Effect of Evening Bromazepam Administration on Blood Pressure and Heart Rate in Mild Hypertensive Patients.

AIM: To assess the effects of chronic evening oral administration of bromazepam alone or in combination with propranolol on ambulatory blood pressure (BP) and heart rate (HR) in mild hypertensive subjects. METHODS: Thirty-seven mild hypertensive patients after a 2-week placebo period were randomized to bromazepam 3 mg, propranolol 40 mg, bromazepam 3 mg plus propranolol 40 mg or placebo for 2 weeks according to a double-blind, double dummy, cross-over design. After each treatment period, 24-h BP and HR ambulatory monitoring was performed by using a non-invasive device. RESULTS: Ambulatory monitoring showed that during night-time SBP and DBP values were unaffected by bromazepam as compared to placebo, whereas SBP was significantly reduced by propranolol both when taken alone and in combination with bromazepam. HR nocturnal values were significantly reduced by propranolol, whereas they were significantly increased by bromazepan both when taken alone (+11.5%, p < 0.05 vs. placebo) and in combination with propranolol (+12.8%, p < 0.05 vs. propranolol). No significant difference in day-time values of SBP, DBP and HR was observed among the 4 treatment groups. CONCLUSIONS: In mild hypertensive patients, evening consumption of bromazepam for a 2-week period did not affect BP, while it increased nocturnal HR. Such an increase was observed both when bromazepam was taken alone and in combination with propranolol, which suggests that it depends on a bromazepam mediated decrease in vagal tone. Whatever the mechanism, the HR nocturnal increase might be of clinical relevance, due to the role of high HR as cardiovascular risk factor, particularly in already at risk hypertensive subjects.

Diazepam as an oral hypnotic increases nocturnal blood pressure in the elderly.

BACKGROUND: No study has evaluated the cardiovascular effects of diazepam in elderly subjects that assume diazepam to induce sleep. PURPOSE: The present study was carried out in order to evaluate the effects of chronic administration of diazepam as hypnotic drug on blood pressure (BP) and heart rate (HR) in healthy elderly subjects. PATIENTS AND METHODS: Healthy, elderly subjects, aged 65-74 years, were treated with diazepam 5 mg or placebo-both administered once a day in the evening-for 4 weeks in two cross-over periods, each separated by a 2-week placebo period, according to a randomized, double-blind, cross-over design. At the end of each study period, clinical as well as 24-h ambulatory BP and HR were evaluated. RESULTS: A total of 25 subjects were included in the analysis. At the end of a 4-week diazepam treatment, clinical as well 24-h BP and HR mean values were not significantly affected. Analysis of sub-periods showed that during night-time, systolic BP (SBP) values under diazepam were 7.6% higher than under placebo, with a mean difference of 7.9 mmHg (p < 0.01), diastolic BP (DBP) values were 5.8% higher, with a mean difference of 3.7 mmHg (p < 0.05 vs placebo) and HR values were 6.6% higher with a mean difference of 4.2 b/min (p < 0.05). The HR increase observed with diazepam persisted during the morning hours, whereas during the afternoon and evening hours SBP, DBP and HR values were similar in the two treatment groups. CONCLUSIONS: In elderly subjects chronic assumption of diazepam as hypnotic agent produced an increase in BP, in particular SBP, during night-time and of HR during night-time and morning hours. These effects, which probably depend on a diazepam-mediated increase in sympathetic drive and decrease in vagal tone, might be of clinical relevance due to the role of increased BP and HR as independent predictors of cardiovascular morbidity and mortality.

Effect of flunitrazepam as an oral hypnotic on 24-hour blood pressure in healthy volunteers.

