ß-Blockers in hypertension: studies and meta-analyses over the years.

ß-Blockers are among the most commonly used medications in the treatment of hypertension. However, 45 years after their initial indication for that treatment, their place in the treatment of hypertensive patients is under evaluation and their usefulness has been questioned based on evidence from meta-analyses of clinical trials. The ß-blocker class consists of various agents with diverse pharmacokinetic and pharmacodynamic properties including lipo- and hydrophilicity, duration of action, intrinsic sympathomimetic activity, vasodilation, and metabolism linked to genetic polymorphisms. Because of their various properties, some ß-blockers are indicated for cardiovascular conditions such as angina, rate control of atrial fibrillation, chronic heart failure, and after myocardial infarction, and other indications such as migraine and essential tremor. There have been more than 17 large trials influencing the recommendations on the use of these agents in the treatment of hypertension. The results of these trials initially led to the widespread recommendation for the use of ß-blockers in the management of hypertension. However, the recent multiple meta-analyses using these trials have raised a controversy on their place in that treatment. The Canadian Hypertension Education Program recommendations have included ß-blockers as a first-line treatment option for patients younger than 60 years of age based on the evidence from these large trials, and this has been supported by 2 of the meta-analyses. This article reviews these studies to help clinicians better understand the role of ß-blockers in managing hypertension.

Effects of demographics on the antihypertensive efficacy of triple therapy with amlodipine, valsartan, and hydrochlorothiazide for moderate to severe hypertension.

OBJECTIVE: To compare the antihypertensive efficacy and safety of once-daily triple therapy with amlodipine (Aml) 10 mg, valsartan (Val) 320 mg, and hydrochlorothiazide (HCTZ) 25 mg versus dual-therapy combinations of these components in patients with moderate to severe hypertension. RESEARCH DESIGN: Subgroup analysis of a multinational, randomized, double-blind, parallel-group, active-controlled trial. METHODS: After antihypertensive washout and a placebo run-in of up to 4 weeks, 2271 patients were randomly allocated in a 1:1:1:1 ratio to receive Aml/Val/HCTZ triple therapy or dual therapy with Val/HCTZ, Aml/Val, or Aml/HCTZ for 8 weeks. Forced titration to the full dose was done over the first 2 weeks of treatment. Efficacy and safety parameters were determined by age group (<65 vs. ≥65 years), gender, race (White vs. Black), ethnicity (Hispanic/Latino vs. non-Hispanic/Latino), and body mass index (BMI, <30 vs. ≥30 kg/m²). MAIN OUTCOME MEASURES: Change from baseline to endpoint in mean sitting systolic blood pressure (MSSBP) and mean sitting diastolic blood pressure (MSDBP); blood pressure (BP) control rate <140/90 mmHg. RESULTS: Triple therapy was numerically superior and, for the majority of comparisons, statistically superior to each dual therapy in reducing MSSBP and MSDBP and in improving BP control rates in all subgroups. Across subgroups, triple therapy reduced MSSBP by 5.7-10.7 mmHg more than Val/HCTZ, 3.4-8.3 mmHg more than Aml/Val, and 4.4-9.4 mmHg more than Aml/HCTZ. Triple therapy was well tolerated across all subgroups. Limitations of our analysis included the lack of stratification of patients by subgroup at randomization and the small sample size of some subgroups (e.g., Blacks, elderly). CONCLUSIONS: Triple therapy with Aml/Val/HCTZ is effective and well tolerated in patients with moderate to severe hypertension regardless of age, gender, race, ethnicity, or BMI. TRIAL REGISTRATION NUMBER: NCT00327587.

Telmisartan or valsartan alone or in combination with hydrochlorothiazide: a review.

The aim of this review was to compare telmisartan and valsartan in the treatment of hypertension. PubMed searches were conducted to identify randomized trials (n = 14) comparing the two agents, alone or combined with hydrochlorothiazide. With one exception, all studies with blood pressure reduction as primary endpoint showed significantly greater reductions with telmisartan than with valsartan. Other studies showed that telmisartan was associated with greater improvements in metabolic measures and inflammatory markers than valsartan. These findings suggest that pharmacologic differences between telmisartan and valsartan may translate into clinically relevant differences between the two drugs in the management of hypertension.

