Patrick Brunel

Cardiorenal end points in a trial of aliskiren for type 2 diabetes

BACKGROUND This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. METHODS In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. RESULTS The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). CONCLUSIONS The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.).

Arterial distensibility and ambulatory blood pressure monitoring in essential hypertension

Arterial distensibility estimated by carotid femoral pulse wave velocity was evaluated in 22 patients with sustained essential hypertension, together with 3 different methods of blood pressure (BP) measurement: mercury sphygmomanometer, semiautomatic BP recording using the Dinamap apparatus and 24-hour ambulatory BP monitoring using a Spacelabs monitor. Although pulse wave velocity did not correlate with BP measured by mercury sphygmomanometer, it strongly and positively correlated with BP measurements using the other 2 procedures. The best correlation was observed with ambulatory BP with respect to systolic BP only (r = 0.685, p less than 0.001). Since cardiovascular morbidity and mortality in hypertensive patients is mainly related to lesions of the large arteries, the determination of pulse wave velocity together with ambulatory BP measurements is proposed for the evaluation of cardiovascular risk.

Efficacy and safety of amlodipine/valsartan compared with amlodipine monotherapy in patients with stage 2 hypertension: a randomized, double-blind, multicenter study: the EX-EFFeCTS Study.

Achieving blood pressure (BP) targets in stage 2 hypertension usually requires two or more drugs, which should be selected from different classes. This study compared the efficacy and tolerability of amlodipine/valsartan with amlodipine in patients with stage 2 hypertension. In this multicenter, randomized, double-blind, 8-week study, 646 patients with stage 2 hypertension (mean sitting systolic blood pressure [MSSBP] >/=160 mm Hg) received amlodipine/valsartan 5/160 mg or amlodipine 5 mg for 2 weeks, prior to being force-titrated to amlodipine/valsartan 10/160 mg or amlodipine 10 mg, respectively, for a further 6 weeks. Hydrochlorothiazide could be added at Week 4 if MSSBP was >/=130 mm Hg. At endpoint Week 4, reductions in MSSBP were significantly greater in patients receiving amlodipine/valsartan than in those receiving amlodipine (30.1 mm Hg vs. 23.5 mm Hg; P < .0001). Likewise, MSSBP reductions in patients with baseline MSSBP >/=180 mm Hg were also greater for amlodipine/valsartan at Week 4 (40.1 mm Hg vs. 31.7 mm Hg for amlodipine; P = .0018). Differences favoring amlodipine/valsartan were also seen for BP control. Amlodipine/valsartan was generally well tolerated. These findings support the rationale for combining agents with complementary mechanisms of action, such as amlodipine and valsartan, in the management of stage 2 hypertension.

Cardiovascular safety of transdermal nicotine patches in patients with coronary artery disease who try to quit smoking

Nicotine patches are commonly used by people who try to quit smoking. Because high doses of nicotine may increase heart rate and potentiate cardiac arrhythmia or ischemia, its use in patients with coronary artery disease was investigated. The objective was to assess the cardiovascular safety of nicotine patches in patients with coronary artery disease (CAD) who try to quit smoking. The study was conducted in a double-blind, placebo-controlled, randomized fashion over a 2-week period. One hundred and six patients with CAD who wished to stop smoking and were taking part in a smoking cessation program were included. Fifty-two patients received nicotine patches (Nicotinell®) and 54 received placebo patches. The cardiovascular effects of nicotine patches were assessed by repeated ambulatory ECG monitoring (AEM) and exercise testing. There were no changes in the resting heart rate and in the systolic or diastolic blood pressure between the screening and the two phases of the study in both the Nicotinell and placebo groups. Repeated 48-hour AEM revealed that there were no significant changes in the number and duration of ischemic episodes in both groups. There was no change in the frequency of atrial or ventricular arrhythmias. Exercise duration and time to 1-mm ST-segment depression increased in both groups during the double-blind treatment phase. More patients in the Nicotinell group claimed tobacco abstinence compared with the placebo group (27% vs. 13%). The use of nicotine patches did not cause aggravation of myocardial ischemia or arrhythmia in coronary patients and therefore can be used as a method to promote smoking cessation in this high-risk group.