PURPOSE: The present study was carried out in order to assess the effects of chronic administration of flunitrazepam (as an oral hypnotic) on 24-h blood pressure (BP) and heart rate (HR) in healthy young adults. MATERIALS AND METHODS: Following a 2-week placebo run-in period, 28 healthy volunteers (13 males and 15 females) between 21 and 30 years were randomized to receive either flunitrazepam 1 mg or placebo (both administered once a day in the evening) for 4 weeks in two cross-over periods; each separated by a 2-week placebo period. At the end of each study period, non-invasive 24-h BP and HR ambulatory monitoring was performed. RESULTS: Flunitrazepam produced a significant decrease in nighttime systolic blood pressure (SBP) (- 6.4 mmHg) and diastolic blood pressure (DBP) (- 4.1 mmHg) (both P < 0.05 vs placebo) without affecting nocturnal HR. During the morning hours, significantly higher values of SBP (+ 7.4 mmHg, P < 0.01), DBP (+ 3.4 mmHg, P < 0.05) and HR (+ 3.9 beats/min, P < 0.05) were observed in the flunitrazepam group compared to the placebo-treated group. No significant differences were noted between the two groups during afternoon and evening hours. CONCLUSIONS: These results suggest that chronic oral administration of 1 mg flunitrazepam as a hypnotic agent causes a significant nocturnal fall in BP and a transient rebound increase of both BP and HR at awakening in the morning. Mechanisms underlying these cardiovascular effects remain unclear, although the direct vasodilatory effect, which is typical of flunitrazepam (with consequent reflex counter-regulatory responses), and the attenuation of baroreflex sensitivity are likely to play a major role.

Effect of Diazepam on 24-Hour Blood Pressure and Heart Rate in Healthy Young Volunteers.

AIM: To assess the effects of evening chronic administration of diazepam on 24-h blood pressure (BP) and heart rate (HR) in healthy young adults. METHODS: This randomized double blind, cross-over study evaluated the effects of diazepam 5 mg or placebo, both ingested in the evening, on 24-h ambulatory BP and HR in healthy subjects aged 21-30. RESULTS: A total of 30 subjects were included in the analysis. At the end of 4-week diazepam intake, an increase in 24-h HR mean values was found (+5.2 beats/min, p < 0.05). Analysis of subperiods showed that diazepam produced a 10.1% increase in night-time HR (+6.1 beats/min, p < 0.01) without affecting BP. A significant HR rise (+4.9 beats/min, p < 0.05) and SBP reduction (-3.8 mm Hg, p < 0.05) were observed in the morning hours. The HR increase persisted in day-time hours (+4.6 beats/min, p < 0.05), while BP values resulted unaffected. CONCLUSIONS: In healthy subjects, diazepam taken as a hypnotic agent induces a significant HR increase, possibly mediated by a decrease in vagal tone. This effect might be of clinical relevance due to the role that HR plays as an independent cardiovascular risk factor.

Effect of ramipril/hydrochlorothiazide and ramipril/canrenone combination on atrial fibrillation recurrence in hypertensive type 2 diabetic patients with and without cardiac autonomic neuropathy.

INTRODUCTION: The aim of this study was to compare the effect of ramipril/canrenone versus ramipril/hydrochlorothiazide (HCTZ) combination on atrial fibrillation (AF) recurrence in type 2 diabetic hypertensives with and without cardiac autonomic neuropathy (CAN). MATERIAL AND METHODS: A total of 289 hypertensive type 2 diabetic patients, 95 with CAN, in sinus rhythm but with at least two episodes of AF in the previous 6 months were randomized to ramipril 5 mg plus canrenone 50 mg (titrated to 10/100 mg) or to ramipril 5 mg plus HCTZ 12.5 mg (titrated to 10/25 mg) or to amlodipine 5 mg (titrated to 10 mg) for 1 year. Clinic blood pressure (BP) and a 24-h ECG were evaluated monthly. Patients were asked to report any episode of symptomatic AF and to perform an ECG as early as possible. Serum procollagen type I carboxy-terminal peptide (PIP) and carboxy-terminal telopeptide of collagen type I (CITP) were evaluated before and after each treatment period. RESULTS: Blood pressure was similarly and significantly reduced by all treatments. A total of 51% of patients with amlodipine had a recurrence of AF, as did 31% of patients with ramipril/HCTZ (p < 0.05 vs. amlodipine) and 13% of patients with ramipril/canrenone (p < 0.01 vs. amlodipine and p < 0.05 vs. ramipril/HCTZ). A similar trend was found in diabetic patients with CAN. Both combinations reduced PIP and increased CITP, but the effects of ramipril/canrenone were significantly more marked. CONCLUSIONS: These findings suggest that in type 2 diabetic hypertensives, ramipril/canrenone treatment was more effective than ramipril/HCTZ in reducing AF recurrence. This could be related to the greater improvement in cardiac fibrosis.

