David H.G. Smith

Application of ambulatory blood pressure monitoring in differentiating between antihypertensive agents

PURPOSEnThis multicenter, double-blind, parallel group study assessed the usefulness of the ambulatory blood pressure monitoring (ABPM) technique in differentiating between the once-daily administration of the beta blockers bisoprolol (10 to 20 mg) and atenolol (50 to 100 mg) in terms of efficacy and duration of action.nnnPATIENTS AND METHODSnThe study population consisted of 659 patients with essential hypertension and an average office diastolic blood pressure (BP) between 95 and 115 mm Hg after 4 weeks of placebo treatment. Office BPs were recorded at the end of the 24-hour dosing interval (trough). ABPM was performed in 11 of the 28 institutions participating in this study in a total of 203 patients. These procedures were performed at the end of the placebo phase and again after 8 weeks of active treatment.nnnRESULTSnWith the use of conventionally measured office BPs, the two drugs significantly (p < 0.001) decreased trough systolic and diastolic BPs to a similar extent. By 24-hour monitoring, bisoprolol demonstrated a 33% greater reduction in whole-day average diastolic BP than did atenolol (11.6 +/- 0.7 mm Hg versus 8.7 +/- 0.8 mm Hg, p < 0.01). Significant treatment differences in systolic (p < 0.05) and diastolic (p < 0.01) BPs were also noted for bisoprolol compared with atenolol during the final 4 hours of the dosing interval (-13.2 +/- 1.5/-10.9 +/- 1.0 mm Hg versus -8.9 +/- 1.6/-7.3 +/- 1.1 mm Hg, respectively), and over the time period 6:00 AM to noon (-14.2 +/- 1.3/-11.5 +/- 0.9 mm Hg versus -9.9 +/- 1.4/-7.7 +/- 0.9 mm Hg).nnnCONCLUSIONSnWhereas conventional BP measurements did not detect differences in the antihypertensive effects of the beta blockers bisoprolol and atenolol, ABPM revealed significant treatment differences in both the efficacy and duration of action of these two agents. These findings indicate the power of this technique to discriminate potentially important differences between apparently similar antihypertensive drugs.

Dependency of arterial compliance on circulating neuroendocrine and metabol factors in normal subjects

Reduced arterial compliance is now recognized as a feature of hypertension. Similarly, metabolic factors such as insulin, catecholamines and lipids are also associated with hypertension. This study explores the possibility that these neuroendocrine and metabolic factors may separately influence arterial compliance. Proximal compliance (aorta and large arteries) and distal compliance (small arteries and arterioles) were measured in 57 volunteers (30 hypertensive and 27 normotensive subjects, mean age 45 years). Compliance was quantified by analysis of arterial pulse wave contours obtained intraarterially together with hemodynamic estimates. Proximal compliance correlated with plasma insulin (r = -0.49; p less than 0.001), norepinephrine (r = -0.50; p less than 0.002), triglycerides (r = -0.39; p less than 0.01), total cholesterol (r = -0.33; p = 0.02) and high-density lipoprotein cholesterol (HDL) (r = 0.37; p less than 0.02). Similarly, distal compliance correlated with insulin (r = -0.37; p less than 0.02), triglycerides (r = -0.39; p less than 0.01), total cholesterol (r = -0.38; p less than 0.01) and HDL (r = 0.51, p less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Valsartan alone or with a diuretic or ACE inhibitor as treatment for African American hypertensives: relation to salt intake.

