Efficacy and Safety of Crystalline Valsartan/Sacubitril (LCZ696) Compared With Placebo and Combinations of Free Valsartan and Sacubitril in Patients With Systolic Hypertension: The RATIO Study.

We compared the systolic blood pressure (SBP)-lowering efficacy and safety of crystalline valsartan/sacubitril (LCZ696, an angiotensin receptor blocker-neprilysin inhibitor) 400 mg daily against valsartan (320 mg once daily) alone or coadministered with placebo or increasing doses of free sacubitril (50, 100, 200, or 400 mg once daily) to identify the optimal antihypertensive combination dose. This multicenter, double-blinded, 7-arm parallel-group study recruited patients with mild-to-moderate systolic hypertension (office SBP 150-179 mm Hg). Primary-dependent variable was change in office SBP from baseline to week 8. At entry (n = 907), mean age was 61.5 years, sitting office BP 160/90.2 mm Hg, and mean 24-hour ambulatory BP 142/82.1 mm Hg; 852 participants completed the study. At week 8, there were greater reductions in sitting office SBP and 24-hour ambulatory SBP with LCZ696 400 mg than with valsartan 320 mg (-5.7 and -3.4 mm Hg, respectively, P < 0.05 each). The SBP reduction with LCZ696 400 daily was similar to coadministered free valsartan 320 mg and sacubitril 200 mg. Effects were similar in those older and younger than 65 years, and active therapies had adverse event rates similar to placebo. We conclude that crystalline valsartan/sacubitril 400 mg daily (1) is superior to valsartan 320 mg daily for lowering SBP, (2) has similar efficacy to the combination of free valsartan 320 mg plus free sacubitril 200 mg, (3) represents the optimal dosage for systolic hypertension in patients of any age, and (4) is safe and well tolerated.

Cardiovascular outcomes at different on-treatment blood pressures in the hypertensive patients of the VALUE trial.

AIMS: Recent hypertension guidelines recommend that also in high cardiovascular (CV) risk, hypertensive patients blood pressure (BP) is lowered to <140/90 mmHg as no evidence is available supporting the lower target of <130/80 mmHg recommended in previous guidelines. Whether this represents the optimal treatment strategy is debated, however. METHODS AND RESULTS: The high CV risk hypertensive patients of the Valsartan Antihypertensive Long-term use Evaluation (VALUE) trial were divided into subgroups according to (i) the percentage of on-treatment visits in which BP was reduced to <140/90 or <130/80 mmHg or (ii) the mean systolic or diastolic BP (SBP/DBP) values achieved during the entire treatment period or up to the occurrence of an event. A progressive increase from <25 to ≥75% of the visits in which BP was <140/90 mmHg was accompanied by a significant, progressive marked decrease in the covariate adjusted risk of CV morbidity and mortality, cause specific CV events (myocardial infarction, heart failure, and stroke), and all-cause mortality. Except for a persistent progressive decrease in stroke, no significant trend to a risk decrease occurred for a similar progressive increment of the proportion of visits with BP <130/80 mmHg. Increasing the proportion of visits with a BP <140/90 mmHg (but not <130/80 mmHg) was accompanied by a decreased risk of events also when differences in baseline risk were adjusted using a propensity score. Finally, compared with patients remaining at a mean on-treatment SBP ≥140 or DBP ≥90 mmHg, the risk of all events was markedly reduced when on-treatment mean SBP was lowered to a mean SBP of 130-139 mmHg or a mean DBP of 80-89 mmHg, whereas at on-treatment mean SBP <130 mmHg or DBP <80 mmHg, an additional risk reduction was found for stroke but for any other type of event, the risk of which remained similar or only slightly greater than that seen at the higher BP target. CONCLUSIONS: In the high CV risk, hypertensives of the VALUE trial reducing BP consistently to <140/90 mmHg had marked beneficial effects both when data were calculated as proportion of visits at BP target or as on-treatment mean BP. Reducing BP to <130/80 mmHg led only to some possible further benefit on stroke, whereas the risk of other outcomes remained substantially similar to or slightly greater than that seen at the higher target. Thus, aggressive BP reductions when CV risk is high may not offer substantial advantages, except perhaps in patients or conditions in which stroke risk is particularly common.

