Influence of gender and age on preventing cardiovascular disease by antihypertensive treatment and acetylsalicylic acid. The HOT study. Hypertension Optimal Treatment.

OBJECTIVE: We have assessed the influence of gender and age on the main outcome results of the Hypertension Optimal Treatment (HOT) study. DESIGN AND INTERVENTIONS: The aims of the HOT study were to study the relationship between three levels of target office diastolic blood pressure (BP) (< or = 90, < or = 85 or < or = 80 mmHg) and cardiovascular (CV) events in hypertensive patients, and to examine the effects of 75 mg acetylsalicylic acid (ASA) daily versus placebo. SETTING: Outpatient clinical trial in 26 countries. PATIENTS: A total of 18790 patients (mean age 61.5 years, range 50-80) were randomized and followed for an average of 3.8 years until 71051 patient-years and 683 events had occurred. MAIN OUTCOME MEASURES: CV death, myocardial infarction (MI) and stroke. RESULTS: There were significantly fewer MIs in those in the lower diastolic BP target groups (3.0 versus 1.2 and 1.7 MIs/1000 patient-years, P for trend = 0.034) in women (n = 8883), whereas the similar but smaller trend (4.1 versus 4.1 and 3.4 MIs/1000 patient-years) was not statistically significant in men nor in the subgroup analysis of younger and older subjects. The effect of ASA on preventing MI was not influenced by age < 65 years (P= 0.02) or age > or = 65 years (P = 0.04) but was influenced by gender (P = 0.38 in women and P = 0.001 in men, lowered by 42% corresponding to a reduction from 5.0 to 2.9 MIs/1000 patient-years). CONCLUSIONS: The data of this HOT study sub-analysis suggest somewhat differentiated optimal gender- and age-dependent effects of anti-hypertensive and anti-platelet therapies; lowering of diastolic BP to about 80 mmHg in hypertensive women and, in addition, the administration of 75 mg of ASA to well-treated hypertensive men appear to effectively reduce the most common cardiovascular complication, i.e. myocardial infarction, in patients with essential hypertension.

Vascular wall thickness in hypertension: the Perindopril Regression of Vascular Thickening European Community Trial: PROTECT.

A high prevalence of increased intima/media thickness of the arterial wall has been documented in hypertension. These alterations in vascular wall structure may be potent determinants for the promotion of the development of atherosclerosis. Direct histologic data from animal models of hypertension, and indirect data from hypertensive patients, have demonstrated a marked regression of increased intima/media thickness by angiotensin-converting enzyme (ACE) inhibition. Long-term effects of ACE inhibition on structural wall changes in humans have not been examined. Therefore, a multicenter, randomized, double-blind European trial was designed to compare the effects of the ACE inhibitor perindopril and the diuretic hydrochlorothiazide in slowing or reversing progression of increased intima/media thickness of carotid and femoral arteries in hypertensive patients. A total of 800 patients at 17 clinical centers in 7 European countries, aged 35-65 years, with hypertension and ultrasonographically proven intima/media thickness > or = 0.8 mm of the common carotid artery will be randomly assigned to receive in a double-blind fashion either perindopril or hydrochlorothiazide and will be followed for 24 months. High resolution duplex sonography will be used to quantify intima/media thickness at baseline and twice a year during follow-up. A change of 0.1 mm of intima/media thickness from baseline is considered to be detectable, and the standard deviations of the changes from baseline are expected not to be higher than 0.2 mm. The primary endpoint of the study is the comparison of changes in intima/media thickness of the common carotid artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Dissociation of renin and aldosterone during low-dose epinephrine infusion.