Previous clinical trials have demonstrated the important influence of ethnicity and dietary salt on the antihypertensive efficacy of drugs that block the renin angiotensin system. Angiotensin II receptor blockers are a new therapeutic entity that have not been widely studied in African American hypertensives, either alone, or in combination with other therapies such as diuretics or angiotensin converting enzyme inhibitors. We performed a pilot, prospective, open label, randomized design clinical trial to evaluate the effects of the angiotensin II receptor blocker valsartan (160 mg once a day) on systolic and diastolic blood pressure in hypertensive African Americans (n = 88) on a low salt (100 mEq Na+/day) for 2 weeks and the same diet supplemented by 100 mEq Na+ for 4 weeks. After this evaluation, while continuing the Na+ supplementation, patients were randomized to valsartan 320 mg/day (n = 28), or the addition of hydrochlorothiazide (HCTZ) 12.5 mg/day (n = 30), or benazepril 20 mg/day to the valsartan 160 mg/day for an additional 6 weeks. Valsartan (160 mg/day) lowered blood pressure significantly in African American patients on both low salt (-6.4/-4.8 mm Hg: P < .001) and a high salt diet (-4.9/-3.8 mm Hg: P = .01). The high salt diet attenuated the antihypertensive effect slightly (1.6/1.3 mm Hg, P = not significant). When comparing the efficacy of the three randomized therapeutic regimens while on the Na+ supplement, the valsartan 160 mg/HCTZ 12.5 mg was the most effective therapy with an incremental reduction in blood pressure of -10.5/-6.9 mm Hg (P < .01), compared to valsartan 160 mg/day alone. Doubling the dose of valsartan to 320 mg incrementally lowered blood pressure by -3.8/-3.3 mm Hg (P = not significant). The least effective approach was adding benazepril 20 mg/day to valsartan 160 mg/day with no incremental reduction in systolic blood pressure and diastolic blood pressure reduction of only 1.7 mm Hg (P = not significant). We conclude that in our open label pilot study, the antihypertensive activity of valsartan is not significantly attenuated by supplemented salt diet in hypertensive African Americans. Moreover, adding a low dose of HCTZ appears to be the most effective strategy in enhancing the antihypertensive activity of this angiotensin II receptor blocker in contrast to either doubling the dose or adding an angiotensin converting enzyme inhibitor.

Heredity and hypertension: Impact on metabolic characteristics

This study was performed to evaluate the possible role of heredity in the clinical characteristics of hypertension. Metabolic, endocrine, and renal measurements were compared in subjects with normal blood pressure who had a family history of hypertension (n = 60) with those of subjects with normal blood pressure who did not have a family history of hypertension (n = 48). The groups were matched for age (mean, 44 +/- 2 years and 45 +/- 2 years) and blood pressure (127 +/- 1/77 +/- 1 mm Hg and 127 +/- 2/77 +/- 1 mm Hg). The following parameters were higher in the patients with a family history of hypertension than in those without. Plasma insulin concentrations (14.1 +/- 1.1 vs 10.8 +/- 1.0 microU/ml; p less than 0.05), insulin-glucose ratio (0.15 +/- 0.01 vs 0.11 +/- 0.010; p less than 0.05), norepinephrine concentrations (315 +/- 24 pg/ml vs 208 +/- 20 pg/ml; p less than 0.01), plasma renin activity (2.1 +/- 0.2 ng Angl/ml/hr vs 1.6 +/- 0.2 ng Angl/ml/hr; p less than 0.02), total cholesterol levels (217 +/- 8 mg/dl vs 197 +/- 0.3 mg/dl; p less than 0.05), creatinine clearance (125 +/- 9 ml/min vs 96 +/- 8 ml/min; p less than 0.01), and albumin excretion rate (3.2 +/- 0.3 micrograms/min vs 2.6 +/- 0.3 micrograms/min; p = 0.1). Moreover, patients with a family history of hypertension had smaller increases in systolic blood pressure during treadmill exercise (55 +/- 3 mm Hg vs 64 +/- 3 mm Hg; p less than 0.03). There were no differences in echocardiographic left ventricular mass index between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular diastolic filling alterations in normotensive young adults with a family history of systemic hypertension

To characterize the cardiovascular consequences of a history of hypertension in first-degree relatives in normotensive young adults, 72 normotensive (diastolic blood pressure [BP] less than 90 mm Hg) healthy volunteers (age 18 to 30 years) were studied with 2 dimensionally guided M-mode echocardiography, pulsed Doppler echocardiography, and 2-hour automated BP monitoring. Of the 72 subjects, 19 (12 men and 7 women) had a family history of hypertension and were compared with 19 subjects without a family history of hypertension who were matched for systolic BP and gender. There were no detectable differences in 2-hour average BP, left ventricular (LV) mass or wall thickness, or echocardiographic systolic functional indexes between subjects with and without a family history of hypertension. Doppler-derived diastolic functional indexes demonstrated more prominent late diastolic filling in subjects with a family history of hypertension. Late diastolic transmitral flow time and flow velocity integral were greater (132 +/- 24 vs 117 +/- 17 ms, p less than 0.05; and 2.5 +/- 0.7 vs 1.9 +/- 0.5 cm, p less than 0.01, respectively). To measure possible gender-related effects of a family history of hypertension, the men and women were analyzed separately. The 12 men with a family history of hypertension had greater peak late (40 +/- 0.9 vs 31 +/- 0.8 cm/s, p less than 0.02) and ratio of late-to-early (0.64 +/- 0.19 vs 0.46 +/- 0.10, p less than 0.01) transmitral flow velocities and greater late transmitral flow velocity integrals (2.6 +/- 0.8 vs 1.9 +/- 0.5 cm, p less than 0.05) than the matched male control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of hypertension with an angiotensin II-receptor antagonist compared with an angiotensin-converting enzyme inhibitor: a review of clinical studies of telmisartan and enalapril.

BACKGROUNDnAngiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ATII)-receptor antagonists suppress the effects of ATII and are effective antihypertensive agents. However, the use of ACE inhibitors is sometimes associated with intolerable side effects (eg, cough, angioedema), and patients may develop a compensatory rise in ATII levels. ATII-receptor antagonists have tolerability profiles similar to that of placebo and inhibit the effects of ATII more completely by blocking the AT1 receptor.nnnOBJECTIVEnThis review summarizes clinical studies comparing the efficacy and tolerability of the ATII-receptor antagonist telmisartan with the ACE inhibitor enalapril in patients with hypertension.nnnMETHODSnRandomized, controlled clinical trials comparing telmisartan with enalapril in patients with primary hypertension were identified through a PubMed search of the English-language literature from 1998 through 2001 and from bibliographic data provided by the manufacturer of telmisartan.nnnRESULTSnIn 2 randomized, double-blind, placebo-controlled trials (total number of patients, 647), telmisartan 40 or 80 mg/d was at least as effective as enalapril 20 mg/d for lowering blood pressure (BP) in patients with mild to moderate hypertension. An open-label, titration-to-response study involving 86 patients with severe hypertension found that telmisartan 80 to 160 mg/d was as efficacious as enalapril 20 to 40 mg/d. The antihypertensive effects of telmisartan 20 to 80 mg/d and enalapril 5 to 20 mg/d were comparable in 278 elderly patients (age > or = 65 years) with mild to moderate hypertension enrolled in a 26-week, double-blind, dose-titration study. A double-blind, titration-to-response study in 71 patients with moderate renal impairment and mild to moderate hypertension found equivalent reductions in BP with telmisartan 40 to 80 mg/d and enalapril 10 to 20 mg/d without any clinically relevant decline in renal function. Telmisartan tended to be better tolerated than enalapril in this study, with fewer patients experiencing treatment-related adverse events (8.9% vs 26.9%, respectively).nnnCONCLUSIONSnBased on the literature included in this review, telmisartan and enalapril produced comparable reductions in BP in a broad range of patients with hypertension. Telmisartan appeared to have a better tolerability profile.

Impact of left ventricular hypertrophy on blood pressure responses to exercise

It is claimed that exaggerated blood pressure (BP) responses to exercise are predictive of future hypertension and may also be indicative of left ventricular (LV) hypertrophy. The relation between LV hypertrophy and maximal exercise BP was examined in 35 normal male volunteers and 65 untreated hypertensive male patients. Multiple stepwise regression analysis revealed that preexercise systolic BP was the major determinant of maximal exercise systolic BP (r = 0.52; p less than or equal to 0.0001), indicating that higher baseline BP predicted higher exercise BP. However, hypertensive patients with LV hypertrophy had the smallest increases in systolic BP with exercise. Accordingly, there was an inverse relation between LV muscle mass and systolic BP responses to exercise in these patients (r = -0.34; p = 0.005). When compared with normotensive subjects, hypertensive patients had lower measures of maximal oxygen uptake and exercise heart rates (p = 0.01). This may indicate lower cardiac performance at maximal exercise and explain the reduced capacity of hypertensive patients with LV hypertrophy to increase systolic BP with exercise. Neither baseline nor exercise BPs correlated with LV mass; instead, the model of regression analysis indicated that body weight was the principal determinant of LV mass. Contrary to previous reports, exaggerated exercise BPs were not associated with LV hypertrophy in hypertensive or normotensive patients.

The circadian pattern of blood pressure: cardiovascular risk and therapeutic opportunities.