Antihypertensive and metabolic effects of Angiotensin receptor blocker/diuretic combination therapy in obese, hypertensive African American and white patients.

A clinical trial showed comparable blood pressure (BP) lowering by valsartan/hydrochlorothiazide and amlodipine/hydrochlorothiazide in obese hypertensive patients. Relative to amlodipine/hydrochlorothiazide, valsartan/hydrochlorothiazide reduced the hyperglycemic response to glucose challenge. An objective of this post hoc analysis was to determine whether this benefit extended to African Americans and whites. Treatments (160/12.5 mg of valsartan/hydrochlorothiazide force titrated to 320/25 mg of valsartan/hydrochlorothiazide at week 4 or 12.5 mg of hydrochlorothiazide force titrated to 25 mg of hydrochlorothiazide at week 4 with 5 and 10 mg of amlodipine added at weeks 8 and 12, respectively) were administered once daily. Both treatments reduced clinic BP from baseline to all visits (P < 0.0001), regardless of race/ethnicity (126 African Americans, 212 whites). In African Americans, there were no significant between-treatment differences in clinic or ambulatory BP lowering at weeks 8 or 16. Whites responded better to valsartan/hydrochlorothiazide. In both racial/ethnic subgroups, the addition of valsartan but not amlodipine mitigated the hyperglycemic response to hydrochlorothiazide through enhanced insulin secretion. Valsartan/hydrochlorothiazide was as effective as amlodipine/hydrochlorothiazide was in reducing BP in obese, hypertensive African Americans and better than amlodipine/hydrochlorothiazide in whites. In both racial/ethnic subgroups, the addition of valsartan to hydrochlorothiazide reduced the negative metabolic effects associated with thiazide therapy.

Antihypertensive response to thiazide diuretic or angiotensin receptor blocker in elderly hypertensives is not influenced by pretreatment plasma renin activity.

PURPOSE: Renin profiling has been proposed as a method to guide antihypertensive drug selection. This prespecified post-hoc analysis examined the influence of baseline plasma renin activity (PRA) on blood pressure (BP) responses. METHODS: A 16-week, randomized, double-blind, prompted-titration trial evaluated initial valsartan (V)/hydrochlorothiazide (HCTZ) combination therapy versus initial HCTZ or V monotherapy in individuals aged ≥ 70 years with systolic hypertension. Sitting PRA was measured at baseline, Week 4, and Week 16. Subjects were stratified into 2 groups for analysis: low renin (baseline PRA < 0.65 ng/mL/h) or normal-high renin (baseline PRA ≥ 0.65 ng/mL/h). RESULTS: PRA data were available in 322/384 subjects: 178 had low PRA and 144 had normal-high PRA. At Week 4, V/HCTZ was more effective than HCTZ or V at reducing mean sitting systolic BP (MSSBP), independent of baseline PRA, with reductions of -16.9, -12.6, and -9.5 mmHg, respectively, in low-renin subjects and -19.4, -11.5, and -8.6 mmHg in normal-high renin subjects. Baseline PRA was similar in responders (subjects not uptitrated at Week 4) and nonresponders (subjects uptitrated at Week 4). In responders, the reactive rise in PRA at Week 4 was related to change in MSSBP, with the greatest increases in PRA observed in the V/HCTZ group. Higher baseline PRA was associated with a greater reactive rise in PRA. CONCLUSIONS: Baseline PRA is not a useful guide to the BP responses of initial combination V/HCTZ in elderly individuals with systolic hypertension.

Improving blood pressure control: increase the dose of diuretic or switch to a fixed-dose angiotensin receptor blocker/diuretic? the valsartan hydrochlorothiazide diuretic for initial control and titration to achieve optimal therapeutic effect (Val-DICTATE) trial.