Ambulatory 24-h ECG monitoring and cardiovascular autonomic assessment for the screening of silent myocardial ischemia in elderly type 2 diabetic hypertensive patients.

The aim of the study was to evaluate the usefulness of Holter monitoring for the detection of silent myocardial ischemia (SMI) in elderly type 2 diabetic patients with hypertension and the possible relationship between SMI and cardiovascular autonomic neuropathy (CAN). Two hundred and forty-three asymptomatic outpatients, aged 65-75 years, with type 2 diabetes and essential hypertension underwent 24-h ECG monitoring and 5 tests for the evaluation of both parasympathetic (heart rate variability, response to breath deeping, and Valsalva manoeuvre) and sympathetic (cold pressor test and orthostatic hypotension test) autonomic function. A total of 518 asymptomatic episodes of ST depression during Holter monitoring indicative of SMI were detected in 51 of the 243 studied patients (20.9 %). None of the patients with ST depression episodes exhibited a normal response to at least one of the evaluated autonomic function tests, whereas 22 of the 192 patients without ST changes (11.4 %) exhibited a normal response to all tests. Abnormality in both parasympathetic and sympathetic function test responses was found in 94.1 % of patients with ST depression episodes vs 26.1 % of those without ST changes (P < 0.001). Statistical evaluation of the relationship between the abnormal response to single autonomic function test and episodes of ST depression was highly significant for all the 5 tests (P < 0.001). These results indicate that: (a) Holter monitoring enables to detect ST segment changes indicative of SMI in 20.9 % of elderly diabetic patients with hypertension; (b) the presence of autonomic cardiac dysfunction in these patients suggests a role of diabetic neuropathy in the pathogenesis of SMI; and

Twenty-four-hour blood pressure profile, orthostatic hypotension, and cardiac dysautonomia in elderly type 2 diabetic hypertensive patients.

PURPOSE: The aim of this study was to evaluate the relationship between orthostatic hypotension (OH), defined as a decrease in systolic blood pressure (SBP) ≥20 mmHg and/or a decrease in diastolic blood pressure (DBP) ≥10 mmHg, and 24-h ambulatory BP profile in elderly hypertensive type 2 diabetic patients. METHODS: After a 2-week antihypertensive wash-out period, 200 hypertensive well-controlled diabetic outpatients, aged 65-75 years, underwent a clinical examination, including BP measurements, ECG, 24-h ABP monitoring (ABPM), an orthostatic test, and three tests for cardiovascular autonomic function assessment [deep breathing, heart rate (HR) variability, resting HR]. RESULTS: According to their nighttime BP profile, patients were divided into three groups: dippers (n = 86) (BP fall during nighttime ≥10 %), non-dippers (n = 80) (BP fall during nighttime 0-10 %), and reverse dippers (n = 34) (nighttime BP > daytime BP). Orthostatic test produced a significantly greater orthostatic SBP fall in dippers and even more in reverse dippers. In these latter, a significant fall was observed also in DBP. Prevalence of OH was 9.3 % in dippers, 30 % in non-dippers, and 79.4 % in reverse dippers. CONCLUSIONS: In elderly hypertensive type 2 diabetics, a blunted nocturnal BP fall is associated with OH and autonomic dysfunction. These data suggest that ABPM should be performed in the assessment of hypertensive diabetic patients in whom the cardiovascular dysautonomia is suspected or the signs of it are present (such as OH).

Comparative effect of canrenone or hydrochlorothiazide addition to valsartan/amlodipine combination on urinary albumin excretion in well-controlled type 2 diabetic hypertensive patients with microalbuminuria.