Besides its dose-dependent alpha- and beta-adrenoceptor-mediated vascular action, hormonal effects of epinephrine also involve the activation of renin secretion by direct stimulation of renal beta 1-adrenoceptors. To determine the interrelation between increased plasma renin activity in response to epinephrine and plasma aldosterone concentration and renal excretion of potassium and sodium, 26 normal subjects were subjected to 4 h of an intravenous infusion of low-dose epinephrine (12 ng/kg/min). Epinephrine infusion raised mean plasma epinephrine concentration 2.8-fold above control (P < .001). Plasma renin activity (PRA) increased by 56% (P < .01) during epinephrine infusion, whereas plasma aldosterone concentration remained constant. Infusion of epinephrine also resulted in markedly suppressed urinary potassium excretion (-32%; P < .025), while urinary sodium excretion was not altered. Serum potassium was decreased by 4.1% during epinephrine (P < .025). Systolic blood pressure and heart rate did not change, and diastolic blood pressure was slightly reduced by 5 mm Hg (P < .025). In summary, during low-dose epinephrine infusion PRA is markedly increased while plasma aldosterone remains unchanged. The fall in urinary potassium excretion in the presence of reduced serum potassium concentration is most likely mediated via the beta-adrenoceptor-mediated shift of potassium into cells. This in turn may prevent a concomitant rise of plasma aldosterone, which subsequently contributes to the blunted kaliuresis and unchanged natriuresis found during the epinephrine-induced rise of PRA. In conclusion, the epinephrine-induced fall in serum potassium appears to be the predominant regulator of plasma aldosterone concentration even in the presence of a stimulated PRA.

Effects of low-dose epinephrine infusion on cardiovascular and renal responses to water immersion in humans.

Elevated plasma epinephrine concentrations may impair blood pressure homeostasis and renal sodium and volume excretion in response to central hypervolemia. We studied the effects of a low-dose epinephrine infusion (12 ng/kg/min) on cardiovascular and renal responses to a thermoneutral head-out water immersion in eleven healthy men. Responses to water immersion without epinephrine were characterized by significant suppression of plasma renin activity (PRA), plasma aldosterone concentration, and renal norepinephrine excretion, and an augmentation of natriuresis and diuresis. Epinephrine infusion, which raised mean plasma epinephrine concentration 4.3-fold, slightly increased plasma norepinephrine and renal norepinephrine excretion, markedly stimulated PRA (+66.7%), but decreased plasma aldosterone (-11.7%), and augmented renal sodium and volume excretion. Despite the presence of the epinephrine infusion, water immersion continued both to suppress PRA and aldosterone, and to increase natriuresis and diuresis in a qualitatively similar pattern. During all conditions blood pressure and heart rate remained unchanged. It is concluded that physiologic responses to central hypervolemia are not impaired at stress levels of circulating epinephrine. During epinephrine infusion, despite a concomitant increase in plasma norepinephrine and a stimulation of PRA, blood pressure remained constant in response to water immersion due to an augmentation of natriuresis and diuresis.

Telmisartan vs losartan plus hydrochlorothiazide in the treatment of mild-to-moderate essential hypertension--a randomised ABPM study.

The objective of this prospective, randomised, open-label, blinded-end point parallel-group, multicentre study was to show that telmisartan 80 mg is not inferior to a fixed-dose combination of losartan 50 mg/hydrochlorothiazide (HCTZ) 12.5 mg in patients with mild-to-moderate hypertension. The criterion for noninferiority was a treatment difference of < or =3.0 mmHg in the reduction of 24-h mean ambulatory diastolic blood pressure (DBP) from the end of the 4-week placebo washout period to the end of the 6-week active treatment period. In the intent-to-treat analysis, the mean reduction in 24-h DBP was 8.3+/-6.7 mmHg among telmisartan-treated patients (n=332) and 10.3+/-6.3 mmHg among losartan/HCTZ-treated patients (n=350). The mean adjusted difference in 24-h DBP between the two treatment groups was 1.9 mmHg, allowing rejection of the a priori null hypothesis of a treatment difference of >3 mmHg. The reduction in mean 24-h systolic blood pressure was 13.2+/-10.2 mmHg with telmisartan and 17.1+/-10.3 mmHg with losartan/HCTZ. Both drugs provided effective control over the 24-h dosing interval. Analyses of morning (0600-1159) ambulatory blood pressure monitoring DBP means and trough cuff DBP confirmed the noninferiority hypothesis of the protocol for telmisartan 80 mg vs losartan 50 mg/HCTZ 12.5 mg. The reductions in office blood pressures measured at trough in patients treated with telmisartan were -16.3/-9.6 and -18.5/-11.1 mmHg in the patients treated with losartan/HCTZ (difference -2.4/-1.2 mmHg). There were no differences between the side-effect profiles of the two treatments.