To assess the strategy of increasing the dose of a diuretic compared with using an angiotensin receptor blocker in combination with a diuretic, the authors performed a multicenter, randomized, parallel group trial in hypertensive patients (baseline blood pressure [BP], 153/97 mm Hg) whose BP remained uncontrolled on initial low-dose diuretic monotherapy (hydrochlorothiazide [HCTZ] 12.5 mg Hg). Patients with stage 1 and 2 hypertension were randomized to treatment with valsartan/HCTZ (160/12.5 mg) or to doubling of the HCTZ dose (25 mg). The primary end point was the percentage of patients whose clinic BP values were <140/90 mm Hg following 4 weeks of double-blind therapy. A significantly higher proportion (P<.001) of hypertensive patients met BP control levels in the valsartan/HCTZ (160/12.5 mg) group compared with the HCTZ 25 mg group (37% vs 16%). Changes from baseline in BP were significantly greater (P<.001) for both systolic BP and diastolic BP in the combination therapy arm compared with the diuretic monotherapy arm (-12. 4/-7.5 mm Hg in valsartan/HCTZ 160/12.5 mg group vs -5.6/-2.1 mm Hg in HCTZ 25 mg group). Tolerability and adverse events were similar in the 2 treatment groups. This study suggests that in the management of hypertension, utilizing an angiotensin receptor blocker/diuretic combination was more effective in lowering BP and achieving BP goals when compared with increasing the dose of the diuretic.

Metabolic and antihypertensive effects of combined angiotensin receptor blocker and diuretic therapy in prediabetic hypertensive patients with the cardiometabolic syndrome.

Hypertensive patients with the cardiometabolic syndrome (CMS) are at increased risk for type 2 diabetes and cardiovascular disease. The authors examined effects of valsartan and hydrochlorothiazide (HCTZ) combined and alone on insulin sensitivity (using homeostasis model assessment-insulin resistance [HOMA-IR]), and inflammatory/metabolic biomarkers in prediabetic hypertensive persons with CMS. Eligible patients entered 16-week therapy with valsartan 320 mg/d (n=189), HCTZ 25 mg/d (n=190), or valsartan/HCTZ 320/25 mg/d (n=187). At the end point, there were no statistically significant differences in HOMA-IR among the 3 groups. HCTZ significantly increased hemoglobin A(1c) and triglyceride concentrations and lowered serum potassium levels vs valsartan. HCTZ also increased plasma aldosterone and C-reactive protein levels. Blood pressure reduction and blood pressure control rates were highest with valsartan/HCTZ. There were no differences between combination valsartan/HCTZ or monotherapies on a measure of insulin sensitivity; however, the negative metabolic effects of HCTZ (increase in triglyceride and hemoglobin A(1c) values) were absent with valsartan/HCTZ, indicating an ameliorating effect of valsartan on these measures.

Prior Medications and the Cardiovascular Benefits From Combination Angiotensin-Converting Enzyme Inhibition Plus Calcium Channel Blockade Among High-Risk Hypertensive Patients.

BACKGROUND: The ACCOMPLISH (Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension) trial demonstrated that combination therapy using amlodipine, rather than hydrochlorothiazide, in conjunction with benazepril provided greater cardiovascular risk reduction among high-risk hypertensive patients. Few trials have evaluated the effect of prior antihypertensive therapy used among participants on the study outcomes. METHODS AND RESULTS: In a post hoc observational analysis, we examined the characteristics of the drug regimens taken before trial enrollment in the context of the primary composite outcome (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac death, and coronary revascularization). In the "primary subgroup" (n=4475), patients previously taking any renin-angiotensin system blockade plus either a diuretic or a calcium channel blocker alone or as part of their antihypertensive regimen, there were 206 of 2193 (9.4%) versus 281 of 2282 (12.3%) primary composite events among those randomized to combination therapy involving amlodipine versus hydrochlorothiazide, respectively (adjusted Cox proportional hazard ratio, 0.74; 95% confidence interval, 0.62-0.89; P=0.0015). All other participants (n=6975) previously taking any antihypertensive regimen not included in the primary subgroup also benefited from randomization to amlodipine plus benazepril (adjusted hazard ratio, 0.84; 95% confidence interval, 0.72-0.98; P=0.024). Outcomes among most other subgroups, including patients previously taking lipid-lowering medications or dichotomized by prior blood pressure control status, showed similar results. CONCLUSIONS: When combined with an angiotensin-converting enzyme inhibitor, amlodipine provides cardiovascular risk reduction superior to hydrochlorothiazide, largely regardless of prior medication use. These findings add further support for the initial use of this combination regimen among high-risk hypertensive patients.

Influence of Age and Race on 24-Hour Ambulatory Blood Pressure Responses to Valsartan, Hydrochlorothiazide, and Their Combination: Implications for Clinical Practice.