OBJECTIVE: To compare the effect of adding canrenone or hydrochlorothiazide (HCTZ) to valsartan/amlodipine combination on urinary albumin excretion (UAE) in microalbuminuric type 2 diabetic hypertensives. RESEARCH DESIGN AND METHODS: After a 2-week placebo period and after 4 weeks of valsartan 160 mg plus amlodipine 5 mg combination, 120 patients whose blood pressure (BP) was not controlled (> 130/80 mmHg) were randomized to canrenone 25 mg or HCTZ 12.5 mg in addition to the previous therapy for 24 weeks. After the first 6 weeks of triple therapy, canrenone or HCTZ doses were doubled in the patients whose BP was yet uncontrolled. At the end of each period (placebo, dual combination and triple combination therapy), clinic and ambulatory BP measurements were recorded and 24 h UAE was evaluated. RESULTS: Both triple combinations produced greater clinical and ambulatory BP reduction than dual therapy, with no difference between the two groups. UAE was reduced by both regimens, but the decrease associated with canrenone add-on therapy was more pronounced. At week 24, UAE decreased by 45.3% in the canrenone group and by 20.3% in the HCTZ group (p < 0.01). CONCLUSIONS: These findings indicate that, despite similar BP-lowering effect, the addition of canrenone to valsartan/amlodipine combination was more effective in reducing UAE than HCTZ addition.

Effect of imidapril versus ramipril on urinary albumin excretion in hypertensive patients with type 2 diabetes and microalbuminuria.

OBJECTIVE: Aim of this study was to compare the antiproteinuric effect of imidapril (I) and ramipril (R) in diabetic hypertensive patients with microalbuminuria. RESEARCH DESIGN AND METHODS: One hundred and seventy-six patients were randomised to I 10 - 20 mg once daily (od) (n = 88) or R 5 - 10 mg od (n = 88) for 24 weeks. Clinic, ambulatory, central blood pressure (BP), urinary albumin excretion (UAE), plasma Angiotensin II (Ang II), bradykinin and brain natriuretic peptide (BNP) were assessed at baseline and after 6, 12 and 24 weeks. RESULTS: Both I and R produced a similar decrease in clinic, ambulatory and central BP (p < 0.001 vs baseline). Both treatments significantly reduced UAE throughout the study, but the decrease in UAE associated with I was more pronounced, being evident at week 6 (p = 0.05) and maximal at week 24 end-point (-42 vs -29%, p < 0.01). BNP and Ang II levels were similarly reduced by I and R, while bradykinin increased more with R (+132 vs +86%, p < 0.05). CONCLUSIONS: These findings showed that in diabetic hypertensive patients with microalbuminuria, despite equivalent BP-lowering effect, I produced a greater antiproteinuric effect than R, which might be due to different intrinsic molecular properties of the two drugs.

Effect of naproxen and acetaminophen on blood pressure lowering by ramipril, valsartan and aliskiren in hypertensive patients.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used for reducing pain and other symptoms in osteoarthritis (OA). NSAIDs have been associated with an increase in blood pressure (BP) in both normotensive and hypertensive individuals and a blunting effect on various anti-hypertensive medications. Acetaminophen effects on anti-hypertensive treatment, instead, are still a matter of debate. OBJECTIVES: To assess the effect of naproxen versus acetaminophen on ramipril, valsartan and aliskiren therapy in hypertensive patients with OA in a double-blind, cross-over study, by measuring clinic, ambulatory BP and heart rate (HR). RESULTS: One hundred seventy four patients were randomly treated with ramipril, valsartan or aliskiren for 8 weeks and 135 patients with normalized BP were randomized to receive naproxen or acetaminophen for 2 weeks. Naproxen significantly increased clinic and ambulatory systolic/diastolic BP (SBP/DBP) values in patients treated with ramipril (p < 0.01) or valsartan (p < 0.05), but did not affect aliskiren effects. Also acetaminophen slightly but significantly affected clinic and ambulatory SBP/DBP in all three groups and, surprisingly, it also produced a slight increase in HR (+3.1, +3.3 and +3.4 b/min day-time HR values, for ramipril, valsartan and aliskiren, respectively; p < 0.05). CONCLUSIONS: Both naproxen and acetaminophen can affect anti-hypertensive therapy with ramipril, valsartan or aliskiren with a different extent. When acetaminophen is chosen for OA management in subjects with hypertension, patients should be evaluated as carefully as when traditional NSAIDs are given.

Time course of antiproteinuric effect of aliskiren in arterial hypertension associated with type 2 diabetes and microalbuminuria.

