BACKGROUND & OBJECTIVES Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have been used to normalize the blood pressure and the dipping pattern in patients with type 1 diabetes mellitus (T1DM) and nephropathy. However, there are no data on the effect of the dual blockade on the dipping pattern in these subjects. We therefore, carried out this study to evaluate the effect of administrating an ACEI followed by ARB in the optimum doses in T1DM patients with nephropathy on 24 h blood pressure (BP) profile and nocturnal dipping pattern. METHODS An open label interventional pilot study was done during a one year period involving 30 consecutive patients who were treated with telmisartan 80 mg (0800-1000 h) for eight weeks followed by addition of ramipril 10 mg (1200-1400 h) for the next eight weeks. Ambulatory BP, dipping pattern and albumin excretion rate were studied after each phase. Twenty patients were hypertensive and 10 patients had macro- and 20 patients had microalbuminuria. RESULTS Telmisartan produced a fall in the clinic BP by 4/1.3 mm Hg (P<0.05 and P<0.362, respectively), 2/1.9 mm Hg in the mean 24 h BP, 1.4/1.1 mm Hg in the day BP and 3.7/3 mm Hg in the trough BP. Addition of ramipril to telmisartan produced a further reduction of 6.3/5.9 mm Hg in the clinic BP (P<0.001 for both), 4.3/4.2 mm Hg in the mean 24 h BP (P<0.01 and P<0.0001, respectively), 5.8/3.9 mm Hg in the day BP (P<0.01 for both), 4.2/2.5 mm Hg in the trough BP, with a reduction of clinic SBP and DBP of 10.3/7.2 mm Hg from the baseline. Telmisartan restored normal systolic dipping pattern in 33.3 per cent of the nondippers (P<0.01) but addition of ramipril was not complimentary. Hyperkalamia (>5.5 mmol/l) was observed only in 2 patients towards the end of the study. INTERPRETATION & CONCLUSIONS The dual blockade with telmisartan and ramipril had complimentary effect on lowering of the BP, however, similar beneficial effect on the nocturnal dipping was not observed. Further studies with large number of subjects with longer duration of follow-up are required to validate these observations.

Telmisartan and angiotensin-converting enzyme inhibitors (ACEIs) are both effective and widely used antihypertensive drugs targeting renin-angiotensin-aldosterone system. The study aimed to estimate the efficacy and tolerability of telmisartan in comparison with different ACEIs as monotherapy in the treatment of hypertension. Cochrane Central Register of Controlled Trials, PubMed and Embase were searched for relevant studies. A meta-analysis of all randomized controlled trials fulfilling the predefined criteria was performed. A random-effect model was used to account for heterogeneity among trials. Twenty-eight randomized controlled trials involving 5157 patients were ultimately identified out of 721 studies. Telmisartan had a greater diastolic blood pressure (DBP) reduction than enalapril (weighted mean difference (WMD) 1.82, 95% confidence interval (CI) 0.66-2.99), ramipril (WMD 3.09, 95% CI 1.94-4.25) and perindopril (WMD 1.48, 95% CI 0.33-2.62). Telmisartan also showed a greater DBP response rate than enalapril (relative risk (RR) 1.15, 95% CI 1.05-1.26), ramipril (RR 1.34, 95% CI 1.11-1.61) and perindopril (RR 1.22, 95% CI 1.05-1.41). There was no statistical difference in DBP reduction or therapeutic response rate between telmisartan and lisinopril (WMD -0.30, 95% CI -0.65 to 0.05; RR 0.99, 95% CI 0.80-1.23, respectively). Telmisartan had fewer drug-related adverse events than enalapril (RR 0.57, 95% CI 0.44-0.74), ramipril (RR 0.44, 95% CI 0.26-0.75), lisinopril (RR 0.70, 95% CI 0.56-0.89) and perindopril (RR 0.52, 95% CI 0.28-0.98). The meta-analysis indicates that telmisartan provides a superior BP control to ACEIs (enalapril, ramipril and perindopril) and has fewer drug-related adverse events and better tolerability in hypertensive patients.

ABSTRACT: BACKGROUND: The Study of Micardis (telmisartan) in Overweight/Obese patients with Type 2 diabetes and Hypertension (SMOOTH) compared hydrochlorothiazide (HCTZ) plus telmisartan or valsartan fixed-dose combination therapies on early morning blood pressure (BP), using ambulatory BP monitoring (ABPM). METHODS: SMOOTH was a prospective, randomized, open-label, blinded-endpoint, multicentre trial. After a 2- to 4-week, single-blind, placebo run-in period, patients received once-daily telmisartan 80 mg or valsartan 160 mg for 4 weeks, with add-on HCTZ 12.5 mg for 6 weeks (T/HCTZ or V/HCTZ, respectively). At baseline and week 10, ambulatory blood pressure (ABP) was measured every 20 min and hourly means were calculated. The primary endpoint was change from baseline in mean ambulatory systolic and diastolic blood pressure (SBP; DBP) during the last 6 hours of the 24-hour dosing interval. RESULTS: In total, 840 patients were randomized. At week 10, T/HCTZ provided significantly greater reductions versus V/HCTZ in the last 6 hours mean ABP (differences in favour of T/HCTZ: SBP 3.9 mm Hg, p < 0.0001; DBP 2.0 mm Hg, p = 0.0007). T/HCTZ also produced significantly greater reductions than V/HCTZ in 24-hour mean ABP (differences in favour of T/HCTZ: SBP 3.0 mm Hg, p = 0.0002; DBP 1.6 mm Hg, p = 0.0006) and during the morning, daytime and night-time periods (p < 0.003). Both treatments were well tolerated. CONCLUSIONS: In high-risk, overweight/obese patients with hypertension and type 2 diabetes, T/HCTZ provides significantly greater BP lowering versus V/HCTZ throughout the 24-hour dosing interval, particularly during the hazardous early morning hours.

