Klaus O. Stumpe

Carotid intima-media thickness and plaque volume changes following 2-year angiotensin II-receptor blockade. The Multicentre Olmesartan atherosclerosis Regression Evaluation (MORE) study

Objective The Multicentre Olmesartan atherosclerosis Regression Evaluation (MORE) study was a double-blind trial in patients with hypertension at increased cardiovascular risk with carotid wall thickening and a defined atherosclerotic plaque that used non-invasive 2- and 3-dimensionaL (D) ultrasound (US), to compare the effects of a 2-year treatment based on either olmesartan medoxomil or atenolol on common carotid (CC) intima-media thickness (IMT) and plaque volume (PV). Methods A total of 165 patients (with systolic/diastolic blood pressure 140—180/ 90—105 mmHg) were randomized to receive either olmesartan (20—40 mg/day) or atenolol (50—100 mg/day). US was performed at baseline and 28, 52 and 104 weeks. The primary efficacy outcome was the change from baseline ( Δ) in CC-IMT assessed by 2D US. Secondary outcomes included Δ PV assessed by 3D US and blood pressure (BP). Results Olmesartan and atenolo produced comparable significant reductions in CC-IMT; mean Δ IMT (SEM) was -0.090 (0.015) mm for oLmesartan and -0.082 (0.014) mm for atenolol. Mean Δ PV was -4.4 (2.3) µl and 0.1 (1.5) µl in the olmesartan and atenolol treated subjects, respectively, without significant between-treatment differences. In the subgroup of patients with baseLine PV ≥ median (33.7 µl), significant between-treatment differences existed in Δ PV (p = 0.023), because PV regressed significantly with olmesartan (Δ PV: -11.5 (4.4) µl) but not with atenolol ( Δ PV: 0.6 (2.5) µl). In these patients BP reductions were comparabLe. Conclusions Carotid IMT and BP decreased similarly with olmesartan and atenolol, but only olmesartan reduced the volume of larger atherosclerotic plaques.

Relative efficacy of an angiotensin II antagonist compared with other antihypertensive agents. Olmesartan medoxomil versus antihypertensives.

Objective To compare the relative efficacy and safety of olmesartan medoxomil (OM) with atenolol, captopril and losartan in phase III trials on mild to severely hypertensive patients. Design Multi‐centre, randomized, double‐blind, parallel group, with dose‐titration studies lasting 12 or 24 weeks. Methods Two studies respectively compared 10 mg OM once daily (o.d.) with: (1) 50 mg atenolol o.d. in moderate to severe hypertensives receiving 25 mg hydrochlorothiazide o.d. over 12 weeks; and (2) 50 mg losartan o.d. in mild to moderate hypertensives over 24 weeks, both with dose doubling at week 4 if required. Study 3 compared 5 mg OM o.d. plus placebo o.d.with 12.5 mg captopril twice daily in mild to moderate hypertensives over 12 weeks, with dose doubling at weeks 4 and 8 if required. The primary outcome measure for all studies was the change from baseline to week 12 in trough mean sitting diastolic blood pressure (DBP). Safety was monitored throughout all studies. Results (1) Atenolol and OM both reduced BP effectively in moderate to severe hypertensives. OM was significantly superior to: (2) losartan (95% confidence interval for baseline to week 12 change in DBP < 0, lower limit < ‐3.6 mmHg); and (3) captopril (95% confidence interval for baseline to week 12 change in DBP < 0, lower limit < ‐4.8 mmHg) in BP reduction for mild to moderate hypertensives. Treatment with OM was safe and well tolerated. Conclusion At the doses tested, olmesartan medoxomil o.d. is as effective as atenolol, and more effective than both losartan and captopril in reducing blood pressure in the hypertensive population.

Neurohormonal and metabolic effects of severe and moderate salt restriction in non-obese normotensive adults

Objective: The effects of severe and moderate sodium restriction on blood pressure, neurohormonal activity and serum lipids were studied in non-obese normotensive adults. Methods: In the first part of the study, 163 subjects were randomly assigned to a diet of 20 or 300 mmol/day sodium for 1 week each. In the second part, 25 subjects were given a diet of 85 or 200 mmol/day sodium for 4 weeks each in random order. Results: After severe salt restriction 19% of the subjects had a significant decline (salt-sensitive group), 15% showed a significant rise (counter-regulator group) and 66% exhibited no change in blood pressure (salt-resistant group). Severe sodium restriction increased plasma renin activity and noradrenaline concentration, as well as serum total and low-density lipoprotein-cholesterol and triglycerides. After correction for haematocrit, only the changes in total and low-density lipoprotein-cholesterol remained significant. The rise in plasma renin activity during salt restriction was steeper in the counter-regulator group than in the other groups, whereas the changes in plasma noradrenaline concentrations were similar in all groups. During moderate salt restriction, plasma renin activity and noradrenaline concentration were significantly increased, but serum lipid concentrations and blood pressure did not change. Conclusion: In non-obese normotensive adults, severe and moderate salt restriction stimulates neurohormonal activity. In contrast to severe salt restriction, a moderate reduction in dietary salt intake does not influence blood lipids in normotensive subjects.