Clinic and ambulatory blood pressure lowering effect of aliskiren/amlodipine/hydrochlorothiazide combination in patients with moderate-to-severe hypertension: a randomized active-controlled trial.

OBJECTIVES: To evaluate the clinic and ambulatory blood pressure (BP)-lowering efficacy and safety of an aliskiren/amlodipine/hydrochlorothiazide (HCT) triple combination compared with the component dual combinations, in patients with moderate-to-severe hypertension. METHODS: This 8-week, double-blind, randomized, active-controlled study, after 1-4 weeks single-blind placebo run-in period, randomized 1191 patients to receive once-daily aliskiren/amlodipine 150/5 mg (n = 287), aliskiren/HCT 150/12.5 mg (n = 298), amlodipine/HCT 5/12.5 mg (n = 296), or aliskiren/amlodipine/HCT 150/5/12.5 mg (up-titrated from aliskiren/HCT 150/12.5 mg after initial 3 days) (n = 310) for 4 weeks, followed by forced titration to double the initial dose for the next 4 weeks. RESULTS: Baseline mean sitting SBP and DBP (msSBP/msDBP) was comparable among treatment groups. The aliskiren/amlodipine/HCT combination resulted in significant least squares mean reduction in msSBP/msDBP from baseline to endpoints (week 4, -30.7/-15.9  mmHg; week 8, -37.9/-20.6  mmHg), superior (P < 0.001) to each of the dual combinations. The triple combination was associated with -27.8  mmHg reduction in msSBP at week 2, significantly better than the dual combinations (P < 0.05). Significantly greater mean SBP/DBP-lowering effect for triple vs. dual combinations was also demonstrated through 24-h, daytime, and night-time ambulatory BP measurements. Significantly greater (P < 0.001) BP control (msSBP/msDBP < 140/90  mmHg) was achieved with triple combination in patients with moderate-to-severe (62.3%) and severe (57.5%) hypertension. CONCLUSION: Aliskiren/amlodipine/HCT at 150/5/12.5 mg (week 4) and 300/10/25 mg (week 8) provided statistically superior reductions in msSBP/msDBP and greater BP control rates vs. the dual combinations, and was well tolerated. The improved efficacy of BP reduction was evident within 2 weeks of initiating triple therapy even at low dose.

The evolving role of ß-adrenergic receptor blockers in managing hypertension.

ß-Adrenergic blocking agents (or ß-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, ß-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 ß-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 ß-blocker-requiring cardiac diseases. Several reports suggest that the lack of consistent outcome data may relate to the use of traditional ß-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 ß-blockers, their pharmacological differences, their metabolic effects, and their usefulness in patients with hypertension.

24-Hour ambulatory blood pressure response to combination valsartan/hydrochlorothiazide and amlodipine/hydrochlorothiazide in stage 2 hypertension by ethnicity: the EVALUATE study.

Several studies reported racial/ethnic differences in blood pressure (BP) response to antihypertensive monotherapy. In a 10-week study of stage 2 hypertension, 320/25 mg valsartan/hydrochlorothiazide (HCTZ) reduced ambulatory BP (ABP) significantly more effectively than 10/25 mg amlodipine/HCTZ. Results (post hoc analysis) are described in Caucasians (n=256), African Americans (n=79), and Hispanics (n=86). Compared with clinic-measured BP (no significant treatment-group differences in ethnic subgroups), least-squares mean reductions from baseline to week 10 in mean ambulatory systolic BP (MASBP) and mean ambulatory diastolic BP (MADBP) favored valsartan/HCTZ over amlodipine/HCTZ in Caucasians (-21.9/-12.7 mm Hg vs -17.6/-9.5 mm Hg; P=.0004/P<.0001). No treatment-group differences in MASBP/MADBP were observed in African Americans (-17.3/-10.6 vs -17.9/-9.5; P=.76/P=.40) or Hispanics (-17.9/-9.7 vs -14.2/-7.2; P=.20/P=.17). Based on ABP monitoring, valsartan/HCTZ is more effective than amlodipine/HCTZ in lowering ABP in Caucasians. In African Americans and Hispanics, both regimens are similarly effective.

Increasing the doses of both diuretics and angiotensin receptor blockers is beneficial in subjects with uncontrolled systolic hypertension.

