Combination Antihypertensive Therapy: Does It Have a Role in Rational Therapy?

The pharmacological treatment of hypertension allows one to reduce substantially the risk of developing a cardiovascular complication. It appears more and more important to bring blood pressure to normal values in order to get the maximal benefit from antihypertensive therapy. Blood pressure lowering drugs make it possible to control blood pressure in about half of the patients when administered as monotherapy. The fraction of patients with a normal blood pressure can be markedly increased by combining drugs acting by different mechanisms. Low doses of antihypertensive agents are generally enough when coadministered. This helps to keep the incidence of side effects minimal and facilitates the patient's compliance with long-term treatment. Low-dose, fixed-dose combination therapy may therefore represent a valuable option not only to treat hypertensive patients unresponsive to drugs given as monotherapy, but also to initiate the treatment. Am J Hypertens 1997;10:131S-137S ©1997 American Journal of Hypertension, Lt

Amlodipine and valsartan as components of a rational and effective fixed-dose combination

Pharmacological treatment of hypertension is effective in preventing cardiovascular and renal complications. Calcium antagonists and blockers of the renin-angiotensin system are widely used today to initiate antihypertensive therapy but, when given as monotherapy, do not suffice in most patients to normalize blood pressure. Combining the two types of agents considerably increases the antihypertensive efficacy, but not at the expense of a deterioration of tolerability. This is exemplified by the experience accumulated with the recently developed fixed dose combination containing the AT1-receptor blocker valsartan (160 mg) and the dihydropyridine amlodipine (5 or 10 mg). In a randomized trial, an 8-week treatment normalized blood pressure (<140/90 mmHg) within 8 weeks in a large fraction of hypertensive patients (78.4% and 85.2% using the 5/160 [n = 371] and 10/160 mg [n = 377] dosage, respectively). Like all AT1-receptor blockers valsartan has a placebo-like tolerability. Valsartan prevents to a large extent the occurrence amlodipine-induced peripheral edema. Both amlodipine and valsartan have beneficial effects on cardiovascular morbidity and mortality, as well as protective effects on renal function. The co-administration of these two agents is therefore very attractive, as it enables a rapid and sustained blood pressure control in hypertensive patients. The availability of a fixed-dose combination based on amlodipine and valsartan is expected therefore to facilitate the management of hypertension, to improve long-term adherence with antihypertensive therapy and, ultimately, to have a positive impact on cardiovascular and renal outcomes

Application in the STRATHE trial of a score system to compare the efficacy and the tolerability of different therapeutic strategies in the management of hypertension

A score system integrating the evolution of efficacy and tolerability over time was applied to a subpopulation of the STRATHE trial, a trial performed according to a parallel group design, with a double-blind, random allocation to either a fixed-dose combination strategy (perindopril/indapamide 2 mg/0.625 mg, with the possibility to increase the dose to 3 mg/0.935 mg, and 4 mg/1.250 mg if needed, n = 118), a sequential monotherapy approach (atenolol 50 mg, followed by losartan 50 mg and amlodipine 5 mg if needed, n = 108), or a stepped-care strategy (valsartan 40 mg, followed by valsartan 80 mg and valsartan 80 mg+ hydrochlorothiazide 12.5 mg if needed, n = 103). The aim was to lower blood pressure below 140/90 mmHg within a 9-month period. The treatment could be adjusted after 3 and 6 months. Only patients in whom the study protocol was strictly applied were included in this analysis. At completion of the trial the total score averaged 13.1 ± 70.5 (mean ± SD) using the fixed-dose combination strategy, compared with −7.2 ± 81.0 using the sequential monotherapy approach and −17.5 ± 76.4 using the stepped-care strategy. In conclusion, the use of a score system allows the comparison of antihypertensive therapeutic strategies, taking into account at the same time efficacy and tolerability. In the STRATHE trial the best results were observed with the fixed-dose combination containing low doses of an angiotensin enzyme converting inhibitor (perindopril) and a diuretic (indapamide)

P-210: Beta-blockade with nebivolol enhances the acetylcholine-induced vasodilation in the cutaneaous vascular bed of normotensive volunteers