Hypertension remains a leading cause of morbidity and mortality, affecting more than 60 million persons in the United States. Although the past 5 decades have witnessed advances in the therapeutic modalities available to treat hypertension and a dramatic decrease in morbidity and mortality related to hypertension, adequate blood pressure control has still not been achieved in a large number of patients. Therapeutic options to manage hypertension include agents that block the sympathetic nervous system, vasodilators, agents to control plasma volume, and drugs that act at various points in the renin-angiotensin system (RAS). Inadequate control of hypertension may be due in part to incomplete blockade of the RAS pathway in some patients; targeting a point earlier in this cascade might possibly improve control. Direct renin inhibitors, a new class of antihypertensive drugs, block the RAS pathway at the point of activation. Inhibition of renin prevents the downstream production of the potent vasoconstrictor angiotensin II, which is responsible for increasing blood pressure. Recent clinical data with aliskiren, a new direct renin inhibitor, suggest favorable results in patients with hypertension and a possible new treatment option.

OBJECTIVE: To perform a systematic review of the antihypertensive activity of the angiotensin II AT1 receptor antagonists (ARB). METHODS: Studies in which blood pressure (BP) was measured using ambulatory BP monitoring for at least 24 h were collected from MEDLINE. Data for each treatment group, ARB, placebo or the drug used for its comparison were obtained from the selected studies. Only studies with a minimum of quality criteria were selected. The final study group contained 36 publications, with a total of 47 patient cohorts receiving ARB in monotherapy, 10 with placebo, 10 with amlodipine, and five with enalapril. The reduction in clinical and ambulatory BP during 24 h, day, night and the last 4-h period for each of the drugs analysed were calculated and adjusted by age, sex, number of participants and by the initial BP level. RESULTS: The global antihypertensive activity of ARB differs from that observed with amlodipine in the sense that the magnitude of the reduction in the BP values does not essentially depend on the initial BP values nor on the dose used. When only ARB were considered, the drug used was a determinant for systolic BP reduction, whereas for diastolic BP the influence was on the BP reduction and the duration of the antihypertensive activity. The dose used had a particular influence on the duration of the antihypertensive activity for both systolic and diastolic BP. CONCLUSION: Among the ARB, the influence is on duration more than on the magnitude of BP reduction. Dose, therefore, is an important factor in the duration of antihypertensive activity.

This randomized, single-blind, parallel-group study was performed to assess pharmacokinetic interactions potentially occurring during concomitant use of telmisartan and nisoldipine. Patients with essential hypertension (n = 37) were treated with once-daily doses of telmisartan, nisoldipine, or their combination for 6 weeks. The regimen was started at low dose with an increase of dosage after 3 weeks of treatment. AUC(ss)(132%; P <.01) of telmisartan applied in doses of 80 mg was significantly higher after concomitant application with nisoldipine (10 mg), whereas CL/f(ss)(-54%; P <.05) and Vz/f(ss)(-72%; P <.05) were significantly lower. Regarding pharmacokinetic parameters of nisoldipine, significant differences between treatment groups were not detected. In conclusion, the results of this study strongly suggest that concomitant treatment with nisoldipine enhances telmisartan bioavailability in hypertensive individuals. Larger crossover trials will have to establish these observations and investigate whether interaction of both drugs affects telmisartan efficacy and tolerability in clinical use.

Systolic hypertension often requires combination therapy. Few data exist comparing angiotensin receptor blocker plus diuretic therapy with other combinations in older patients. In a prospective, randomized, open-label, blinded-end point trial, patients (>/=60 years of age) with predominantly systolic hypertension received telmisartan 40-80 mg or amlodipine 5-10 mg for 8 weeks, before the addition of hydrochlorothiazide (HCTZ) 12.5 mg for a further 6 weeks. Twenty-four-hour ambulatory blood pressure monitoring showed that telmisartan plus HCTZ (n=448) and amlodipine plus HCTZ (n=424) changed systolic blood pressure for the last 6 hours of the dosing interval by -18.3 and -17.4 mm Hg, respectively (p=0.2520). Over the 24-hour period, telmisartan plus HCTZ was superior (-19.3 and -17.2 mm Hg, respectively; p=0.001) and provided higher systolic control rates (65.9% and 58.3%, respectively; p=0.0175). Adverse events (41.2% and 53.7%, respectively) and discontinuations (5.0% and 11.3%, respectively) were lower (p<0.0001) with telmisartan than with amlodipine, mainly due to peripheral edema (1.2% and 24.3%, respectively).

