ALTITUDE will determine whether dual RAAS blockade with the direct renin inhibitor aliskiren in combination with an ACEi or ARB will reduce major morbidity and mortality in a broad range of high-risk patients with type 2 diabetes.
AimsThe renin-angiotensin-aldosterone system (RAAS) represents a key therapeutic target in heart failure (HF) management. However, conventional agents that block this system induce a reflex increase in plasma renin activity (PRA), which may lead to RAAS 'escape'. Direct renin inhibitors (DRIs) have been developed that decrease PRA and thus may provide a greater RAAS blockade. Aliskiren is the first orally active DRI. Plasma levels of B-type natriuretic peptide (BNP) have been observed to be reduced with aliskiren compared with placebo. The aim of the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE) study is to evaluate the effect of both aliskiren and enalapril monotherapy and aliskiren/enalapril combination therapy on cardiovascular death and HF hospitalization in patients with chronic systolic HF, NYHA functional class II -IV symptoms, and elevated plasma levels of BNP. MethodsPatients tolerant to at least 10 mg or equivalent of enalapril will undergo an open-label run-in period where they receive enalapril then aliskiren. Approximately 7000 patients tolerating this run-in period will then be randomized 1:1:1 to aliskiren monotherapy, enalapril monotherapy, or the combination. The primary endpoints of ATMOSPHERE are (i) whether the aliskiren/enalapril combination is superior to enalapril monotherapy in delaying time to first occurrence of cardiovascular death or HF hospitalization and (ii) whether aliskiren monotherapy is superior or at least non-inferior to enalapril monotherapy on this endpoint. PerspectiveThe ATMOSPHERE study will definitively determine the role of a DRI strategy additional to or as an alternative to conventional RAAS blockade in patients with chronic systolic HF. ----------------------------------------------------------------------- KeywordsChronic heart failure † Renin -angiotensin † Renin † ACE-inhibitor † Aliskiren
Experimental studies of animals have previously demonstrated the validity of [1-ttClacetate as a tracer of oxidative metabolism for use with positron emission tomography. The present study was undertaken to define in normal human volunteers the relation between myocardial clearance kinetics of [1-"C]acetate, and the rate-pressure product as an index of myocardial oxygen consumption. Twenty-two studies were performed of 12 volunteers. The rate-pressure product was increased with continuous supine bicycle exercise in six studies. Of the 16 resting studies, seven were performed in the fasted state and nine following an oral glucose load, to define possible effects of substrate availability on the tracer-tissue kinetics. Myocardial tissue time-activity curves were biexponential. Clearance of activity was homogeneous throughout the myocardium. The rate constants ki, obtained from biexponential fitting, and kn..n, obtained by monoexponential fitting of the initial linear portion of the time-activity curves, correlated well with the rate-pressure product. Although the correlation coefficient was higher for kl than for km.,, (0.95 vs. 0.91), analysis on a sectorial basis showed less regional variability in kn..O. This suggests that korno,0 which is more practical than kl because it requires shorter acquisition times, may be more clinically and experimentally useful for detection of myocardial segments with abnormal oxygen consumption. Overall, changes in myocardial substrate supply were without significant effect on the relation between the rate constants (kl and k...0) and the rate-pressure product, although a small decrease in km0,,0/rate-pressure product was observed following oral glucose by paired analysis in four subjects. It is concluded that [1-"C]acetate can be used for the noninvasive measurement of myocardial oxygen consumption in humans with positron emission tomography, and, thus, has clinical and experimental potential as a tool for the understanding and diagnosis of myocardial disease. (Circulation 1989;80:863-872) acid kinetics in myocardium.3-12 Although characteristic changes in uptake and clearance of labeled fatty acids have been observed in myocardial ischemia, these changes reflect the net effect of diminished oxygen supply on each of the steps in fatty acid utilization and are not specific for impairment of 3-oxidation.2 Uptake and clearance of labeled fatty acids are markedly affected by substrate availability,13-15 in addition to myocardial workload.16 To characterize more precisely the metabolic state of the myocardium, a selective tracer of mitochondrial oxidative function is required.In the early 1980s, [1-1"C]acetate was examined both in animal studies17 and in patients with coro-
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 PARTICIPANTSA 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 MEASURESThe 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 mm 3 ; 95% CI, −6.27 to −1.94 mm 3 ) and placebo (−2.1 mm 3 ; 95% CI, −4.21 to 0.07 mm 3 ) (between-group difference, −2.04 mm 3 [95% CI, −5.03 to 0.95 mm 3 ]; 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
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