The effects of race and age on 24-hour mean ambulatory systolic blood pressure (maSBP) responses to sequential 4-week periods of angiotensin receptor blocker therapy (valsartan [VAL] 160 mg/d then 320 mg/d and combination VAL/hydrochlorothiazide [HCTZ] 320/12.5 mg/d) were compared in 304 patients with stage 1 or 2 hypertension. There were lesser blood pressure (BP) responses from baseline with VAL monotherapy in black than Caucasian patients (-2.9 and -4.0 mm Hg vs -8.2 and -9.3 mm Hg, respectively; P<.001 each) but VAL/HCTZ BP responses were similar in both groups (-12 vs -15 mm Hg). Participants 65 years and older had lower BP responses with VAL 160 mg/d and 320 mg/d than those younger than 65 years (-2.8 and -4.5 mm Hg vs -6.5 and -7.5 mm Hg, respectively; P<.001) but similar responses to VAL/HCTZ (-14 vs -17 mm Hg). No BP response differences were found between those older than and those younger than 55 years. The authors conclude that: (1) adding low-dose HCTZ (12.5 mg daily) to VAL is more effective than VAL titration, irrespective of age or race, (2) VAL BP efficacy is lower in blacks than Caucasians, and (3) ARB responses are diminished in patients older than 65 years. Guidelines for stage 1 or 2 hypertension that suggest age 55 should determine initial monotherapy choice (eg, ARB vs thiazide diuretic) or that fail to recommend initial ARB-thiazide combination therapy should be reconsidered.

Effects of Sacubitril/Valsartan Versus Olmesartan on Central Hemodynamics in the Elderly With Systolic Hypertension: The PARAMETER Study.

Effective treatment of systolic hypertension in elderly patients remains a major therapeutic challenge. A multicenter, double-blind, randomized controlled trial with sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, was conducted to determine its effects versus olmesartan (angiotensin receptor blocker) on central aortic pressures, in elderly patients (aged ≥60 years) with systolic hypertension and pulse pressure >60 mm Hg, indicative of arterial stiffness. Patients (n=454; mean age, 67.7 years; mean seated systolic blood pressure, 158.6 mm Hg; mean seated pulse pressure, 69.7 mm Hg) were randomized to receive once-daily sacubitril/valsartan 200 mg or olmesartan 20 mg, force titrated to double the initial doses after 4 weeks, before primary assessment at 12 weeks. The study extended double-blind treatment for 12 to 52 weeks, during which amlodipine (2.5-5 mg) and subsequently hydrochlorothiazide (6.25-25 mg) were added-on for patients not achieving blood pressure target (<140/90). At week 12, sacubitril/valsartan reduced central aortic systolic pressure (primary assessment) greater than olmesartan by -3.7 mm Hg (P=0.010), further corroborated by secondary assessments at week 12 (central aortic pulse pressure, -2.4 mm Hg, P<0.012; mean 24-hour ambulatory brachial systolic blood pressure and central aortic systolic pressure, -4.1 mm Hg and -3.6 mm Hg, respectively, both P<0.001). Differences in 24-hour ambulatory pressures were pronounced during sleep. After 52 weeks, blood pressure parameters were similar between treatments (P<0.002); however, more patients required add-on antihypertensive therapy with olmesartan (47%) versus sacubitril/valsartan (32%; P<0.002). Both treatments were equally well tolerated. The PARAMETER study (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Measuring Arterial Stiffness in the Elderly), for the first time, demonstrated superiority of sacubitril/valsartan versus olmesartan in reducing clinic and ambulatory central aortic and brachial pressures in elderly patients with systolic hypertension and stiff arteries.

Long-term safety of high-dose angiotensin receptor blocker therapy in hypertensive patients with chronic kidney disease.