BACKGROUND: Blood pressure (BP) has a circadian pattern with a morning surge that is associated with an increased risk of acute coronary and cerebrovascular events. In a prospective, randomized, open-label, blinded-endpoint, parallel-group, multicenter, forced-titration study of telmisartan and ramipril, the efficacy of both drugs on mean ambulatory diastolic BP (DBP) and systolic BP (SBP) during the last 6 h of a 24-h dosing interval was evaluated. METHODS: After screening and a single-blind run-in phase, 812 adults with mild-to-moderate hypertension (defined as a mean seated DBP > or =95 mm Hg and < or =109 mm Hg and a 24-h ABPM mean DBP 7 > or = 85 mm Hg) were randomized to the open-label, 14-week, forced-titration, active-treatment phase as follows: telmisartan 40 mg/80 mg/80 mg (n = 405) or ramipril 2.5 mg/5 mg/10 mg (n = 407), once daily in the morning. The primary efficacy variable was change from baseline in the last 6-h mean DBP and SBP at 8 and 14 weeks as assessed by ambulatory BP monitoring (ABPM). Secondary efficacy variables were changes from baseline in BP control during each of the 24-h periods and in-clinic trough cuff BP. RESULTS: Telmisartan 80 mg was superior to ramipril 5 mg and 10 mg in change from baseline in the last 6-h ABPM mean DBP and SBP at both 8 and 14 weeks (both P <.0001), respectively. At 14 weeks, the adjusted mean change from baseline in DBP for telmisartan 80 mg was -8.8 mm Hg compared with that for ramipril 10 mg of -5.4 mm Hg (P <.0001). For SBP, the adjusted mean change from baseline for telmisartan 80 mg was -12.7 mm Hg compared with that for ramipril 10 mg of -7.9 mm Hg (P <.0001). At 14 weeks, telmisartan 80 mg also yielded superior reductions from baseline in trough cuff BP compared with ramipril 10 mg (DBP:-11.0 mm Hg v -7.8 mm Hg, respectively; SBP:-14.3 mm Hg v -9.1 mm Hg, respectively; both P <.0001). Measures of 24-h BP control favored telmisartan 80 mg versus ramipril 10 mg (P <.0001), as did other secondary ABPM endpoints during the daytime, night-time, and morning periods. Treatment-related adverse events were uncommon; patients treated with ramipril had a higher incidence of cough than those treated with telmisartan (10.1% v 1.5%, respectively). CONCLUSIONS: Telmisartan 80 mg was consistently more effective than ramipril 10 mg in reducing both DBP and SBP during the last 6 h of the dosing interval, a measure of the early morning period when patients are at greatest risk of life-threatening cardiovascular and cerebrovascular events. Telmisartan 80 mg was also more effective than ramipril 10 mg in reducing BP throughout the entire 24-h dosing interval. Both drugs were well tolerated.

OBJECTIVE To compare the efficacy and safety of once-daily telmisartan and ramipril on blood pressure (BP) reductions during the last 6 h of the dosing interval. PATIENTS AND METHODS In a prospective, randomized, open-label, blinded-endpoint study using ambulatory BP monitoring, 801 patients with mild-to-moderate hypertension were randomly assigned to once-daily treatment with telmisartan 80 mg for 14 weeks or ramipril 5 mg for 8 weeks and then force titrated to ramipril 10 mg for the last 6 weeks. Primary endpoints were the reduction from baseline in the last 6-h mean ambulatory systolic BP (SBP) and diastolic BP (DBP). Secondary endpoints included changes in 24-h, morning, daytime and night-time mean ambulatory BP and ambulatory BP response rates. RESULTS Telmisartan 80 mg produced greater reductions in the last 6-h mean ambulatory SBP and DBP compared with ramipril 5 mg (P < 0.0001) and 10 mg (P < 0.0001), and was superior to ramipril for all secondary ambulatory SBP and DBP endpoints (P < 0.05). Ambulatory BP response rates (24-h mean ambulatory SBP/DBP < 130/80 mmHg or reduction from baseline > or = 10 mmHg) were greater with telmisartan 80 mg (P < 0.01) than with ramipril 5 and 10 mg. Ramipril was associated with a higher incidence of treatment-related cough (5.7 versus 0.5% for telmisartan). CONCLUSIONS Telmisartan was significantly more effective than ramipril in reducing BP throughout the 24-h dosing interval and particularly during the last 6 h, a time when patients appear to be at greatest risk of cerebro- and cardiovascular events. Both drugs were well tolerated, although ramipril was associated with a higher incidence of cough.

An open-label drug substitution study showed that controlled-release isradipine (Dynacirc-CR) can be safely substituted for amlodipine on a mg-for-mg basis in patients with mild-to-moderate hypertension. When controlled-release isradipine was substituted for amlodipine, blood pressure was more effectively controlled, and edema rates were reduced. When subjects resumed amlodipine therapy, the previous gain in blood pressure reduction and lessening of edema vanished. The basis for this more favorable pattern of efficacy and side-effects with controlled-release isradipine, although mechanistically unresolved, may relate to a lesser degree of sympathetic nervous system activation.