Blood pressure response, but not adverse event incidence, correlates with dose of angiotensin II antagonist.

Objective To assess the efficacy and safety of the novel angiotensin II antagonist olmesartan medoxomil in patients with mild to moderate essential hypertension, using a meta‐analysis of the combined database from seven US and European clinical trials. Design Studies were randomized, double‐blind, placebocontrolled and dose‐finding (2.5–80 mg), with treatment duration of 6–52 weeks. Setting Hospital outpatient clinics. Patient population A total of 3095 patients in the safety population and 3055 patients in the intent‐to‐treat (efficacy) population. Methods All studies used conventional sphygmomanometry for blood pressure measurements at trough (end of the dosing interval). Three studies also used 24‐h ambulatory blood pressure monitoring for the principal efficacy evaluations. Main outcome measures Percentage of patients achieving diastolic blood pressure (DBP) ≤ 90 mmHg or decrease ≥ 10 mmHg (responder rate), percentage of patients achieving a target DBP ≤ 90 mmHg or target systolic blood pressure (SBP) ≤ 140 mmHg (normalization rate), and mean decrease in DBP from baseline to last visit. Results Efficacy variables tended to be dose related up to the 40 mg dose level. All olmesartan medoxomil doses were statistically significantly more effective than placebo for responder rate, DBP and SBP normalization rates, and mean decrease in DBP. A clinically relevant decrease of ≥ 5 mmHg from baseline in sitting DBP was also observed at doses of 20 mg and above after correction for placebo effect. The safety profile of olmesartan medoxomil was similar to that of placebo and was not dose related. Conclusions Olmesartan medoxomil was safe and highly effective in lowering blood pressure in patients with mild to moderate essential hypertension in these studies.

Effect of Irbesartan Versus Atenolol on Left Ventricular Mass and Voltage: Results of the CardioVascular Irbesartan Project

Regression of hypertensive left ventricular hypertrophy (LVH) is associated with improved prognosis. The aim of this trial was to compare the effects of irbesartan versus atenolol on LVH in subjects with essential hypertension. Because electrocardiographic and echocardiographic parameters of LVH carry disparate prognostic information, both methods were applied in this trial. In the randomized, double-blind, multicenter trial CardioVascular Irbesartan Project, 240 patients with essential hypertension were treated with irbesartan or atenolol for 18 months. Voltage criteria used for LVH were Sokolow index, Cornell index, Cornell voltage×QRS duration product and Lewis index. In parallel, left ventricular mass (LVM) was determined by 2-dimensional guided M-mode echocardiography. After 6 and 18 months, reductions of LVM and voltage criteria for LVH were only found in subjects treated with irbesartan. However, a reduction of LVM was only detectable in subjects within the highest quartile of baseline LVM but not overall. In contrast, reductions of voltage criteria for LVH were detectable after 6 and 18 months even within commonly used normal limits. In conclusion, treatment of hypertension with irbesartan resulted in a significant reduction in the voltage criteria for LVH, although an effect on LVM was only seen in subjects with high baseline LVM. In contrast, atenolol did not lead to reductions in electrocardiographic or echocardiographic parameters of LVH. Because voltage criteria for LVH have been shown to predict cardiovascular outcome independently from LVM, we suggest that both methods should be used to accurately assess the benefits of antihypertensive treatment.

High-normal serum homocysteine concentrations are associated with an increased risk of early atherosclerotic carotid artery wall lesions in healthy subjects.