BACKGROUND: Reducing urinary protein excretion in patients with renal disease is an important therapeutic target to prevent the progression of renal and cardiovascular disease. Drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs), which block the actions of the renin-angiotensin-aldosterone system, are recommended because they reduce blood pressure and proteinuria. Recently, the use of higher doses of ARBs, up to three times the maximal approved dose, resulted in further reductions in protein excretion. Despite the effectiveness of this therapeutic approach, no long-term safety analysis has been conducted in patients receiving high-dose ARB treatment. OBJECTIVE: To study the long-term safety of high-dose ARB treatment. METHODS: We observed 48 patients [44 men and 4 women; ages 64 +/- 15 years (mean +/- SD), weight 88 +/- 28 kg, estimated glomerular filtration rate 53 +/- 23 ml/min] receiving treatment with high doses (1.5-5 times greater than the maximum approved dose) of ARBs, for 40 +/- 24 months (range 6-98 months). RESULTS: The average ARB dose tended to increase over time and was 3.2 +/- 1.2 times greater at the end of the study than that at the start. Systolic blood pressure was similar at the beginning and end of the study period (132 +/- 20 and 125 +/- 20 mmHg, respectively), but diastolic blood pressure showed a decrease throughout the study and was significantly reduced (P < 0.05) in association with 1.5x and 2x the maximum ARB dose (73 +/- 11 and 72 +/- 10 mmHg, respectively) when compared with baseline (78 +/- 11 mm Hg). There was a trend (P > 0.05) for increases in concentrations of serum potassium (0.2 +/- 0.9 mmol/l) and creatinine (0.3 +/- 0.7 mg/dl) with increases in dose from baseline to the end of the study. Serum creatinine concentration was greater (P < 0.05) at the periods of 3x and 4x the maximum dose, but this represented increases of only 12 and 20% from baseline, respectively. CONCLUSIONS: High-dose ARB treatment in patients with chronic renal disease is not associated with any clinically significant long-term negative effects on serum creatinine or potassium and is thus a important therapeutic modality with which to achieve further reductions in urinary protein excretion.

Cardiovascular Outcomes According to Systolic Blood Pressure in Patients With and Without Diabetes: An ACCOMPLISH Substudy.

To evaluate the effects of achieved systolic blood pressure (SBP) during treatment on cardiovascular (CV) outcomes, the authors measured event rates of a composite primary endpoint (CV death or nonfatal myocardial infarction or stroke) at on-treatment SBPs of ≥140 mm Hg and the 10 mm Hg intervals of <140 mm Hg, <130 mm Hg, and <120 mm Hg in 6459 patients with diabetes (mean age, 67) and 4246 patients without diabetes (mean age, 69) from the Avoiding Cardiovascular Events in Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial. In the diabetic cohort, the primary endpoint was 49% lower (P<.001) at <140 mm Hg than at ≥140 mm Hg, and the separate components of this endpoint were also significantly reduced. Further SBP reductions did not improve outcomes, and at <120 mm Hg they were no longer different (except for stroke) from ≥140 mm Hg. In contrast, in the nondiabetic cohort, the primary endpoint event rate fell steadily (although not significantly) through the decreasing SBP categories until it was reduced by 45% (P=.0413) at <120 mm Hg. Total stroke rates for both the diabetic (-56%, P=.0120) and nondiabetic (-68%, P=.0067) cohorts were lowest at <120 mm Hg, and adverse renal events (serum creatinine increase ≥50%) were significantly lowest in the range of 130 mm Hg to 139 mm Hg for both cohorts. Diabetic patients (<140 mm Hg or <130 mm Hg) and nondiabetic patients (<120 mm Hg) may require different SBP targets for optimal CV protection, although stroke and renal considerations should also influence the selection of blood pressure targets.

Time of administration important? Morning versus evening dosing of valsartan.