OBJECTIVE: To determine the effects of 8 weeks of therapy with amlodipine, ramipril or telmisartan on the autonomic system over 24 h in hypertensives. METHODS: After a placebo run-in, 57 patients were included in a prospective randomized open-label design protocol for therapy with amlodipine (5 mg for 4 weeks followed by 10 mg for 4 weeks, n = 22), or ramipril (2.5 mg for 1 week, 5.0 mg for 3 weeks and 10 mg for 4 weeks, n = 17) or telmisartan (80 mg for 8 weeks, n = 18). Autonomic functions were assessed by norepinephrine (NE) and epinephrine (E), as well as by the spectral analysis of heart rate variability (HRV). RESULTS: The 24-h ambulatory blood pressure, plasma NE and HRV demonstrated the characteristic day-night circadian rhythm in hypertensives. Higher values for SBP and DBP and for NE levels, as well as for spectral analysis components - low frequency band (LF) and low frequency/high frequency (LF/HF) ratio - were found during the day, whereas the HF was higher during the night. In patients treated with amlodipine, the HF decreased significantly during the night, while the LF and the LF/HF ratio increased during the day in association with the rise in NE. The therapy with telmisartan did increase the HF during the night and the day, while ramipril did not influence all HRV components during the night but significantly increased the HF, and decreased the LF/HF ratio during the day. No changes were observed in plasma NE with telmisartan or ramipril, but a 50% increase in NE levels throughout the 24-h period was found in amlodipine-treated patients. CONCLUSION: These data suggest a sympathetic activation during the day and a decrease in parasympathetic activity during the night after therapy with amlodipine, correlated with increases in plasma NE. In contrast, the therapy with telmisartan significantly increased parasympathetic activity without changes in NE during the night and day. The therapy with ramipril increased the parasympathetic activity only during the day.

BACKGROUND: The aldosterone-to-renin ratio (ARR) is frequently used to screen primary hyperaldosteronism. This study, part of a clinical trial, was designed to measure the influence of circadian rhythms, antihypertensive drugs, and body posture on plasma renin, on aldosterone, and on their interrelation. METHODS: In a prospective, randomized, open-label, parallel-designed protocol, 57 essential hypertensives (41 men, 16 women) were randomized to a morning dose of telmisartan (80 mg), ramipril (10 mg), or amlodipine (10 mg) for 8 weeks. At baseline and after 8 weeks of therapy, blood pressure (BP), plasma renin (in nanograms per liter), and plasma aldosterone (in picomoles per liter) concentrations were assessed in the supine position every 4 h for 24 h and after 10 min of standing at 9 am. RESULTS: There was no significant association between renin, aldosterone, the ARR and demographic factors, or BP. Circadian variations of plasma renin and aldosterone were clearly present. Aldosterone variations were of greater relative amplitude with earlier-occurring peaks than renin. The ARR exhibited statistically and clinically significant circadian variations with the low and peak values averaging 55.9 +/- 32.3 and 161.84 +/- 85.4 pmol/L/ng/dL, respectively. Telmisartan, ramipril, and amlodipine significantly decreased the ARR. Telmisartan had the greatest influence on the ARR. Posture had a clinically significant but statistically nonsignificant effect on the ARR. CONCLUSIONS: Renin, aldosterone, and their interrelation are influenced by circadian rhythms, telmisartan, ramipril, and amlodipine in patients with essential hypertension. Telmisartan has a greater impact on these parameters than ramipril and amlodipine. Measurement of the ARR in treated hypertensive patients should take these influences into account.

The QT interval corrected for heart rate (QTc) is believed to reflect sympathovagal balance. It has also been established that beta-blockers and dihydropyridine-type calcium channel blockers (DHPCCB) influence the autonomic nervous system. This study tested the hypothesis that QTc interval length is a predictor of the blood pressure reduction induced by beta1-selective beta-blockers or DHPCCB. The predictive values of pretreatment heart rate and of the heart rate change with therapy were also evaluated. The authors conducted an historical reanalysis of 5 clinical trials that looked at the antihypertensive effects of beta-blockers (nebivolol) or DHPCCB (amlodipine, felodipine, isradipine, nifedipine). Correlation and quintile analyses were performed to measure the association between QTc interval, heart rate, or heart rate change and therapeutic blood pressure response. Separate analyses were undertaken for beta-blockers and DHPCCB. Seventy-three and 98 hypertensive subjects respectively were included in the beta-blocker and DHPCCB analyses. QTc interval, pretreatment heart rate, and heart rate change with therapy were not associated with therapeutic blood pressure response. In this study, QTc interval length, pretreatment heart rate, and heart rate change with therapy were not good predictors of the blood pressure response to beta1-selective beta-blockers or DHPCCB in hypertensive subjects.

β-Adrenergic blocking agents (or β-blockers) have been widely used for the treatment of hypertension for the past 50 years, and continue to be recommended as a mainstay of therapy in many national guidelines. They have also been used in a variety of cardiovascular conditions commonly complicating hypertension, including angina pectoris, myocardial infarction (MI), acute and chronic heart failure, as well as conditions like essential tremor and migraine. Moreover, they have played a primary role in controlling blood pressure in patients with these specific comorbidities and in reducing cardiovascular risk with regard to the composite outcome of death, stroke, and MI among patients younger than 60 years of age. However, in patients 60 years of age or older, β-blockers were not associated with significantly lower rates of MI, heart failure or death, and demonstrated higher rates of stroke compared with other first-line therapies. Consequently, the Canadian Hypertension Education Program recommends the use of β-blockers as first-line therapy in hypertensive patients younger than 60 years of age but not for those age 60 and older, with the exception of patients with concomitant β-blocker-requiring cardiac diseases. Several reports suggest that the lack of consistent outcome data may relate to the use of traditional β-blockers such as atenolol and their ability only to reduce cardiac output, without beneficial effect on peripheral vascular resistance. The present report will describe the clinically relevant mechanisms of action of β-blockers, their pharmacological differences, their metabolic effects, and their usefulness in patients with hypertension.