OBJECTIVE: Moderate hyperhomocysteinaemia is common in the general population and has been linked with systemic atherosclerotic vascular disease. We studied the relation of sonographically determined carotid intima-media wall thickness to serum homocysteine concentrations in asymptomatic, healthy subjects. METHODS AND RESULTS: Seventy-five male and female untreated subjects (mean age 49 years, range 22-75) with normal serum folate concentrations were included. High-resolution duplex sonography was used to determine intima-media thickness of the common carotid artery. Serum homocysteine concentration was measured by high-performance liquid chromotography with fluorescence detection. Mean intima-media thickness (+/- SD) was 0.78 +/- 0.19 mm (range 0.5-1.35) and mean serum homocysteine concentration was 10.5 +/- 2.81 micromol/l (range 5.7-19.6). In stepwise regression models, statistically significant predictors of intima-media thickness included age, body mass index, LDL cholesterol and homocysteine (R2 = 0.51). Homocysteine concentration was independently associated with intima-media thickness after adjustment for the other variables (P < 0.001) and explained an additional 18% of the variation of intima-media thickness. CONCLUSIONS: In healthy subjects, high-normal serum homocysteine concentrations are associated with an increased prevalence of carotid artery wall thickening. The significance of the contribution of homocysteine to the variation of carotid intima-media thickness, even at concentrations previously believed to be normal, suggests a role for homocysteine as an independent risk factor for early carotid artery atherosclerosis in the asymptomatic subjects.

Comparison of the effects of losartan and atenolol on common carotid artery intima-media thickness in patients with hypertension: results of a 2-year, double-blind, randomized, controlled study.

BACKGROUND Hypertension induces progressive pathologic changes in the arterial wall. Experimental findings suggest that these changes, which include intima-media thickening, may be mediated, at least in part, by angiotensin II (AII). OBJECTIVE The Losartan Vascular Regression Study (LAARS) was a double-blind, parallel-group, randomized, controlled, multicenter study designed to compare the effects of the AII antagonist losartan and the beta-blocker atenolol on ultrasonographically determined intimamedia thickness (IMT) of the common carotid artery (CCA) in patients with mild to moderate essential hypertension. METHODS The primary end point of the study was the yearly rate of change (YRC) from baseline of the mean IMT of the CCA (CCA-IMT(mean)) averaged over 2 years of treatment. Secondary end points included IMT of the common femoral artery and sitting systolic and diastolic blood pressures (SiSBP/SiDBP). Safety assessments of losartan and atenolol were made by statistical and clinical review of the incidence of adverse experiences as well as review of vital signs and laboratory values. A total of 414 patients with essential hypertension were screened for study inclusion at 36 study centers in Germany and Brazil. Patients received losartan (50 mg once daily) or atenolol (50 mg once daily) for 24 months. Target blood pressure (SiSBP/SiDBP <140/<90 mm Hg) was achieved by adding hydrochlorothiazide 12.5 mg once daily, doubling the dose of study drug, or adding an open-label calcium channel blocker sequentially, as needed. RESULTS Of the original 414 patients screened, 280 hypertension patients (SiDBP 95-115 mm Hg), aged 35 to 65 years, with an IMT of 0.8 to 1.5 mm of the right or left CCA, were randomized to treatment with either losartan (n = 142) or atenolol (n = 138). Both losartan and atenolol therapy produced comparable reductions in CCA-IMTmean over 24 months compared with baseline; the average YRC was -0.038 +/- 0.004 mm/y (P < or = 0.001) for losartan and -0.037 +/- 0.004 mm/y (P < or = 0.001) for atenolol. There were no significant differences between groups. Losartan showed a greater reduction of femoral artery IMT than did atenolol; the average YRC was -0.024 mm/y (P < or = 0.05) for losartan and -0.017 mm/y for atenolol (P = NS), with no significant difference between groups. Both agents produced similar significant reductions in SiSBP and SiDBP and were generally well tolerated. Approximately 7% of losartan patients had drug-related clinical adverse events, compared with 12% of atenolol patients. CONCLUSIONS The findings of LAARS, the first large study with an AII antagonist that examined IMT, suggest that AII antagonism reverses the early stages of vascular hypertrophy in patients with hypertension. Further studies are needed to delineate the relative importance of AII antagonism versus blood pressure reduction per se in mediating the beneficial vascular effects of losartan.

Olmesartan compared with other angiotensin II receptor antagonists: Head-to-head trials