Comparison of Estimates of Insulin Sensitivity From Minimal Model Analysis of the Insulin-Modified Frequently Sampled Intravenous Glucose Tolerance Test and the Isoglycemic Hyperinsulinemic Clamp in Subjects With NIDDM

Minimal model (MINMOD) analysis of the frequently sampled intravenous glucose tolerance test (FSIVGTT) is dependent on an adequate insulin response to the glucose load. As this is characteristically deficient in subjects with non-insulin-dependent diabetes mellitus (NIDDM), the technique has been modified by the use of an intravenous bolus of insulin. Previous validation of this modification in humans has relied on agreement between insulin sensitivity indexes (SI) estimated from tolbutamide- and insulin-modified tests and not on direct comparison with estimates derived from the isoglycemic glucose clamp. We have compared estimates of insulin sensitivity derived from minimal modeling of a 4-h insulin-modified FSIVGTT and the glucose clamp in subjects with NIDDM. Twelve subjects underwent an insulin-modified FSIVGTT and an isoglycemic hyperinsulinemic clamp in random order 2–4 weeks apart. Fasting plasma glucose (8.4 vs. 9.0 mmol/l) and immunoreactive insulin (IRI) concentrations (104.5 vs. 101.5 pmol/l) were not different between the 2 study days. SI(clamp) was derived from the steady-state glucose infusion rate during the 3rd h of the clamp, corrected for the ambient insulin and glucose concentrations. SI(ivgtt) was derived using MINMOD. SI(ivgtt) was 1.06 ± 0.18 min−1 · mU−1 · ml × 104, and mean SI(clamp) was 4.97 ± 0.69 l · min−1/pmol · 1−1 × 104 (mean ± SE). SI(ivgtt) was positively correlated with SI(clamp) (r = 0.73, P = 0.004) and negatively correlated with body mass index (r = −0.7, P = 0.005) and fasting IRI(ivgtt) (r = −0.64, P = 0.008). In summary, MINMOD analysis of the insulin-modified FSIVGTT provides a valid measure of insulin sensitivity in subjects with NIDDM.

Effect of aliskiren on progression of coronary disease in patients with prehypertension: The AQUARIUS randomized clinical trial

IMPORTANCE Blood pressure reduction and renin-angiotensin-aldosterone system inhibition are targets for treatment of atherosclerosis. The effect of renin inhibition on coronary disease progression has not been investigated. OBJECTIVE To determine the effects of renin inhibition with aliskiren on progression of coronary atherosclerosis. DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, multicenter trial (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study) comparing aliskiren with placebo in 613 participants with coronary artery disease, systolic blood pressure between 125 and 139 mm Hg (prehypertension range), and 2 additional cardiovascular risk factors conducted at 103 academic and community hospitals in Europe, Australia, and North and South America (enrollment from March 2009 to February 2011; end of follow-up: January 31, 2013). INTERVENTIONS Participants underwent coronary intravascular ultrasound (IVUS) imaging and were randomized to receive 300 mg of aliskiren (n = 305) or placebo (n = 308) taken orally daily for 104 weeks. Disease progression was measured by repeat IVUS examination after at least 72 weeks of treatment. MAIN OUTCOMES AND MEASURES The primary efficacy parameter was the change in percent atheroma volume (PAV) from baseline to study completion. Secondary efficacy parameters included the change in normalized total atheroma volume (TAV) and the percentage of participants with atheroma regression. Safety and tolerability were also assessed. RESULTS Evaluable imaging data were available at baseline and follow-up for 458 participants (74.7%). The primary IVUS efficacy parameter, PAV, did not differ between participants treated with aliskiren (-0.33%; 95% CI, -0.68% to 0.02%) and placebo (0.11%; 95% CI, -0.24% to 0.45%) (between-group difference, -0.43% [95% CI, -0.92% to 0.05%]; P = .08). The secondary IVUS efficacy parameter, TAV, did not differ between participants treated with aliskiren (-4.1 mm3; 95% CI, -6.27 to -1.94 mm3) and placebo (-2.1 mm3; 95% CI, -4.21 to 0.07 mm3) (between-group difference, -2.04 mm3 [95% CI, -5.03 to 0.95 mm3]; P = .18). There were no significant differences in the proportion of participants who demonstrated regression of PAV (56.9% vs 48.9%; P = .08) and TAV (64.4% vs 57.5%; P = .13) in the aliskiren and placebo groups, respectively. CONCLUSIONS AND RELEVANCE Among participants with prehypertension and coronary artery disease, the use of aliskiren compared with placebo did not result in improvement or slowing of progression of coronary atherosclerosis. These findings do not support the use of aliskiren for regression or prevention of progression of coronary atherosclerosis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00853827.