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2012. The new recommendations are:(1) use of home blood pressure monitoring to confirm a diagnosis of white coat syndrome;(2) mineralocorticoid receptor antagonists may be used in selected patients with hypertension and systolic heart failure;(3) a history of atrial fibrillation in patients with hypertension should not be a factor in deciding to prescribe an angiotensin-receptor blocker for the treatment of hypertension; and (4) the blood pressure target for patients with nondiabetic chronic kidney disease has now been changed to < 140/90 mm Hg from < 130/80 mm Hg. We also reviewed the recent evidence on blood pressure targets for patients with hypertension and diabetes and continue to recommend a blood pressure target of less than 130/80 mm Hg.

We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2011. The major guideline changes this year are:(1) a recommendation was made for using comparative risk analogies when communicating a patient's cardiovascular risk;(2) diagnostic testing issues for renal artery stenosis were discussed;(3) recommendations were added for the management of hypertension during the acute phase of stroke;(4) people with hypertension and diabetes are now considered high risk for cardiovascular events if they have elevated urinary albumin excretion, overt kidney disease, cardiovascular disease, or the presence of other cardiovascular risk factors;(5) the combination of an angiotensin-converting enzyme (ACE) inhibitor and a dihydropyridine calcium channel blocker (CCB) is preferred over the combination of an ACE inhibitor and a thiazide diuretic in persons with diabetes and hypertension; and (6) a recommendation was made to coordinate with pharmacists to improve antihypertensive medication adherence. We also discussed the recent analyses that examined the association between angiotensin II receptor blockers (ARBs) and cancer.

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Goal blood pressure levels are only being achieved in approximately a third of hypertensive patients, which suggests that there is a need for new and/or improved approaches to the treatment of hypertension. The majority of patients with hypertension require combination therapy to control their blood pressure. The use of a combination of drugs with complementary mechanisms of action may provide greater efficacy and tolerability compared with monotherapy, and may allow more rapid achievement of target blood pressure. Moreover, the use of single-pill combinations has the potential to increase adherence and persistence, and reduce costs. The single-pill combination of valsartan plus hydrochlorothiazide was recently approved by the US FDA for first-line use in hypertensive patients who are likely to need multiple drugs to achieve their blood pressure goals. The focus of this article is on those randomized, double-blind trials in which this combination was administered as first-line therapy in patients with essential hypertension.

Background: Midodrine is an alpha-agonist prodrug of desglymidodrine (DGM) that has been reported to be of clinical benefit in patients with neurocardiogenic syncope. Its effects may be mediated not only by its hypertensive properties but also by its neurohumoral influences independent of blood pressure (BP). Objective: The present study aimed to simultaneously characterize the effects of midodrine on BP, plasma catecholamines, plasma atrial natriuretic peptide (ANP), and power spectral analysis of heart rate (HR) in healthy volunteers. Methods: This was a prospective, randomized, single-blind, 2-period, crossover study in which a single, oral, 5-mg dose of midodrine was compared with placebo. The washout period between midodrine and placebo was 1 week. The study parameters included plasma DGM (as measured by high-performance liquid chromatography [HPLC]); systolic and diastolic BP (as measured with an oscillometric monitor); HR; plasma catecholamines (measured by HPLC); plasma ANP, also known as venous return (measured by a radio-immunoassay); and low- and high-frequency HR variation (calculated from computerized 5-minute electrocardiographic recordings). All study parameters were measured simultaneously 12 times just before and over a period of 8 hours after drug administration. Results: Fifteen healthy nonsmoking male subjects (14 white, 1 black; mean [SD] age, 28.6 [4.7] years; weight, 74.5 [16.4] kg; seated BP, 109.9 [9.0]/73.6 [9.5] mm Hg; seated HR, 63.8 [8.4] bpm) were randomized. No significant effects of midodrine on BP were observed. At C(max), midodrine decreased norepinephrine from 188.4 (30.6) to 162.5 (29.8) pg/mL (P = 0.011) and HR from 57.2 (7.3) to 54.9 (6.6) bpm (P = 0.022). A significant correlation was found between DGM concentration and HR ( varphi -0.61; P = 0.014). A DGM-related increase in plasma ANP (+29.6 [90.0] fmoL/mL) was observed. Conclusion: This study in healthy male volunteers found that midodrine has sympatholytic influences that are independent of BP but related to augmented venous return.

