the protocol of Syst-Eur, a multicentre trial designed by the European Working Party on High Blood. Pressure in the Elderly (EWPHE), to test the hypothesis that antihypertensive treatment of elderly patients with isolated systolic hypertension results in a significant change in stroke morbidity and mortality. Secondary endpoints include cardiovascular events, such as myocardial infarction and congestive heart failure.To be eligible patients must be at least 60 years old and have a systolic blood pressure averaging 160–219 mmHg with a diastolic pressure less than 95 mmHg. Patients must give their informed consent and be free of major cardiovascular and non-cardiovascular diseases at entry. The patients are randomized to active treatment or placebo. Active treatment consists of nitrendipine (10–40 mg/day), combined with enalapril (5–20 mg/day) and hydrochlorothiazide (12.5–25 mg/day), as necessary. The patients of the control group receive matching placebos. The drugs (or matching placebos) are stepwise titrated and combined in order to reduce systolic blood pressure by 20 mmHg at least to a level below 150 mmHg. Morbidity and mortality are monitored to enable an intention-to-treat and perprotocol comparison of the outcome in the 2 treatment groups.A one-year pilot trial (1989) showed that the protocol is practicable. The Ethics Committee therefore decided to start the definite study (1990), in which randomized patients will be followed for 5 years. Recruitment of new centres and of the required 3,000 patients will last 3 years (until 1993).

Blood pressure control and risk of stroke in untreated and treated hypertensive patients screened from clinical practice : results of the Forlife study

Objectives Stroke has a high prevalence in Italy, and is the third cause of death worldwide. Hypertension is the most important risk factor contributing to the risk of stroke. The aims of this study were to assess the risk of stroke in a large cohort of hypertensive patients, and to determine the percentage with controlled blood pressure, to establish the contribution of this factor to the risk of stroke. Methods The study involved general practitioners to make it representative of clinical practice. They were asked to recruit 10 consecutive hypertensive patients, treated and untreated. Data collection included a full medical history and a physical examination. The 10-year absolute risk of stroke was calculated by an algorithm derived, with some modification, from the Framingham study. Results Most untreated hypertensive patients were grade 1 or 2. In treated hypertensive patients, controlled blood pressure values occurred in 18.4%, the percentage being less in patients with left ventricular hypertrophy and diabetes. In diabetic hypertensive patients the more stringent blood pressure control recommended by the guidelines was achieved in only 3.0% of cases. The average 10-year stroke risk was 17%, a greater risk being more common in elderly patients, diabetic individuals and in those with left ventricular hypertrophy. Conclusion Current antihypertensive treatment achieved blood pressure control in a limited fraction of hypertensive patients seen by general practitioners. The risk of stroke in hypertensive patients is by no means negligible, which emphasizes the need for more attention to be paid to the prevention of this disease.

Low-dose aspirin does not interfere with the blood pressure-lowering effects of antihypertensive therapy

Background It has been reported that aspirin (ASA) may interfere with the blood pressure (BP)-lowering effect of various antihypertensive agents and attenuate the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in patients with congestive heart failure. Methods and results Data from the Hypertension Optimal Treatment (HOT) Study, in which 18 790 intensively treated hypertensive patients were randomized to either ASA 75 mg daily or placebo for 3.8 years (with a 15% reduction in cardiovascular events and a 36% reduction in myocardial infarction in ASA-treated patients), were reanalysed for the whole group of patients and for various subgroups with particular attention to the possible effects of ASA on BP and renal function. In ASA-treated and placebo-treated patients: (1) systolic blood pressure (SBP) and diastolic blood pressure (DBP) values achieved with antihypertensive treatment were superimposable, with clinically irrelevant differences; (2) these superimposable SBP and DBP were achieved with antihypertensive therapies, that were quantitatively and qualitatively similar, and (3) changes in serum creatinine and in estimated creatinine clearance and the number of patients developing renal dysfunction were also similar. Furthermore, the cardiovascular benefits of ASA were of the same magnitude in hypertensive patients receiving or not receiving ACE-inhibitors. Conclusions Even long-term, low-dose ASA does not interfere with the BP-lowering effect of antihypertensive agents, including combinations with ACE inhibitors, or with renal function. No negative interaction occurs between ACE inhibition and the cardiovascular benefits of small dose of ASA. Our conclusions cannot be extended to larger doses of ASA, or to patients with congestive heart failure.

Control of renin release: A review of experimental evidence and clinical implications

Present knowledge of the mechanisms regulating release of renin is reviewed with particular emphasis on neural factors. Evidence is given for a direct effect of renal innervation on beta adrenergic receptors in juxtaglomerular cells, and for the involvement of reflex release of renin in conditions such as tilting and acute salt depletion. Participation of neural and nonneural mechanisms of control is also shown to occur in other conditions, such as aortic constriction and hemorrhage. The view is held that neural sympathetic factors might explain some of the renin disturbances found in essential hypertension. First, in patients with high renin hypertension part of the hypertension is renin-dependent, and these pressor levels of renin seem to be neurally induced since they can commonly be suppressed by beta adrenoreceptor blocking agents. Second, the hypothesis is presented that patients with low renin hypertension, at least those who have no volume disturbance, have a blunted sympathetic control of renin release. Therefore a sufficiently precise test of sympathetic activity, and possibly of body fluid volumes, should be associated with renin profiles for a better understanding of the pathophysiology of arterial hypertension and as a better guide to therapeutic management. Indeed, most of the available antihypertensive drugs act on sympathetic activity, body fluid volume or renin, and this multifaceted profile would provide more rational guidelines for treatment.