OBJECTIVE: Studies suggest that bedtime dosing of an angiotensin-converting enzyme (ACE)-inhibitor or angiotensin receptor blocker shows a more sustained and consistent 24-h antihypertensive profile, including greater night-time blood pressure (BP) reduction. We compared the antihypertensive effects of morning (a.m.) and evening (p.m.) dosing of valsartan on 24-h BP. METHODS: This 26-week, multicentre, randomized, double-blind study evaluated the efficacy and safety of valsartan 320 mg, dosed a.m. or p.m., versus lisinopril 40 mg (a.m.), a long-acting ACE-inhibitor, in patients with grade 1-2 hypertension and at least one additional cardiovascular risk factor. Patients (n = 1093; BP = 156 ±â€Š11/91 ±â€Š8 mmHg; 62 years, 56% male, 99% white) received (1 : 1 : 1) valsartan 160 mg a.m. or p.m. or lisinopril 20 mg a.m. for 4 weeks, then force-titrated to double the initial dose for 8 weeks. At Week 12, hydrochlorothiazide (HCTZ) 12.5 mg was added for 14 weeks if office BP was more than 140/90 mmHg and/or ambulatory BP more than 130/80 mmHg. RESULTS: Mean 24-h ambulatory SBP change from baseline to Weeks 12 and 26 was comparable between valsartan a.m. (-10.6 and -13.3 mmHg) and p.m. (-9.8 and -12.3 mmHg) and lisinopril (-10.7 and -13.7 mmHg). There was no benefit of valsartan p.m. versus a.m. on night-time BP, early morning BP and morning BP surge. Evening dosing also did not improve BP lowering in patients requiring add-on HCTZ or in nondippers at baseline. All treatments were well tolerated. CONCLUSION: Once-daily dosing of valsartan 320 mg results in equally effective 24-h BP efficacy, regardless of dosing time. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00241124.

Amlodipine+benazepril is superior to hydrochlorothiazide+benazepril irrespective of baseline pulse pressure: subanalysis of the ACCOMPLISH trial.

Pulse pressure (PP) is an independent risk factor for cardiovascular (CV) disease and death but few studies have investigated the effect of antihypertensive treatments in relation to PP levels before treatment. The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial showed that the combination of benazepril+amlodipine (B+A) is superior to benazepril+hydrochlorothiazide (B+H) in reducing CV events. We aimed to investigate whether the treatment effects in the ACCOMPLISH trial were dependent on baseline PP. High-risk hypertensive patients (n=11,499) were randomized to double-blinded treatment with single-pill combinations of either B+A or B+H and followed for 36 months. Patients were divided into tertiles according to their baseline PP and events (CV mortality/myocardial infarction or stroke) were compared. Hazard ratios (HRs) for the treatment effect (B+A over B+H) were calculated in a Cox regression model with age, coronary artery disease, and diabetes mellitus as covariates and were compared across the tertiles. The event rate was increased in the high tertile of PP compared with the low tertile (7.2% vs 4.4% P<.01). In the high and medium PP tertiles, HRs were 0.75 (95% confidence interval [CI], 0.60-0.95; P=.018) and 0.74 (CI, 0.56-0.98, P=.034), respectively, in favor of B+A. There was no significant difference between the treatments in the low tertile and no significant differences in treatment effect when comparing the HRs between tertiles of PP. B+A has superior CV protection over B+H in high-risk hypertensive patients independent of baseline PP although the absolute treatment effect is enhanced in the higher tertiles of PP where event rates are higher.

Rationale and study design of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study.

INTRODUCTION: Hypertension in elderly people is characterised by elevated systolic blood pressure (SBP) and increased pulse pressure (PP), which indicate large artery ageing and stiffness. LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is being developed to treat hypertension and heart failure. The Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study will assess the efficacy of LCZ696 versus olmesartan on aortic stiffness and central aortic haemodynamics. METHODS AND ANALYSIS: In this 52-week multicentre study, patients with hypertension aged ≥60 years with a mean sitting (ms) SBP ≥150 to <180 and a PP>60 mm Hg will be randomised to once daily LCZ696 200 mg or olmesartan 20 mg for 4 weeks, followed by a forced-titration to double the initial doses for the next 8 weeks. At 12-24 weeks, if the BP target has not been attained (msSBP <140 and ms diastolic BP <90 mm Hg), amlodipine (2.5-5 mg) and subsequently hydrochlorothiazide (6.25-25 mg) can be added. The primary and secondary endpoints are changes from baseline in central aortic systolic pressure (CASP) and central aortic PP (CAPP) at week 12, respectively. Other secondary endpoints are the changes in CASP and CAPP at week 52. A sample size of 432 randomised patients is estimated to ensure a power of 90% to assess the superiority of LCZ696 over olmesartan at week 12 in the change from baseline of mean CASP, assuming an SD of 19 mm Hg, the difference of 6.5 mm Hg and a 15% dropout rate. The primary variable will be analysed using a two-way analysis of covariance. ETHICS AND DISSEMINATION: The study was initiated in December 2012 and final results are expected in 2015. The results of this study will impact the design of future phase III studies assessing cardiovascular protection. CLINICAL TRIALS IDENTIFIER: EUDract number 2012-002899-14 and ClinicalTrials.gov NCT01692301.