OBJECTIVE: The aim was to compare the antiproteinuric effect of aliskiren and ramipril in hypertensive patients with type 2 diabetes and microalbuminuria. RESEARCH DESIGN AND METHODS: A total of 138 patients were treated with aliskiren 300 mg/day or ramipril 10 mg/day for 12 weeks and checked after 1, 2, 4, 8 and 12 weeks and 2 and 4 weeks after treatment withdrawal. MAIN OUTCOME MEASURES: Clinic and ambulatory BP, urinary albumin excretion rate (UAER) and plasma aldosterone were measured. RESULTS: Both aliskiren and ramipril induced a similar lowering in clinic and ambulatory BP (p < 0.001 vs baseline). However, such a lowering persisted longer after stopping aliskiren than after stopping ramipril regimen. Both treatments reduced UAER, but the decrease in UAER associated with aliskiren was more pronounced, the difference vs ramipril being maximal at week 12 (-42 vs -15%, p < 0.01). Two weeks after stopping therapy, UAER remained below baseline values with aliskiren, but not in the ramipril group. Plasma aldosterone decreased in the aliskiren group, whereas in the ramipril group it decreased until week 8 and thereafter increased toward baseline values. CONCLUSIONS: Aliskiren has a greater and more prolonged antiproteinuric effect than R; it might partly be related to a higher degree of intrarenal renin-angiotensin-aldosterone system blockade.

Effect of telmisartan on paroxysmal atrial fibrillation recurrence in hypertensive patients with normal or increased left atrial size.

BACKGROUND: Hypertension is the most prevalent and potentially modifiable risk factor for atrial fibrillation (AF). In a previous secondary prevention study, the authors observed that the angiotensin II receptor blocker telmisartan was more effective than the calcium channel blocker amlodipine in preventing AF relapse in hypertensive patients with normal atrial size. HYPOTHESIS: Telmisartan may be more effective than amlodipine in preventing AF recurrence in hypertensive patients with paroxysmal AF and normal or increased left atrial dimension (LAD). METHODS: The authors assigned 378 mild hypertensive outpatients in sinus rhythm, but with ≥2 episodes of AF in the previous 6 months, to 1 of 2 groups. Group 1 comprised patients with LAD <40 mm in females and <45 mm in males. Group 2 comprised patients with LAD >40 mm and <45 mm in females and >45 mm and <50 mm in males. In both groups, patients were randomly treated with telmisartan or amlodipine for 1 year. RESULTS: Systolic and diastolic blood pressure were similarly reduced by telmisartan and amlodipine in both groups. The AF recurrence rate was significantly lower in the telmisartan-treated patients than in the amlodipine-treated patients in both group 1 (12 vs 39, P < 0.01) and group 2 (40 vs 59, P < 0.05). Under telmisartan, the AF recurrence rate was significantly lower in group 1 than in group 2 (12.9% vs 42.1%, P < 0.05). Time to a first AF relapse was significantly longer with telmisartan than with amlodipine in both group 1 (176 ± 94 days vs 74 ± 61 days, P < 0.05) and group 2 (119 ± 65 days vs 38 ± 35 days, P < 0.05). CONCLUSIONS: Telmisartan was more effective than amlodipine in preventing AF recurrences in hypertensive patients with paroxysmal AF.

Effects of valsartan or ramipril addition to amlodipine/hydrochlorothiazide combination on left ventricular mass in diabetic hypertensive patients with left ventricular hypertrophy.

OBJECTIVE: The objective of this study was to compare valsartan or ramipril addition to amlodipine + hydrochlorothiazide (HCTZ) on blood pressure (BP) and left ventricular hypertrophy (LVH) in hypertensive diabetic patients with LVH. RESEARCH DESIGN AND METHODS: 293 patients were treated with amlodipine 10 mg + HCTZ 12.5 combination and then randomized to receive valsartan 160 mg or ramipril 5 mg, in addition to the previous therapy, for 1 year. MAIN OUTCOME MEASURES: Clinic BP was measured every month; echocardiographic assessments were performed at the end of the placebo period, both before the randomization and after 1-year of triple combination therapy. RESULTS: Both triple regimens similarly reduced SBP/DBP values (-13.5/10.9 mm Hg in the valsartan group and -13.4/10.4 mm Hg in the ramipril group). Triple combination including valsartan better reduced LVMI (-20.1%, p < 0.001), interventricular septal thickness (IVST) (-20.3%, p < 0.001) and left ventricular posterior wall thickness (PWT) (-16.3%, p < 0.001), compared with triple combination including ramipril (-14%, p < 0.01; -16.2%, p < 0.001 and -9%, p < 0.01, respectively); the difference between treatments being statistically significant (p < 0.05). Triple combination with valsartan gave a greater increase of E/A ratio (p < 0.05 between groups). CONCLUSIONS: Valsartan addition to dual therapy with amlodipine + HCTZ was more effective than ramipril addition in reducing LVH.