BACKGROUND: Blood pressure (BP) control is frequently difficult to achieve in patients with predominantly elevated systolic BP. Consequently, these patients frequently require combination therapy including a thiazide diuretic such as hydrochlorothiazide (HCTZ) and an agent blocking the renin-angiotensin-aldosterone system. Current clinical practice usually limits the daily dose of HCTZ to 25 mg. This often leads to the necessity of using additional antihypertensive agents to control BP in a high proportion of patients. OBJECTIVES: To compare the efficacy of two doses of losartan (LOS)/HCTZ combinations in patients with uncontrolled ambulatory systolic hypertension after six weeks of treatment with LOS 100 mg/HCTZ 25 mg (LOS100/HCTZ25). METHODS: Following a two- to four-week washout period, subjects with a mean clinic sitting systolic BP of 160 mmHg or higher and a mean ambulatory daytime systolic BP (MDSBP) of 135 mmHg or higher on LOS100/HCTZ25 (n=105; 33 women and 72 men) were randomly assigned to receive LOS 150 mg/HCTZ 25 mg (group 1; n=53) or LOS 150 mg/HCTZ 37.5 mg (LOS150/HCTZ37.5, group 2; n=52). The primary end point was the difference in MDSBP reductions. RESULTS: At the end of the six-week treatment period, the respective additional decreases in MDSBP were 1.2 mmHg (P=0.335) on LOS 150 mg/HCTZ 25 mg and 5.6 mmHg (P<0.0001) on LOS150/HCTZ37.5 (difference of 4.4 mmHg; P=0.011). Daytime systolic ambulatory BP goal (lower than 130 mmHg) achievement tended to be higher (25% versus 17%; P=0.313) with LOS150/HCTZ37.5, while it was significantly higher (65% versus 43%; P=0.024) for mean daytime diastolic BP (lower than 80 mmHg). No deleterious metabolic changes were observed. CONCLUSIONS: In patients with uncontrolled systolic ambulatory hypertension receiving LOS100/HCTZ25, increasing both HCTZ and LOS dosages simultaneously to LOS150/HCTZ37.5 may be an effective strategy that does not affect metabolic parameters.

Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study.

BACKGROUND: LCZ696 is a first-in-class inhibitor of the angiotensin II receptor and neprilysin. We aimed to establish whether the dual actions of LCZ696 lead to further lowering of blood pressure, compared with the angiotensin-receptor blocker valsartan. METHODS: 1328 patients aged 18-75 years with mild-to-moderate hypertension were randomly assigned (double-blind) to 8 weeks' treatment in one of eight groups: 100 mg (n=156 patients), 200 mg (n=169), or 400 mg (n=172) LCZ696; 80 mg (n=163), 160 mg (n=166), or 320 mg (n=164) valsartan; 200 mg AHU377 (n=165); or placebo (n=173). The primary endpoint was the mean difference across the three single-dose pairwise comparisons of LCZ696 versus valsartan (100 mg vs 80 mg, 200 mg vs 160 mg, and 400 mg vs 320 mg) in mean sitting diastolic blood pressure during the 8-week treatment period. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00549770. FINDINGS: 1215 patients completed the 8-week treatment period. The average reduction in mean sitting diastolic blood pressure across the doses of LCZ696 versus the appropriate comparator dose of valsartan showed significantly greater reductions with LCZ696 (mean reduction: -2.17 mm Hg, 95% CI -3.28 to -1.06; p<0.0001). The reduction in mean sitting diastolic blood pressure was significantly different for 200 mg LCZ696 versus 160 mg valsartan (-2.97 mm Hg, 95% CI -4.88 to -1.07, p=0.0023) and for 400 mg LCZ696 versus 320 mg valsartan (-2.70 mm Hg, -4.61 to -0.80, p=0.0055). LCZ696 was well tolerated and no cases of angio-oedema were reported; only three serious adverse events occurred during the 8-week treatment period, of which none was judged to be related to the study drug, and no patients died. INTERPRETATION: Compared with valsartan, dual-acting LCZ696 provides complementary and fully additive reduction of blood pressure, which suggests that the drug holds promise for treatment of hypertension and cardiovascular disease. FUNDING: Novartis.

Effect of intensive versus standard blood pressure lowering on diastolic function in patients with uncontrolled hypertension and diastolic dysfunction.