This study was undertaken to assess whether the beta1-adrenoceptor blocker nebivolol(N) increases the vasodilatory response to acetylcholine(Ach) when administered orally to healthy subjects. To this end 12 volunteers were randomly allocated to a 8-day treatment with nebivolol (n), 5 mg once a day, and atenolol(A),50 mg once a day, according to a cross-over design, with a 1 week wash-out period between the two treatment phases. The forearm skin blood flow(SBF) response to Ach applied by iontophoresis was determined using a laser-Doppler scanner imaging system before(T0) and 3 hours(T3) after N or A dosing, both on the first (Day 1) and the last day (Day 8) of treatment. The following Table shows the responses of SBF (perfusion units) (means±SD; *p<0.05 versus T0): Day 1 Day 8 T0 T3 T0 T3 Nebivolol 98±93 441±109* 393±110 426±105* Atenolol 396±97 410±99 380±109 394±98 Iontophoresis of 0.09% NaCl had no effect on SBF. These data indicate that nebivolol (administered at a dose commonly used in clinical practice), but not atenolol, enhances in humans the vasorelaxant activity of Ach in the skin vascular bed, which is compatible with a facilitation by this beta-blocker of the endothelium-dependent vasodilatio

Hypertension and microvascular remodelling

In the present review, microvascular remodelling refers to alterations in the structure of resistance vessels contributing to elevated systemic vascular resistance in hypertension. We start with some historical aspects, underscoring the importance of Folkow's contribution made half a century ago. We then move to some basic concepts on the biomechanics of blood vessels, and explicit the definitions proposed by Mulvany for specific forms of remodelling, especially inward eutrophic and inward hypertrophic. The available evidence for the existence of remodelled resistance vessels in hypertension comes next, with relatively more weight given to human, in comparison with animal data. Mechanisms are discussed. The impact of antihypertensive drug treatment on remodelling is described, again with emphasis on human data. Some details are given on the three studies to date which point to remodelling of subcutaneous resistance arteries as an independent predictor of cardiovascular risk in hypertensive patients. We terminate by considering the potential role of remodelling in the pathogenesis of end-organ damage and in the perpetuation of hypertensio

P-101: Blunted vasodilatory responses in the cutaneous microcirculation of cigarette smokers

Background: To assess the vasodilatory response to acetylcholine (Ach, endothelium-dependent vasodilator) and Na nitroprusside (SNP, endothelium-independent vasodilator) in the skin microcirculation of habitual cigarette smokers. Methods: Male healthy habitual smokers taking no medication acting on the cardiovascular system were included. They were divided in younger (Group 1, n = 10, age: 18 to 35 years; mean = 7 pack-years) and older (Group 2, n = 10, age: 40 to 60 years; mean =30 pack-years). Younger (Group 3, n = 10) and older controls (Group 4, n = 10) consisted of age-matched non-smokers. On the day of the experiment the subjects of Groups 1 and 2 were asked to smoke at least 15 cigarettes starting in the morning. At 4 p.m. they had to smoke within 5 min a filter cigarette containing 1 mg nicotine. Subjects of Groups 3 and 4 had a sham-smoking session at 4 p.m. Ach, 1%, and SNP, 0.1%, were administered transcutaneously for 7 min on the volar face of the right forearm using iontophoresis. This was done 15 min and 40 min after the end of the smoking session for Ach and SNP, respectively. The skin blood flow responses were evaluated using a laser-Doppler flowmeter allowing to scan the surface of Ach and SNP application (circular area, 1 cm diameter). Results: The following Table shows the peak changes induced by Ach and SNP (perfusion units, means±SD): Younger Older Ach SNP Ach SNP Non-smokers 505±65 425±99 473±91 392±71 Smokers 466±102 416±59 302±50** 301±104* *p<0.05; **p<0.01, Smokers versus Non-smokers Conclusion: These data show that the vasodilatory response of the skin microvasculature is impaired in subjects having smoked cigarettes for many years. This abnormality involves both the Ach and the SNP responses, which implies a diminished relaxant capacity of vascular smooth muscle cells, even if an underlying endothelial dysfunction cannot be ruled ou

Cardiac mass in glucocorticoid-hypertensive rats with and without circulating adrenaline

There is evidence that catecholamines may promote the development of cardiac hypertrophy in hypertension. To test the hypothesis that adrenaline directly determines left ventricular mass, normotensive Wistar rats were made adrenaline-deficient by adrenalectomy and hypertensive by administration of glucocorticoid. Blood pressure, heart rate, and body weight of the adrenalectomised group were not significantly different from a glucocorticoid treated control group with intact adrenals. Heart weight was significantly lower in the adrenalectomised rats, but this difference disappeared when heart weight was adjusted for body weight. It appears therefore that the presence or absence of adrenaline does not significantly affect cardiac mass in the presence of hypertension in this animal mode