Effects of valsartan versus olmesartan addition to amlodipine/hydrochlorothiazide combination in treating stage 2 hypertensive patients.

OBJECTIVE: The objective of this study was to assess the effects of valsartan or olmesartan addition to dual therapy with amlodipine + hydrochlorothiazide (HCTZ) in the treatment of stage 2 hypertension. RESEARCH DESIGN AND METHODS: 180 patients with diastolic blood pressure (DBP) ≥ 99 and < 110 mm Hg were treated with amlodipine 5 mg + HCTZ 12.5 mg combination. After 4 weeks, 149 patients whose blood pressure (BP) was not controlled, were randomized to the combination of valsartan 160 mg + amlodipine 5 mg + HCTZ 12.5 mg or olmesartan 20 mg + amlodipine 5 mg + HCTZ 12.5 mg for 4 weeks. MAIN OUTCOME MEASURES: At the end of each period, clinical and ambulatory BP measurements were recorded. RESULTS: Both triple combinations produced greater ambulatory and clinical SBP/DBP reduction than dual therapy. However, mean reduction from baseline in the valsartan + amlodipine + HCTZ-treated patients was significantly greater than in the olmesartan + amlodipine + HCTZ-treated patients. Compared with dual therapy, the add-on effect of valsartan was significantly greater than that of olmesartan, the difference being more evident for nighttime SBP/DBP values (-3.3 (95% CI 0.44 - 3.51)/3.0 (95% CI 0.59 - 3.34) mm Hg, p < 0.01). CONCLUSIONS: The addition of valsartan to amlodipine + HCTZ produced greater BP reduction than the addition of olmesartan.

Effects of losartan and amlodipine alone or combined with simvastatin in hypertensive patients with nonalcoholic hepatic steatosis.

OBJECTIVES: The inhibition of the renin-angiotensin system and of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase could improve hepatic steatosis. The aim of this study was to evaluate the effects of losartan or amlodipine alone or combined with simvastatin on hepatic steatosis degree, and on insulin sensitivity in normocholesterolemic, hypertensive patients with nonalcoholic hepatic steatosis. METHODS: Patients were treated with losartan, 100 mg/day, or amlodipine, 10 mg/day, for 6 months; subsequently simvastatin, 20 mg/day was added to both treatments for a further 6 months. The patients performed an ultrasound examination [steatosis degree, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) diameter], an euglycemic hyperinsulinemic clamp [glucose infusion rate (GIR)], and a blood sample (fasting plasma glucose, fasting plasma insulin, triglycerides, and inflammatory parameters) at baseline, and after 6 and 12 months, respectively. RESULTS: Both losartan and amlodipine induced a significant and similar systolic blood pressure/diastolic blood pressure reduction (P<0.001 vs. baseline). Losartan significantly increased GIR (P<0.05 vs. baseline) compared with amlodipine therapy, and the addition of simvastatin to losartan further increased GIR compared with the simvastatin added to amlodipine therapy (P<0.01 and P<0.05 vs. baseline, respectively). Losartan significantly decreased the steatosis degree, SAT, and VAT diameter compared with amlodipine therapy (P<0.05 vs. baseline with losartan for all). The addition of simvastatin to losartan therapy further decreased the steatosis degree, SAT, and VAT diameter. CONCLUSION: Losartan and simvastatin combination significantly improved the hepatic steatosis indices compared with amlodipine and simvastatin combination.

Effect of telmisartan and ramipril on atrial fibrillation recurrence and severity in hypertensive patients with metabolic syndrome and recurrent symptomatic paroxysmal and persistent atrial fibrillation.