Does response of RAS blockade on serum K+ levels influence its glycemic-mitigating response when combined with hydrochlorothiazide?

The authors previously reported that addition of valsartan ameliorated the negative metabolic effects of hydrochlorothiazide in obese hypertensive patients through an enhanced postprandial insulin response. In this secondary analysis, the authors tested whether this enhanced insulin response to valsartan/hydrochlorothiazide was influenced by serum potassium levels, which were reduced to a lesser extent, when compared with amlodipine/hydrochlorothiazide. Results showed that the early insulin response with valsartan plus hydrochlorothiazide occurred regardless of serum potassium levels. Heightened insulin response was, however, not significantly different when patients with normal potassium (>3.9 mEq/L) at baseline and low potassium (≤3.9 mEq/L) at the end of the study were compared with the amlodipine/hydrochlorothiazide group. Despite the influence of serum potassium on insulin secretory response to a glucose challenge, the addition of valsartan maintained normoglycemia in patients given hydrochlorothiazide. Thus, the metabolic response to hydrochlorothiazide was improved with addition of valsartan through an enhanced insulin response that was not greatly affected by changes in potassium levels.

Changes in aortic pulse wave velocity in hypertensive postmenopausal women: comparison between a calcium channel blocker vs angiotensin receptor blocker regimen.

Postmenopausal women are at greater risk for hypertension-related cardiovascular disease. Antihypertensive therapy may help alleviate arterial stiffness that represents a potential modifiable risk factor of hypertension. This randomized controlled study investigated the difference between an angiotensin receptor blocker and a calcium channel blocker in reducing arterial stiffness. Overall, 125 postmenopausal hypertensive women (age, 61.4 ± 6 years; systolic blood pressure/diastolic blood pressure [SBP/DBP], 158 ± 11/92 ± 9 mm Hg) were randomized to valsartan 320 mg ± hydrochlorothiazide (HCTZ) (n = 63) or amlodipine 10 mg ± HCTZ (n = 62). The primary outcome was carotid-to-femoral pulse wave velocity (PWV) changes after 38 weeks of treatment. Both treatments lowered peripheral blood pressure (BP) (-22.9/-10.9 mm Hg for valsartan and -25.2/-11.7 mm Hg for amlodipine, P = not significant) and central BP (-15.7/-7.6 mm Hg for valsartan and -19.2/-10.3 mm Hg for amlodipine, P<.05 for central DBP). Both treatments similarly reduced the carotid-femoral PWV (-1.9 vs -1.7 m/s; P = not significant). Amlodipine was associated with a higher incidence of peripheral edema compared with the valsartan group (77% vs 14%, P<.001). BP lowering in postmenopausal women led to a reduction in arterial stiffness as assessed by PWV measurement. Both regimens reduced PWV to a similar degree after 38 weeks of treatment despite differences in central BP lowering, suggesting that the effect of valsartan on PWV is mediated through nonhemodynamic effects.

Cardiovascular outcomes in hypertensive patients: comparing single-agent therapy with combination therapy.

OBJECTIVES: To determine whether blood pressure (BP) control in hypertensive patients achieved with combination drug therapy provides the same cardiovascular benefits as with single-agent therapy. BACKGROUND: Drug combinations, most often including hydrochlorothiazide (HCTZ), are now recommended for routine BP management, but their effects on cardiovascular event rates have not been compared with effective monotherapy. METHODS: We conducted retrospective analyses of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) data. VALUE compared cardiovascular event rates of valsartan and amlodipine. Patients with BPs not controlled (<140/90  mmHg) by the single agents had HCTZ and, if required, additional drugs of different classes, added. Using data pooled from the two treatment arms, we have now divided patients into those controlled on monotherapy and those controlled or not controlled by combination therapy. The primary study endpoint was first occurrence of cardiovascular death or nonfatal myocardial infarction or stroke. Comparisons between groups were by Cox regression, adjusted for on-treatment BP, age, prior cardiovascular events and left ventricular hypertrophy; the comparison between the monotherapy and combination therapy controlled groups was based on events occurring after 3 months by when the decision to use monotherapy or combination therapy was made. RESULTS: The primary endpoint occurred in 505 of 5924 (8.5%) monotherapy and 511 of 4621 (11.1%) combination therapy controlled patients: hazard ratio was 0.80 [95% confidence interval (CI) 0.70-0.90]. If these two groups were matched for baseline BPs and all events included from study baseline, the hazard ratio was 0.76 (95% CI 0.67-0.86). The difference between combination controlled and uncontrolled [434 of 3390 (12.8%)] groups was not significant [hazard ratio 0.90 (95% CI 0.80-1.03], nor when they were matched for baseline BPs [hazard ratio 0.95 (95% CI 0.81-1.11)]. CONCLUSION: Independent of prior cardiovascular history or baseline BP, hypertensive patients requiring combination therapy, which includes a thiazide diuretic for BP control, have a poorer cardiovascular prognosis than those controlled by monotherapy and only a nonsignificantly lower event rate than noncontrolled patients.