Observational studies have shown that 24-h and morning ambulatory blood pressure (BP) control is low. This large-scale, practice-based study evaluated the effects of telmisartan 40 or 80 mg alone or in combination with hydrochlorothiazide (HCTZ) 12.5 mg on these BP parameters over 8 weeks; treatment was adjusted if clinic BP remained 140/90 mm Hg. A total of 863 patients were evaluated (baseline mean clinic BP, morning and 24-h ambulatory BP: 155±15/93±10 mm Hg, 137±15/83±11 mm Hg, 133±14/79±10 mm Hg, respectively; 68% were previously treated at baseline). Telmisartan with/without HCTZ significantly reduced the mean morning ambulatory BP (-8.2/-4.9 mm Hg), daytime ambulatory BP (-8.0/-4.7 mm Hg), 24-h ambulatory BP (-7.9/-4.7 mm Hg) and clinic BP (-22.3/-13.2 mm Hg)(all P<0.001) in previously untreated and in treated patients who switched to telmisartan and telmisartan/HCTZ. After treatment with telmisartan with/without HCTZ, the morning ambulatory BP control increased from 36.5 to 64.4%; daytime ambulatory BP control increased from 40.8 to 67.6%; 53.0% of patients achieved 24-h ambulatory BP <125/80 mm Hg and 62% achieved <130/80 mm Hg targets. Only 0.8%(7/863) reported an adverse event. In summary, telmisartan and telmisartan/HCTZ increased smooth 24-h BP control in daily management of hypertension.Hypertension Research advance online publication, 15 November 2012; doi:10.1038/hr.2012.171.

Hypertension is a major risk factor for vascular disease, yet blood pressure (BP) control is unsatisfactory low, partly due to side-effects. Transcutaneous electrical nerve stimulation (TENS) is well tolerated and studies have demonstrated BP reduction. In this study, we compared the BP lowering effect of 2.5 mg felodipin once daily with 30 min of bidaily low-frequency TENS in 32 adult hypertensive subjects (mean office BP 152.7/90.0 mmHg) in a randomized, crossover design. Office BP and 24-h ambulatory BP monitoring (ABPM) were performed at baseline and at the end of each 4-week treatment and washout period. Felodipin reduced office BP by 10/6 mmHg (p <0.001 respectively) and after washout BP rose to a level still significantly lower than at baseline. TENS reduced office BP by 5/1.5 mmHg (p <0.01, ns). After TENS washout, BP was further reduced and significantly lower than at baseline, but at levels similar to BP after felodipin washout and therefore reasonably caused by factors other than the treatment per se. ABPM revealed a significant systolic reduction of 3 mmHg by felodipin, but no significant changes were noted after TENS. We conclude that our study does not present any solid evidence of BP reduction of TENS.

BACKGROUND Eplerenone is claimed to be a more selective blocker of the mineralocorticoid receptor than spironolactone being associated with fewer antiandrogenic side-effects. We compared the efficacy, safety and tolerability of eplerenone versus spironolactone in patients with hypertension associated with primary aldosteronism. METHODS The study was multicentre, randomized, double-blind, active-controlled, and parallel group design. Following a single-blind, placebo run-in period, patients were randomized 1: 1 to a 16-week double-blind, treatment period of spironolactone (75-225 mg once daily) or eplerenone (100-300 mg once daily) using a titration-to-effect design. To be randomized, patients had to meet biochemical criteria for primary aldosteronism and have a seated DBP at least 90 mmHg and less than 120 mmHg and SBP less than 200 mmHg. The primary efficacy endpoint was the antihypertensive effect of eplerenone versus spironolactone to establish noninferiority of eplerenone in the mean change from baseline in seated DBP. RESULTS Changes from baseline in DBP were less on eplerenone (-5.6 ± 1.3 SE mmHg) than spironolactone (-12.5 ± 1.3 SE mmHg)[difference,-6.9 mmHg (-10.6,-3.3); P<0.001]. Although there were no significant differences between eplerenone and spironolactone in the overall incidence of adverse events, more patients randomized to spironolactone developed male gynaecomastia (21.2 versus 4.5%; P=0.033) and female mastodynia (21.1 versus 0.0%; P=0.026). CONCLUSION The antihypertensive effect of spironolactone was significantly greater than that of eplerenone in hypertension associated with primary aldosteronism.

ABSTRACT: BACKGROUND: The Study of Micardis (telmisartan) in Overweight/Obese patients with Type 2 diabetes and Hypertension (SMOOTH) compared hydrochlorothiazide (HCTZ) plus telmisartan or valsartan fixed-dose combination therapies on early morning blood pressure (BP), using ambulatory BP monitoring (ABPM). METHODS: SMOOTH was a prospective, randomized, open-label, blinded-endpoint, multicentre trial. After a 2- to 4-week, single-blind, placebo run-in period, patients received once-daily telmisartan 80 mg or valsartan 160 mg for 4 weeks, with add-on HCTZ 12.5 mg for 6 weeks (T/HCTZ or V/HCTZ, respectively). At baseline and week 10, ambulatory blood pressure (ABP) was measured every 20 min and hourly means were calculated. The primary endpoint was change from baseline in mean ambulatory systolic and diastolic blood pressure (SBP; DBP) during the last 6 hours of the 24-hour dosing interval. RESULTS: In total, 840 patients were randomized. At week 10, T/HCTZ provided significantly greater reductions versus V/HCTZ in the last 6 hours mean ABP (differences in favour of T/HCTZ: SBP 3.9 mm Hg, p < 0.0001; DBP 2.0 mm Hg, p = 0.0007). T/HCTZ also produced significantly greater reductions than V/HCTZ in 24-hour mean ABP (differences in favour of T/HCTZ: SBP 3.0 mm Hg, p = 0.0002; DBP 1.6 mm Hg, p = 0.0006) and during the morning, daytime and night-time periods (p < 0.003). Both treatments were well tolerated. CONCLUSIONS: In high-risk, overweight/obese patients with hypertension and type 2 diabetes, T/HCTZ provides significantly greater BP lowering versus V/HCTZ throughout the 24-hour dosing interval, particularly during the hazardous early morning hours.