This study evaluated the effect of telmisartan, ramipril, and amlodipine on atrial fibrillation (AF) recurrence and severity in hypertensive patients with metabolic syndrome. A total of 391 hypertensive outpatients with metabolic syndrome, in sinus rhythm but with at least 2 episodes of AF in the previous 6 months were randomized to telmisartan, ramipril, or amlodipine for 1 year. At the first AF, ventricular rate (VR) and plasma cardiac troponin I (TnI) were evaluated. P-wave dispersion (PWD) and procollagen type I carboxy-terminal peptide (PIP) were evaluated before and after 12 months of treatment. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were similarly and significantly reduced by all treatments (P < .001). In all, 49% of patients treated with amlodipine had a recurrence of AF as did 25.5% of patients with ramipril and 12.9% of patients with telmisartan (P < .01 vs amlodipine and P < .05 vs ramipril). Ventricular rate and TnI at the first AF recurrence were significantly lower with telmisartan and ramipril than with amlodipine. P-wave dispersion was reduced by ramipril (-5.1 ms, P < .05) and even more by telmisartan (-11 ms, P < .01). Telmisartan and ramipril induced a similar PIP reduction (-52.8 and -49.8 µg/L, respectively, P < .01). These findings suggested that in these patients telmisartan was more effective than ramipril in reducing AF recurrence and severity as well as in improving PWD, despite a similar BP reduction and a similar improvement in cardiac fibrosis. This could be related to a specific effect of telmisartan on atrial electric remodeling.

Effect of telmisartan addition to amlodipine on ankle edema development in treating hypertensive patients.

OBJECTIVE: The objective of this research was to evaluate the effect of telmisartan addition to amlodipine, on peripheral edema in hypertensive patients. RESEARCH DESIGN AND METHODS: Seventy-five outpatients were randomized to amlodipine (A) 10 mg or telmisartan (T) 80 mg, or amlodipine 10 mg plus telmisartan 80 mg, for 6 weeks, in three crossover periods. MAIN OUTCOME MEASURES: Blood pressure, ankle foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP) were evaluated, as were plasma norepinephrine and plasma active renin (PAR). RESULTS: Amlodipine-telmisartan combination induced greater SBP/DBP reduction (-28.1/21.7 mmHg, p < 0.0001 vs baseline) compared with monotherapy with both amlodipine and telmisartan. Amlodipine monotherapy increased AFV by 26.7%, and PSTP by 83.2% (both p < 0.01). Adding telmisartan to amlodipine produced a significantly lesser increase in both AFV (+7.9%, p < 0.01 vs amlodipine) and PSTP (+23.8%, p < 0.01 vs amlodipine). Plasma norepinephrine levels were increased by amlodipine (+134.3 pg/ml, p < 0.01); such an increase was attenuated by the addition of telmisartan (+55 pg/ml, p < 0.05 vs amlodipine). PAR was slightly increased by amlodipine (+21.5 pg/ml, p < 0.05) and more by telmisartan alone (+62.5 pg/ml) and telmisartan-amlodipine combination (+71.3 pg/ml; both p < 0.01). CONCLUSIONS: The addition of telmisartan to amlodipine significantly attenuated amlodipine-induced edema formation. The reduction of amlodipine-induced reflex-sympathetic activation by telmisartan might have contributed to such an effect.

Role of angiotensin II in plasma PAI-1 changes induced by imidapril or candesartan in hypertensive patients with metabolic syndrome.