Varying patterns of the antihypertensive and antialbuminuric response to higher doses of renin-angiotensin-aldosterone system blockade in albuminuric hypertensive type 2 diabetes mellitus patients.

OBJECTIVE: In patients with type 2 diabetes mellitus (T2DM), blocking of the renin-angiotensin-aldosterone system (RAAS) has demonstrated efficacy in lowering blood pressure (BP) and urinary albumin excretion rate (UAER). Nonetheless, not all patients successfully respond to RAAS blockade with a reduction in BP and UAER. METHODS: This secondary analysis of a double-blind study of 391 patients with T2DM assessed the importance of using higher doses of the RAAS blocker valsartan to improve the BP and UAER response in patients initially identified as prompt or delayed responders. All patients received a starting dose of valsartan 160 mg for a 4-week run-in period to classify them as either prompt responders (SBP < 130 mmHg or reduction in SBP ≥10 mmHg, 53%) or delayed responders (47%). All patients were then subsequently randomized to one of three valsartan doses: 160, 320, or 640 mg/day for 26 weeks. RESULTS: Higher doses of valsartan (640 mg) demonstrated additional reductions in SBP among the prompt responders and led to greater SBP reductions from baseline (19.8 mmHg) compared with valsartan 160 (14.4 mmHg, P < 0.05) and 320 mg (16.5 mmHg). Among delayed responders, SBP reductions from baseline to end of study were similar (11-14 mmHg, P > 0.05) across all valsartan doses. For UAER, higher valsartan doses produced further reductions by week 30, regardless of initial response. CONCLUSION: Higher doses of valsartan did not appear to recruit delayed responders, but enhanced the prompt responder effects in patients with T2DM. Not all patients successfully respond in concordance to RAAS blockade with both reductions in BP and UAER. Reduction in BP dominates the antialbuminuric effect in both valsartan prompt responders and delayed responders independent of dose.

Office and ambulatory blood pressure-lowering effects of combination valsartan/hydrochlorothiazide vs. hydrochlorothiazide-based therapy in obese, hypertensive patients.

The authors evaluated the blood pressure (BP)-lowering effects of combination valsartan/hydrochlorothiazide (HCTZ) vs. amlodipine/HCTZ in a 16-week, double-blind, randomized, forced-titration study and ambulatory BP monitoring (ABPM) substudy involving centrally obese hypertensive patients 40 years and older. Patients were started on valsartan/HCTZ 160/12.5 mg or HCTZ 12.5 mg monotherapy, force-titrated at week 4 to valsartan/HCTZ 320/25 mg and HCTZ 25 mg, respectively. The HCTZ group initiated amlodipine 5 mg at week 8 and 10 mg at week 12. A subset of patients had 24-hour ABPM at baseline and weeks 8 and 16. At week 16 in the intent-to-treat population (n=401), valsartan/HCTZ and amlodipine/HCTZ lowered office systolic BP (-30.6 vs. -28.3 mm Hg; P=.14). In the ABPM subgroup (n=111), valsartan/HCTZ was more effective than amlodipine/HCTZ in reducing 24-hour systolic BP (-20.6 vs. -14.5 mm Hg; P=.011). In obese hypertensive patients, valsartan/HCTZ reduced office BP similar to amlodipine/HCTZ but lowered 24-hour systolic BP more.