Diastolic dysfunction may precede development of heart failure in hypertensive patients. We randomized 228 patients with uncontrolled hypertension, preserved ejection fraction, and diastolic dysfunction to 2 targeted treatment strategies: intensive, with a systolic blood pressure target of <130 mm Hg, or standard, with a systolic blood pressure target of <140 mm Hg, using a combination of valsartan, either 160 or 320 mg, plus amlodipine, either 5 or 10 mg, with other antihypertensive medications as needed. Echocardiographic assessment of diastolic function was performed at baseline and after 24 weeks in a prospective, open-label, blinded end point design. Blood pressure was reduced significantly in both groups, from 161.2+/-13.9/90.1+/-12.0 to 130.8+/-12.3/74.9+/-9.1 mm Hg (P<0.0001) in the intensive arm and from 162.1+/-13.2/93.7+/-12.2 to 137.0+/-12.9/79.6+/-11.0 mm Hg (P<0.0001) in the standard arm (P<0.003 for between-group comparisons). Myocardial relaxation velocity improved from 7.6+/-1.1 to 9.2+/-1.7 cm/s (Delta 1.54+/-1.4 cm/s; P<0.0001) in the intensive arm and from 7.5+/-1.3 to 9.0+/-1.9 cm/s (Delta 1.48+/-1.6 cm/s; P<0.0001) in the standard arm, with no difference between the 2 strategies in the achieved improvement (P=0.58). The degree of improvement in annular relaxation velocity was associated with the extent of systolic blood pressure reduction, and patients with the lowest achieved systolic blood pressure had the highest final diastolic relaxation velocities.

Valsartan plus hydrochlorothiazide for first-line therapy in hypertension.

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.

Triple antihypertensive therapy with amlodipine, valsartan, and hydrochlorothiazide: a randomized clinical trial.

Many patients with hypertension require > or =3 agents to achieve target blood pressure (BP). The efficacy/safety of the dual combinations of valsartan (Val)/hydrochlorothiazide (HCTZ) and amlodipine (Aml)/Val in hypertension are well established. This randomized, double-blind study evaluated the efficacy/safety of triple therapy with Aml/Val/HCTZ for moderate or severe hypertension (mean sitting systolic BP: > or =145 mm Hg; mean sitting diastolic BP: > or =100 mm Hg). The study included a single-blind, placebo run-in period, followed by double-blind treatment for 8 weeks; patients were randomly assigned to 1 of 4 groups titrated to Aml/Val/HCTZ 10/320/25 mg, Val/HCTZ 320/25 mg, Aml/Val 10/320 mg, or Aml/HCTZ 10/25 mg once daily. Dual-therapy recipients received half of the target doses of both agents for the first 2 weeks, titrating to target doses during week 3. Those on triple therapy received Val/HCTZ 160.0/12.5 mg during week 1, Aml/Val/HCTZ 5.0/160.0/12.5 mg during week 2, and target doses of all 3 of the agents during week 3. Of the 4285 patients enrolled, 2271 were randomly assigned to treatment, and 2060 completed the study. Triple therapy was significantly superior to all of the dual therapies in reducing mean sitting systolic BP and mean sitting diastolic BP from baseline to end point (all P<0.0001). Significantly more patients on triple therapy achieved overall BP control (<140/90 mm Hg; P<0.0001) and systolic and diastolic control (P< or =0.0002) compared with each dual therapy. Aml/Val/HCTZ was well tolerated. The benefits of triple therapy over dual therapy were observed regardless of age, sex, race, ethnicity, or baseline mean sitting systolic BP. In conclusion, this study demonstrates the efficacy/safety of treating moderate and severe hypertension with Aml/Val/HCTZ 10/320/25 mg.

Effects of force-titrated valsartan/hydrochlorothiazide versus amlodipine/hydrochlorothiazide on ambulatory blood pressure in patients with stage 2 hypertension: the EVALUATE study.