It has been known for many years that humans possess internal time clocks that regulate multiple physiologic factors (chronobiology). Epidemiologic studies have demonstrated that the peak incidence of many diseases, including respiratory disease (asthma, allergy), cardiovascular disease (hypotension, angina, myocardial infarction, stroke), as well as several others, tends to occur in a circadian pattern. In particular, studies utilizing ambulatory blood pressure monitoring have demonstrated that blood pressure has a very definite and reproducible circadian pattern over a 24-h period. Blood pressure is highest during the day; lowest during sleep, and then rapidly increases during the period 0400 h to 1200 h. Because recent data have demonstrated a possible cause-effect relationship between increases in blood pressure and angina, effective antihypertensive control in the early morning is desirable. Some once-a-day drugs taken in the morning may lose efficacy in the last few hours of the dosing interval, resulting in increases in blood pressure during the early morning period. In an attempt to ensure peak plasma levels during the early morning period, novel, controlled-onset, extended release-delivery systems have been developed. Studies using these delivery systems have demonstrated that, when dosed at night, these formulations provide maximal plasma levels during the period 0600 h to 1200 h, when blood pressure is physiologically rising at its greatest rate. The use of drugs designed to have peak efficacy at certain desirable times in the circadian pattern is referred to as chronotherapeutics.

Coadministered Amlodipine and Atorvastatin Produces Early Improvements in Arterial Wall Compliance in Hypertensive Patients With Dyslipidemia

BACKGROUNDnCombining statins with antihypertensive therapy has been demonstrated to provide an early reduction in cardiovascular events. This nested substudy of the AVALON trial assessed the effects of coadministered amlodipine and atorvastatin vs. either therapy alone or placebo on arterial compliance, to evaluate the vascular benefits of coadministered therapy.nnnMETHODSnDuring an initial 8-week, double-blind phase, patients with concomitant hypertension and dyslipidemia were randomized into four treatment groups (placebo, amlodipine 5 mg, atorvastatin 10 mg, or coadministered amlodipine 5 mg and atorvastatin 10 mg). The sustained effect of combined therapy was evaluated during subsequent 8-week, single-blind, and 12-week, open-label periods. In the single-blind phase, all patients were coadministered amlodipine 5 mg and atorvastatin 10 mg, which were then titrated to optimize blood pressure and low-density lipoprotein cholesterol control during the open-label phase. Arterial compliance was assessed every 4 weeks using the HDI/Pulsewave CR-2000.nnnRESULTSnOverall, 668 patients (61% male, mean age 55 years) were randomized to treatment. A 19% improvement in small artery compliance (C2) was observed with coadministered amlodipine and atorvastatin from baseline to week 8, which was significantly greater than with either treatment alone or with placebo (P = 0.03 to 0.0001). After 28 weeks, C2 was increased from baseline in all groups, but the overall improvement was greatest in the group receiving coadministered drugs for the entire study period (P < 0.05).nnnCONCLUSIONSnEarly and sustained improvement in small artery compliance was observed following coadministration of amlodipine and atorvastatin, thus demonstrating a vascular benefit with simultaneous treatment of hypertension and dyslipidemia.

Circulatory and extracirculatory effects of angiotensin-converting enzyme inhibition

The antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors cannot be fully explained by their actions on the circulating renin-angiotensin system (RAS). Agents such as captopril or enalapril maintain efficacy during long-term therapy even when plasma concentrations of converting enzyme or angiotensin II are not fully suppressed. Components of the entire RAS exist at several sites, thereby making it possible for drugs to produce effects at extracirculatory locations. An ACE inhibitor such as quinapril that has a comparatively short plasma concentration half-life binds strongly to plasma ACE as well as to ACE in key tissues including artery wall, heart, and kidney. The effects of ACE inhibition on the tissue RAS are of potential importance in fully explaining the blood pressure-lowering effects of these drugs. ACE inhibitors might also reduce blood pressure by blocking nonhemodynamic actions of angiotensin II. They affect vascular properties by increasing compliance of arteries and they act on baroreceptors and central regulatory mechanisms. Furthermore, ACE inhibitors affect other neuroendocrine systems, including aldosterone, kinins, and prostaglandins; attenuation of sympathetic activity can contribute further to their antihypertensive properties. Actions independent of circulating renin effects do not necessarily require plasma ACE inhibition throughout a 24-hour period. Sustained antihypertensive effects by drugs with short durations of plasma ACE inhibition give credibility to therapeutic targets beyond the circulating RAS.