INVEST: results of combined strategies to control blood pressure.

The treatment of hypertension continues to be challenging due to the lack of understanding regarding underlying modulators of blood pressure as well as co-existing conditions such as atherosclerosis and diabetes. This has led to uncertainty regarding treatment strategy and intensity. The INternational VErapamil SR/trandolapril STudy (INVEST) is designed to evaluate the relationship between cardiovascular risk and blood pressure modulators. Based on a review of preliminary data, it appears that the treatment regimen used in the INVEST trial has been more successful than other studies at controlling systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure. These preliminary data from INVEST suggest that a high proportion of coronary artery disease (CAD) patients with hypertension should receive combination therapy to achieve contemporary blood pressure targets.

[The Hypertension Optimal Treatment (HOT) study: results of 12-month therapy related to age]. / Die "Hypertension Optimal Treatment" (HOT)-Studie. Behandlungsergebnisse nach zwölfmonatiger Therapie in Abhängigkeit vom Alter.

BACKGROUND AND OBJECTIVE: The prospective, randomized multicentre HOT study (Hypertension Optimal Treatment) is at present being undertaken in 26 countries. The cardinal questions to be answered were: (1) the relationship between three targeted diastolic pressures (< or = 90, < or = 85 and < or = 80 mm Hg, respectively) and cardiovascular morbidity and mortality rates among hypertensives; and (2) the effect of low dosage aspirin (75 mg daily) on morbidity and mortality rates, compared with a placebo. PATIENTS AND METHODS: A total of 19,193 patients (9056 women, 10,137 men; age range 50-80 years) with a diastolic blood pressure of > or = 100 to < or = 115 mm Hg were randomized. Antihypertensive treatment was begun with the calcium-channel blocker felodipine (5 mg once daily; step 1). When the target could not be reached at this dosage, an angiotensin-converting enzyme inhibitor (ACEI) or beta-receptor blocker was added (stage two), after which felodipine, 10 mg daily, could be given, if necessary (step 3). Any necessary changes in dosage (step 4) were made according to a prescribed plan. As fifth and final step a diuretic could be additionally administered. One-year results are now available for all patients and reported here. Results of older patients (> or = 65 years, n = 6113) were compared to those of younger patients (< 65 years, n = 13,080). RESULTS: Average diastolic pressure in the previously < or = 90 mm Hg group had been reduced to 86 mm Hg, in the < or = 85 group to 83 mm Hg, and in the < or 80 mm Hg group to 81 mm Hg. The percentage proportion of patients in whom the targeted pressures had been reached after 12 months of treatment were: 84% for the < 90 mm Hg group, 72% in the < 85 mm Hg group and 57% in the < 80 mm Hg group. In a subgroup of elderly patients (> 65 years, n = 6113) the corresponding percentage proportions were higher: 86%, 76% and 61%. Side effects were noted only rarely, despite the intensive treatment (> 65 years and < 65 years): ankle oedema in 2.6% and 3.0%; and cough in 1.3 and 0.8%, an overall incidence of > or = 1%. The same treatment (with felodipine) was still being given after one year to 88% of all patients. CONCLUSION: These results after one year indicate that most patients well tolerate consistent blood pressure reduction. This raises the hope that the primary questions of the study can be answered.

Efficacy and safety of two different galenic formulations of a transdermal clonidine system in the treatment of hypertension.