BACKGROUND: Previous studies using the combination of angiotensin-receptor blockers and hydrochlorothiazide (HCTZ) have shown superior ambulatory blood pressure (ABP) reduction in study participants with stage 2 hypertension compared with monotherapy. OBJECTIVE: This multicenter, double-blind, parallel group, forced-titration study of individuals with stage 2 hypertension, compared the efficacy of valsartan and amlodipine in combination with HCTZ on ABP reduction. METHODS: After a 2-week washout period, participants (n=482) with mean office sitting systolic BP >or=160 mmHg and

Effects of aerobic exercise training and irbesartan on blood pressure and heart rate variability in patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVES: The present pilot study was undertaken to evaluate the efficacy of an aerobic exercise training (AET) program alone or combined with an antihypertensive agent (irbesartan) to reduce blood pressure (BP) and enhance heart rate variability (HRV) in chronic obstructive pulmonary disease patients. METHODS: Twenty-one patients were randomly assigned to a double-blind treatment with exercise and placebo (n=11) or exercise and irbesartan (n=10). Subjects underwent 24 h BP monitoring and 24 h electrocardiographic recording before and after the 12-week AET. HRV was investigated using three indexes from the power spectral analysis and three indexes calculated from the time domain. The AET program consisted of exercising on a calibrated ergocycle for 30 min three times per week. Five patients in the placebo group were excluded during follow-up because they were not compliant. RESULTS: There was no change in 24 h systolic and diastolic BP before (130+/-14 mmHg and 70+/-3 mmHg, respectively) and after (128+/-8 mmHg and 70+/-8 mmHg, respectively) exercise training in the placebo group, whereas in the irbesartan group systolic and diastolic BP decreased from 135+/-9 mmHg and 76+/-9 mmHg to 126+/-12 mmHg and 72+/-8 mmHg, respectively (P<0.02). There were no changes in HRV parameters in either group. CONCLUSIONS: The present study suggests that a 12-week AET program is not associated with a significant reduction in BP or enhancement in HRV, whereas an AET program combined with irbesartan is associated with a reduction in 24 h BP.

Aortic diameter, wall stiffness, and wave reflection in systolic hypertension.

Systolic hypertension is associated with increased pulse pressure (PP) and increased risk for adverse cardiovascular outcomes. However the pathogenesis of increased PP remains controversial. One hypothesis suggests that aortic dilatation, wall stiffening and increased pulse wave velocity result from elastin fragmentation, leading to a premature reflected pressure wave that contributes to elevated PP. An alternative hypothesis suggests that increased proximal aortic stiffness and reduced aortic diameter leads to mismatch between pressure and flow, giving rise to an increased forward pressure wave and increased PP. To evaluate these two hypotheses, we measured pulsatile hemodynamics and proximal aortic diameter directly using tonometry, ultrasound imaging, and Doppler in 167 individuals with systolic hypertension. Antihypertensive medications were withdrawn for at least 1 week before study. Patients with PP above the median (75 mm Hg) had lower aortic diameter (2.94+/-0.36 versus 3.13+/-0.28 cm, P<0.001) and higher aortic wall stiffness (elastance-wall stiffness product: 16.1+/-0.7 versus 15.7+/-0.7 ln[dyne/cm], P<0.001) with no difference in augmentation index (19.9+/-10.4 versus 17.5+/-10.0%, P=0.12). Aortic diameter and wall stiffness both increased with advancing age (P<0.001). However, an inverse relation between PP and aortic diameter remained significant (P<0.001) in models that adjusted for age, sex, height, and weight and then further adjusted for aortic wall stiffness, augmentation index, and mean arterial pressure. Among individuals with systolic hypertension, increased PP is primarily attributable to increased wall stiffness and reduced aortic diameter rather than premature wave reflection.

Identifying which treated hypertensive patients without known coronary artery disease should be tested for the presence of myocardial ischemia by perfusion imaging.

Stress dipyridamole technetium-99(m) sestamibi single photon emission computed tomographic imaging was used to study myocardial perfusion in 1116 hypertensive patients without known coronary artery disease (CAD). The test confirmed the presence of CAD in 28.9% of patients. As expected, patients with diabetes mellitus (DM) had a significantly higher prevalence of myocardial perfusion abnormalities (35.9% vs 23.9%; odds ratio, 1.79; 95% confidence interval [CI], 1.38-2.33; P<.0001) and high-risk myocardial imaging (16.4% vs 10.6%; odds ratio, 1.67; 95% CI, 1.18-2.37; P=.004) than those without DM. Odd ratios further increased, again as expected, with dyslipidemia (2.19; 95% CI, 1.54-3.12; P<.0001), peripheral arterial disease (2.61; 95% CI, 1.77-3.85; P<.0001), microalbuminuria (3.03; 95% CI, 1.91-4.82; P<.0001), and abnormal electrocardiographic findings (3.06; 1.68; 95% CI, 2.08-4.48; P<.0001). This large cohort study showed that more than 1 of 4 treated hypertensive patients have subclinical CAD. These study data should be clinically helpful in selecting hypertensive patients who are the most suitable candidates to screen for the presence of CAD.