OBJECTIVES: The period of early morning blood pressure surge is associated with a higher incidence of cardiovascular events than at other times of the day. Antihypertensive medication given once daily in the morning may not protect against this surge if its duration of action is too short. We compared telmisartan, an angiotensin II receptor blocker with a trough-to-peak ratio >90%, with ramipril, an angiotensin-converting enzyme inhibitor with a trough-to-peak ratio of around 50%. METHODS: Data from two prospective, randomized, open-label, blinded endpoint studies comparing telmisartan force titrated to 80 mg once daily and ramipril 10 mg once daily were pooled. Patients had mild-to-moderate hypertension and were assessed using 24-h ambulatory blood pressure monitoring at baseline and endpoint. Early morning blood pressure surge was defined as the difference between mean blood pressure within 2 h after arising and night-time low. Patients were grouped into quartiles according to their baseline systolic surge. RESULTS: Data from 1279 patients were analyzed. Telmisartan changed the overall mean (SE) systolic surge by -1.5 (0.47) mmHg, and ramipril by +0.3 (0.47) mmHg (P=0.0049). The magnitude of surge reduction was greatest in the quartile with highest baseline systolic surge: telmisartan -12.7 (0.91), ramipril -7.8 (1.02) mmHg (P=0.0004). Telmisartan also reduced the surge compared with ramipril in dippers, but there were no differences between the two groups in nondippers. CONCLUSIONS: Telmisartan significantly reduced the early morning systolic blood pressure surge compared with ramipril. A reduction in this surge may help to reduce cardiovascular events in the morning period.

The effect of telmisartan on ambulatory blood pressure, plasma neurohormonal parameters, and oxidation of serum albumin has not been investigated in hemodialysis (HD) patients. Thirteen hypertensive HD patients were treated with 40 mg telmisartan once daily, and 24-h ambulatory blood pressure monitoring was performed after 0, 4, and 8 weeks of treatment. Plasma renin activity, plasma aldosterone concentration (PAC), brain natriuretic peptide (BNP) level, and serum oxidized albumin level were determined at the same time points. Serum telmisartan concentration was also measured at 4 and 8 weeks. Telmisartan significantly reduced systolic blood pressure and diastolic blood pressure (both awake and sleeping) after 4 weeks, and these pressures showed a further significant decrease after 8 weeks. Plasma levels of aldosterone, BNP, and serum oxidized albumin were markedly decreased after 4 weeks and these lower levels were maintained at 8 weeks. The trough serum telmisartan concentration was not significantly different at 8 weeks compared with 4 weeks. Throughout the treatment period, there were no significant adverse effects. Telmisartan effectively lowers blood pressure and reduces PAC, BNP, and oxidative stress and is safe and well-tolerated by HD patients. A long-term study in a large population is required to determine the influence of telmisartan therapy on cardiovascular mortality and morbidity in HD patients.

BACKGROUND: Blood pressure (BP) has a circadian pattern with a morning surge that is associated with an increased risk of acute coronary and cerebrovascular events. In a prospective, randomized, open-label, blinded-endpoint, parallel-group, multicenter, forced-titration study of telmisartan and ramipril, the efficacy of both drugs on mean ambulatory diastolic BP (DBP) and systolic BP (SBP) during the last 6 h of a 24-h dosing interval was evaluated. METHODS: After screening and a single-blind run-in phase, 812 adults with mild-to-moderate hypertension (defined as a mean seated DBP > or =95 mm Hg and < or =109 mm Hg and a 24-h ABPM mean DBP 7 > or = 85 mm Hg) were randomized to the open-label, 14-week, forced-titration, active-treatment phase as follows: telmisartan 40 mg/80 mg/80 mg (n = 405) or ramipril 2.5 mg/5 mg/10 mg (n = 407), once daily in the morning. The primary efficacy variable was change from baseline in the last 6-h mean DBP and SBP at 8 and 14 weeks as assessed by ambulatory BP monitoring (ABPM). Secondary efficacy variables were changes from baseline in BP control during each of the 24-h periods and in-clinic trough cuff BP. RESULTS: Telmisartan 80 mg was superior to ramipril 5 mg and 10 mg in change from baseline in the last 6-h ABPM mean DBP and SBP at both 8 and 14 weeks (both P <.0001), respectively. At 14 weeks, the adjusted mean change from baseline in DBP for telmisartan 80 mg was -8.8 mm Hg compared with that for ramipril 10 mg of -5.4 mm Hg (P <.0001). For SBP, the adjusted mean change from baseline for telmisartan 80 mg was -12.7 mm Hg compared with that for ramipril 10 mg of -7.9 mm Hg (P <.0001). At 14 weeks, telmisartan 80 mg also yielded superior reductions from baseline in trough cuff BP compared with ramipril 10 mg (DBP:-11.0 mm Hg v -7.8 mm Hg, respectively; SBP:-14.3 mm Hg v -9.1 mm Hg, respectively; both P <.0001). Measures of 24-h BP control favored telmisartan 80 mg versus ramipril 10 mg (P <.0001), as did other secondary ABPM endpoints during the daytime, night-time, and morning periods. Treatment-related adverse events were uncommon; patients treated with ramipril had a higher incidence of cough than those treated with telmisartan (10.1% v 1.5%, respectively). CONCLUSIONS: Telmisartan 80 mg was consistently more effective than ramipril 10 mg in reducing both DBP and SBP during the last 6 h of the dosing interval, a measure of the early morning period when patients are at greatest risk of life-threatening cardiovascular and cerebrovascular events. Telmisartan 80 mg was also more effective than ramipril 10 mg in reducing BP throughout the entire 24-h dosing interval. Both drugs were well tolerated.