To evaluate the relationship between plasma plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) changes during treatment with imidapril and candesartan in hypertensive patients with metabolic syndrome. A total of 84 hypertensive patients with metabolic syndrome were randomized to imidapril 10 mg or candesartan 16 mg for 16 weeks. At weeks 4 and 8, there was a dose titration to imidapril 20 mg and candesartan 32 mg in nonresponders (systolic blood pressure (SBP) >140 and/or diastolic blood pressure (DBP) >90 mm Hg). We evaluated, at baseline and after 2, 4, 8, 12 and 16 weeks, clinic blood pressure, Ang II and PAI-1 antigen. Both imidapril and candesartan induced a similar SBP/DBP reduction (-19.4/16.8 and -19.5/16.3 mm Hg, respectively, P<0.001 vs. baseline). Both drugs decreased PAI-1 antigen after 4 weeks of treatment, but only the PAI-1 lowering effect of imidapril was sustained throughout the 16 weeks (-9.3 ng ml(-1), P<0.01 vs. baseline), whereas candesartan increased PAI-1 (+6.5 ng ml(-1), P<0.05 vs. baseline and P<0.01 vs. imidapril). Imidapril significantly decreased Ang II levels (-14.6 pg ml(-1) at week 16, P<0.05 vs. baseline), whereas candesartan increased them (+24.2 pg ml(-1), P<0.01 vs. baseline and vs. imidapril). In both groups there was a positive correlation between Ang II and PAI-1 changes (r=0.61, P<0.001 at week 16 for imidapril, and r=0.37, P<0.005 at week 16 for candesartan). Imidapril reduced plasma PAI-1 and Ang II levels, whereas candesartan increased them. This suggests that the different effect of angiotensin-converting enzyme inhibitors and Ang II blockers on Ang II production has a role in their different influence on fibrinolysis.

Effect of aliskiren addition to amlodipine on ankle edema in hypertensive patients: a three-way crossover study.

OBJECTIVE: The aim of this study was to assess the effect of aliskiren and amlopidine on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP). RESEARCH DESIGN AND METHODS: After 4-week placebo, 120 outpatients with grade 1 - 2 hypertension were randomized to amlodipine 10 mg or aliskiren 300 mg or their combination for 8 weeks in three crossover periods. At the end of each treatment, blood pressure, AFV, PSTP, plasma renin activity (PRA) and norepinephrine were assessed. RESULTS: Both monotherapies similarly reduced systolic blood pressure (SBP; p < 0.001) and diastolic blood pressure (DBP; p < 0.001), but the reduction was greater with amlodipine/aliskiren combination (SBP: - 24.6 mmHg, p < 0.001 vs monotherapy; DBP: -20.9 mmHg, p < 0.01 vs monotherapy). Amlodipine increased both AFV (+ 28.4%, p < 0.01) and PSTP (+ 80.4%, p < 0.01), while the combination produced a less marked increase in AFV (+ 6.6%, p < 0.01 vs amlodipine) and PSTP (+ 20.1%, p < 0.01 vs amlodipine). Plasma norepinephrine increased with amlodipine (+ 53.5%, p < 0.01) and this increase was not reduced by aliskiren addition. PRA was unaffected by amlodipine, while it was reduced by both aliskiren monotherapy (- 77.7%, p < 0.01) and aliskiren/amlodipine combination (- 75.7%, p < 0.01). CONCLUSIONS: Direct renin inhibition by aliskiren partially counteracts the microcirculatory changes responsible for calcium-channel-induced edema formation, possibly through preferential vasodilation of venous capacitance vessels.

A drug safety evaluation of valsartan.

INTRODUCTION: Angiotensin receptor blockers (ARBs) as a class are generally considered safe and better tolerated than other antihypertensive drugs. The purpose of this report is to review the main data on the safety and tolerability of the second generation ARB valsartan after > 10 years since its initial approval. AREAS COVERED: We searched Medline for clinical studies published between 1997 and 2010 that involve valsartan and focus on its safety and tolerability profile. The main large-scale studies in hypertension, heart failure, post-myocardial infarction (MI) and chronic kidney disease are reviewed. EXPERT OPINION: Valsartan demonstrates to be safe and well tolerated both in monotherapy and in combination therapy of hypertension in a broad range of patients, including the elderly, children, diabetics, obese patients and patients at high cardiovascular risk. The most frequently reported adverse events (AEs) are malaise/fatigue, dizziness, headache and nausea/vomiting, whose incidence, however, is similar to that observed with placebo. Cough, a common class effect of ACE inhibitors, occurs less frequently with valsartan. When combined with hydrochlorothiazide, valsartan counteracts the adverse metabolic effects of the diuretic, whereas it reduces ankle edema formation when combined with amlodipine. In diabetic hypertensives, valsartan does not adversely affect glucose and lipid metabolism and even improves it. In post-MI patients, the rate of discontinuation due to AE, mainly hypotension, cough and increased serum creatinine, is lower in valsartan than in ACE inhibitor treated patients. Valsartan is also safe and well tolerated in patients with nephropathy although serum potassium levels need to be monitored more closely.