Telmisartan/hydrochlorothiazide versus valsartan/hydrochlorothiazide in obese hypertensive patients with type 2 diabetes: the SMOOTH study.

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. CONCLUSION: 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.

Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial.

BACKGROUND: Diastolic dysfunction might represent an important pathophysiological intermediate between hypertension and heart failure. Our aim was to determine whether inhibitors of the renin-angiotensin-aldosterone system, which can reduce ventricular hypertrophy and myocardial fibrosis, can improve diastolic function to a greater extent than can other antihypertensive agents. METHODS: Patients with hypertension and evidence of diastolic dysfunction were randomly assigned to receive either the angiotensin receptor blocker valsartan (titrated to 320 mg once daily) or matched placebo. Patients in both groups also received concomitant antihypertensive agents that did not inhibit the renin-angiotensin system to reach targets of under 135 mm Hg systolic blood pressure and under 80 mm Hg diastolic blood pressure. The primary endpoint was change in diastolic relaxation velocity between baseline and 38 weeks as determined by tissue doppler imaging. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00170924. FINDINGS: 186 patients were randomly assigned to receive valsartan; 198 were randomly assigned to receive placebo. 43 patients were lost to follow-up or discontinued the assigned intervention. Over 38 weeks, there was a 12.8 (SD 17.2)/7.1 (9.9) mm Hg reduction in blood pressure in the valsartan group and a 9.7 (17.0)/5.5 (10.2) mm Hg reduction in the placebo group. The difference in blood pressure reduction between the two groups was not significant. Diastolic relaxation velocity increased by 0.60 (SD 1.4) cm/s from baseline in the valsartan group (p<0.0001) and 0.44 (1.4) cm/s from baseline in the placebo group (p<0.0001) by week 38. However, there was no significant difference in the change in diastolic relaxation velocity between the groups (p=0.29). INTERPRETATION: Lowering blood pressure improves diastolic function irrespective of the type of antihypertensive agent used.

The effect of telmisartan and ramipril on early morning blood pressure surge: a pooled analysis of two randomized clinical trials.

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.

Augmentation index and central aortic stiffness in middle-aged to elderly individuals.

BACKGROUND: Increased aortic stiffness contributes to systolic hypertension and increased cardiovascular risk. The augmentation index (AI), ie, the percentage of central pulse pressure attributed to reflected wave overlap in systole, was proposed as a noninvasive indicator of increased arterial stiffness. We evaluated this hypothesis by investigating relations between AI and other direct measures of aortic stiffness. METHODS: Tonometric carotid- and femoral-pressure waveforms, Doppler aortic flow, and aortic-root diameter were assessed in 123 individuals with uncomplicated systolic hypertension and 29 controls of comparable age and sex. Carotid-femoral pulse-wave velocity (PWV) was assessed from the carotid-femoral time delay and body-surface measurements. Aortic PWV was assessed from the ratio of the upstroke of carotid pressure and aortic flow velocity and was used to calculate proximal aortic compliance as [aortic area]/[1.06 x (aortic PWV)(2)]. RESULTS: Partial correlations (adjusted for age, sex, presence of hypertension, height, weight, and systolic ejection period) showed no association between AI and carotid-femoral PWV (R = -0.05, P = .54). The AI was significantly though weakly related directly with aortic compliance (R = 0.21, P = .012) and inversely with aortic PWV (R = -0.198, P = .017). However, higher stiffness (lower compliance and higher PWV) was associated with lower AI. CONCLUSIONS: Increased AI is not a reliable surrogate for increased aortic stiffness. Decreasing AI with decreasing compliance (increasing aortic stiffness) may be attributable to impedance matching and reduced wave reflection at the interface between the aorta and the muscular arteries.