Hypertension is risk factor for cardiovascular morbidity and mortality, and stroke. A critical surge in blood pressure occurs during the early morning hours coincident with increased incidences of myocardial infarction, unstable angina, stroke and sudden cardiac death. This suggests that, in patients with hypertension, it may be important to maintain the efficacy of antihypertensive medication over the 24-h dosing interval, especially in the risky early morning hours. In order to evaluate the antihypertensive efficacies of fixed-dose combinations of angiotensin II receptor blockers with hydrochlorothiazide (HCTZ) 12.5 mg, a multicenter, randomized, prospective, open-label, blinded-endpoint study was performed in 805 patients with mild-to-moderate hypertension randomized to once-daily treatment with telmisartan 40 mg plus HCTZ (T40/H12.5), losartan 50 mg plus HCTZ (L50/H12.5), or telmisartan 80 mg plus HCTZ (T80/H12.5), with the primary objective of comparing T40/H12.5 with L50/H12.5 and evaluating the additional response of T80/H12.5. Efficacy was assessed by ambulatory blood pressure monitoring (ABPM), clinic seated cuff sphygmomanometry and calculated responder rates after 6 weeks' active treatment. The primary endpoint was reduction from baseline in the last 6-h mean (relative to dosing) diastolic blood pressure (DBP) measured using 24-h ABPM. Compared with the L50/H12.5 group, the mean reductions in the last 6-h mean DBP for the T40/H12.5 and T80/H12.5 groups were significantly greater:-2.0 mmHg (p=0.0031) and -2.8 mmHg (p=0.0003), respectively. We conclude that T40/H12.5 provided clinically and statistically significantly superior blood pressure reductions compared with L50/H12.5 during the last 6 h of the 24-h dosing interval, which corresponds to the high-risk early-morning hours, and that T80/H12.5 provided additional blood pressure reductions.

OBJECTIVE To compare the efficacy and safety of once-daily telmisartan and ramipril on blood pressure (BP) reductions during the last 6 h of the dosing interval. PATIENTS AND METHODS In a prospective, randomized, open-label, blinded-endpoint study using ambulatory BP monitoring, 801 patients with mild-to-moderate hypertension were randomly assigned to once-daily treatment with telmisartan 80 mg for 14 weeks or ramipril 5 mg for 8 weeks and then force titrated to ramipril 10 mg for the last 6 weeks. Primary endpoints were the reduction from baseline in the last 6-h mean ambulatory systolic BP (SBP) and diastolic BP (DBP). Secondary endpoints included changes in 24-h, morning, daytime and night-time mean ambulatory BP and ambulatory BP response rates. RESULTS Telmisartan 80 mg produced greater reductions in the last 6-h mean ambulatory SBP and DBP compared with ramipril 5 mg (P < 0.0001) and 10 mg (P < 0.0001), and was superior to ramipril for all secondary ambulatory SBP and DBP endpoints (P < 0.05). Ambulatory BP response rates (24-h mean ambulatory SBP/DBP < 130/80 mmHg or reduction from baseline > or = 10 mmHg) were greater with telmisartan 80 mg (P < 0.01) than with ramipril 5 and 10 mg. Ramipril was associated with a higher incidence of treatment-related cough (5.7 versus 0.5% for telmisartan). CONCLUSIONS Telmisartan was significantly more effective than ramipril in reducing BP throughout the 24-h dosing interval and particularly during the last 6 h, a time when patients appear to be at greatest risk of cerebro- and cardiovascular events. Both drugs were well tolerated, although ramipril was associated with a higher incidence of cough.

In this open-label, non-comparative study, the anti-hypertensive efficacy and effect on left ventricular hypertrophy (LVH) of 24 weeks' treatment with once-daily telmisartan 40-80 mg was evaluated in 24 patients with mild-to-moderate hypertension and LVH. Patients were titrated to the higher dose of study drug at week 4 if they did not achieve blood pressure normalization (i.e. systolic blood pressure [SBP]/diastolic blood pressure [DBP] remained > or = 140/90 mmHg). The anti-hypertensive action of telmisartan was assessed using clinic cuff measurements and 24-h ambulatory blood pressure monitoring, and left ventricular mass index (LVMI) was determined by two-dimensional echocardiography at baseline and after 24 weeks of therapy. Telmisartan significantly reduced mean 24-h, daytime and night-time SBP and DBP compared with baseline after 12 and 24 weeks of therapy. Target blood pressure levels, defined as SBP/DBP < 140/90 mm Hg, were achieved in 16 (69.6%) patients at the end of the treatment period. After 24 weeks of telmisartan treatment, LVMI decreased from 151.6 +/- 5.4 to 135.1 +/- 5.9 g/m2. In conclusion, anti-hypertensive treatment with telmisartan for 24 weeks produced significant reductions in blood pressure and regression of LVH, as assessed by LVMI, in patients with hypertension and LVH.