Novel Description of the 24-Hour Circadian Rhythms of Brachial Versus Central Aortic Blood Pressure and the Impact of Blood Pressure Treatment in a Randomized Controlled Clinical Trial: The Ambulatory Central Aortic Pressure (AmCAP) Study

&NA; Elevated brachial blood pressure (BP) is associated with increased cardiovascular risk and predicts morbidity and mortality in humans. Recently, 24-hour ambulatory BP monitoring and assessment of central aortic BP have been introduced to improve BP phenotyping. The Ambulatory Central Aortic Pressure (AmCAP) study combines these approaches and describes, for the first time, the diurnal patterns of simultaneously measured 24-hour ambulatory brachial and central pressures in a prespecified substudy embedded within a clinical trial of BP lowering in patients with hypertension. Twenty-four–hour ambulatory brachial and central pressure measurements were acquired using a tonometer mounted into the articulating strap of a wristwatch-like device (BPro) in 171 participants with hypertension recruited into the ASSERTIVE (AliSkiren Study of profound antihypERtensive efficacy in hyperTensIVE patients) trial. Participants were randomly assigned to BP lowering with either aliskiren 300 mg QD or telmisartan 80 mg QD for 12 weeks. Ambulatory brachial and central BP was measured in all participants both at baseline and at study end. Brachial and central BP both demonstrated typical diurnal patterns with lower pressures at night. However, night time was associated with smaller reductions in central relative to brachial pressure and decreased pulse pressure amplification (P<0.0001 for both). These effects were not modulated after BP lowering and were maintained after adjustment for day and night-time BP and heart rate (P=0.02). This study demonstrates that brachial and central pressure show different diurnal patterns, which are not modulated by BP-lowering therapy, with relatively higher night-time central pressures. These novel data indicate that night-time central BP may provide prognostic importance and warrants further investigation. Clinical Trial Registration– URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865020.

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.

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.

Sustained decrease in blood pressure following missed doses of aliskiren or telmisartan: the ASSERTIVE double-blind, randomized study.

Objectives: The AliSkiren Study of profound antihypERtensive efficacy in hyperTensIVE patients (ASSERTIVE) study was designed to assess the sustained blood pressure (BP)-lowering effect of aliskiren vs. telmisartan after a 7-day treatment withdrawal in patients with hypertension. Methods: Patients were randomized to once-daily aliskiren 150 mg (N = 414) or telmisartan 40 mg (N = 408). After 2 weeks, all patients were uptitrated to double the initial dose for 10 weeks; subsequently, all patients were treated with placebo to simulate a 7-day treatment withdrawal. Results: At the end of active treatment (EoA), similar decreases in mean ambulatory BP were observed with aliskiren and telmisartan. From EoA to day 7 of treatment withdrawal (end of withdrawal, EoW), the least squares mean increase in 24-h mean ambulatory SBP was smaller for aliskiren (2.7 mmHg) vs. telmisartan (6.5 mmHg). Between-treatment difference was significant in favour of aliskiren (−3.8 mmHg; P < 0.0001). Similar effects were observed for the increase in 24-h mean ambulatory DBP after EoW (−2.1 mmHg; P < 0.0001). Mean sitting SBP and DBP were also significantly lower with aliskiren than telmisartan after EoW with SBP (2.0 mmHg) and DBP (1.1 mmHg) differences in favour of aliskiren, already evident on day 2 after a single ‘missed dose’. Conclusion: Aliskiren showed a greater and more sustained BP-lowering effect than telmisartan during a 7-day treatment withdrawal. Aliskiren may provide sustained BP lowering during 1 day or more missed dose.