The efficacy and safety of two different galenic formulations of transdermal clonidine systems were compared in 905 patients with mild to moderate essential hypertension during a 12 weeks observation period. 449 patients were treated with the matrix controlled clonidine transdermal (C-TD) system and 456 patients with the membrane controlled clonidine system (C-TTS). The mean blood pressure was reduced from 168/102 mmHg to 146/87 mmHg in the C-TD and from 169/102 mmHg to 148/88 mmHg in the C-TTS group. There was no difference in the response rate. The pattern of systemic side-effects appeared to correspond to those seen during oral clonidine treatment but with a lower frequency and intensity. The C-TD patch improved skin tolerability and the drop-out rate due to skin reactions was 2.2 times lower compared with the C-TTS group. Local skin reactions led to withdrawal in 35 of 449 C-TD treated and in 79 of 456 C-TTS treated patients. In conclusion, the improved carrier system for the transdermal clonidine treatment reduced local side-effects which in turn may further enhance acceptability and compliance in treated patients.

Long-term effects of minoxidil therapy on renal function of patients with refractory hypertension: the significance of albuminuria.

The addition of minoxidil therapy reduced blood pressure effectively for 6--52 months (average, 24) in 25 of 28 patients with refractory hypertension. One patient was nonresponsive; 2 were noncompliant. Patients who had a serum creatinine up to 4 mg% and greater than 750 mg of albuminuria per day had further deterioration of renal function of 5.3 +/- 1.4% per month compared to that of 0.2 +/- 0.4% per month in patients without albuminuria (p less th5% was not as helpful predicting preservation of renal function in patients with refractory hypertension after adding minoxidil as was the absence of albuminuria.

Effects of sympathetic inhibition on blood pressure and renal responses to central hypervolaemia in normal humans.

The purpose of this study was to evaluate the effects of short-term sympathetic inhibition with clonidine on blood pressure and renal responses to central hypervolaemia induced by thermoneutral head-out water immersion. Eleven healthy subjects were randomly studied on two occasions, during a 1 h pre-immersion period, 2 h of water immersion and a 1 h post-immersion period, after either placebo or clonidine treatment. Clonidine caused a significant suppression of plasma adrenaline, plasma noradrenaline, urinary noradrenaline excretion and mean arterial blood pressure. Blood pressure remained constant during water immersion after both placebo and clonidine, compared with the respective pre-immersion control values. The suppression pattern of plasma catecholamines and urinary noradrenaline in response to water immersion during placebo was similar after clonidine treatment. Renal volume excretion was not affected by clonidine. In contrast, clonidine caused a significant attenuation of the immersion-induced stimulation of natriuresis (maximum -33 +/- 12%, P < 0.01, compared with placebo). These data indicate that the renal capacity to excrete sodium is impaired during moderate blood pressure reduction by short-term sympathetic inhibition with clonidine, whereas the regulation of arterial blood pressure in response to central hypervolaemia is maintained.

Role of epinephrine-induced hypokalemia in the regulation of renin and aldosterone in humans.

Circulating epinephrine induces both stimulation of plasma renin activity (PRA) and a decrease in serum potassium concentration. This study was designed to determine the dose-response effects of systemic epinephrine infusion on the relationship of PRA and plasma aldosterone concentration. Twenty-one men with normal blood pressure received either an intravenous infusion of epinephrine at 12.5, 25, and 50 ng/(kg x min) by stepwise increments for 1 hour each or isotonic saline solution. Infusion of epinephrine led to a dose-dependent increase in plasma epinephrine concentration, systolic blood pressure, and heart rate, whereas diastolic blood pressure was decreased. PRA was elevated in a dose-dependent manner, whereas the plasma aldosterone concentration was reduced. During infusion of epinephrine, the serum potassium concentration and renal potassium excretion were significantly decreased. We conclude that despite marked stimulation of PRA, the plasma aldosterone concentration was further decreased because of a dose-dependent decrease in serum potassium concentration induced by epinephrine. Thus hypokalemia appears to be the predominant regulator of plasma aldosterone during incremental epinephrine infusion.