BACKGROUND Drugs that block the renin-angiotensin system represent one of the most significant therapeutic interventions available for the treatment of hypertension. The angiotensin II receptor antagonists (AIIRAs), also known as sartans, are one such class of drugs that block the effects of angiotensin II by antagonizing the angiotensin II type 1 receptor. Olmesartan is the newest member of this class. OBJECTIVE The present article reviews 3 head-to-head trials directly comparing the antihypertensive efficacy of olmesartan with that of 4 other AIIRAs, at recommended maintenance doses, already in clinical use for the treatment of hypertension. RESULTS In the first study, olmesartan 10 mg/d was compared with losartan 50 mg/d in 316 patients with mild to moderate hypertension (mean baseline diastolic blood pressure [DBP], 95-114 mm Hg). Dosage was doubled at week 4 and hydrochlorothiazide was added at week 12 if blood pressure response was inadequate. Olmesartan was significantly more effective than losartan with respect to the reduction in blood pressure at weeks 2, 4, and 12, and to the responder rate at weeks 2 and 4 (with the starting dose of the respective drug). In a second study, olmesartan 20 mg/d was shown to be significantly more effective than losartan 50 mg/d, valsartan 80 mg/d, and irbesartan 150 mg/d in 588 patients with mild to moderate hypertension (mean sitting baseline DBP, 100-115 mm Hg) (P < or = 0.05). At week 2, the reduction in blood pressure observed with olmesartan was significantly greater than that of the comparator treatments (P < or = 0.05). The superiority of olmesartan was maintained at week 8. The third study involved 643 evaluable patients with moderate to severe hypertension (mean DBP, 100-120 mm Hg; mean systolic blood pressure, >150 mm Hg). Olmesartan 20 mg/d was more effective than candesartan 8 mg/d in lowering 24-hour blood pressure at week 8 (P < or = 0.05). Most of this treatment effect was evident after only 1 or 2 weeks, with greater reductions in blood pressure compared with candesartan. CONCLUSIONS These data indicate that, at the doses studied, olmesartan is more effective than other AIIRAs tested at their recommended doses, in terms of reduction of cuff or 24-hour ambulatory blood pressure, in patients with essential hypertension. These differences in blood pressure reduction between these agents may be clinically relevant and have important long-term implications. Additional studies will further define the role of olmesartan in the management of cardiovascular diseases, such as atherosclerosis.

ACE-inhibition with perindopril in essential hypertensive patients with concomitant diseases

PURPOSE Many hypertensive patients have other, usually long-term diseases. Antihypertensive therapy may interfere with these diseases and their therapies. In the present study, the possible interactions of the ACE-inhibitor perindopril with several of the most common long-term diseases was evaluated. PATIENTS AND METHODS In a multicenter, double-blind, randomized, placebo-controlled trial, the effect of perindopril was evaluated in 490 patients with mild essential hypertension and any one of the following concomitant diseases: hyperlipidemia, type II diabetes mellitus, ischemic heart disease, cardiac arrhythmia, peripheral arterial occlusive disease, nephropathy with proteinuria, chronic obstructive pulmonary disease, or degenerative joint disease treated with nonsteroidal anti-inflammatory drugs (NSAIDs). After a 3-week single-blind placebo run-in, the patients received either perindopril (4 mg/d) or matching placebo for 6 weeks. RESULTS Blood pressure was effectively reduced by perindopril irrespective of the associated disease. The rate of spontaneously reported side effects was low. Treatment with perindopril was free from adverse interactions with the concomitant diseases and therapies. Moreover, favorable actions could be observed in patients with ischemic heart disease (reduction of maximal ST-segment depression during peak exercise and decrease in the number of angina attacks), in patients with proteinuria (decrease in albuminuria in patients with normal serum creatinine levels), and in patients with NSAID-treatment (increase in prostaglandin E2 concentration in gastric mucosa suggesting gastric cytoprotection). CONCLUSION This trial shows that ACE-inhibition with perindopril represents a simple, safe, and effective short-term therapeutic option for the large proportion of patients with mild essential hypertension and concomitant diseases and therapies.

Effect of angiotensin receptor blockade on central haemodynamics in essential hypertension: results of a randomised trial.

Objective. Angiotensin-converting enzyme (ACE) inhibitors have been shown to lower central augmentation index (cAI), an index of arterial wave reflection, more than β-blockers. We tested whether this is also true for long-term treatment with an angiotensin receptor blocker (ARB). Methods. One-hundred and fifty-six subjects with essential hypertension were randomised to treatment with either irbesartan or atenolol. cAI and central blood pressure (BP) were determined by pulse wave analysis from the radial and the carotid artery after six and after 18 months treatment. Results. Peripheral and central systolic and diastolic BP were reduced to a similar extent A in the two groups. cAI was reduced with irbesartan, but increased with atenolol (derived from the carotid artery: -6±10 vs. -4±12% after six months, p<0.001; —4±12 vs. +1±11% after 18 months; p=0.011). Furthermore, central to peripheral pulse pressure (PP) amplification was unaffected by treatment with irbesartan, but decreased with atenolol. Conclusions. Although treatment with irbesartan and atenolol similarly decreased peripheral and central BP, only treatment with irbesartan had beneficial effects on arterial wave reflection and preserved PP amplification. These haemodynamic effects may at least partly explain the reported differential effects of ARB versus β-blocker treatment on cardiovascular mortality in patients with essential hypertension.