Effects of the Oral Direct Renin Inhibitor Aliskiren in Patients With Symptomatic Heart Failure
ABSTRACT Loss of negative feedback inhibition of renin release during chronic treatment with an angiotensin-converting enzyme (ACE) inhibitor leads to a compensatory rise in renin secretion and downstream components of the renin-angiotensin-aldosterone (RAAS) cascade. This may overcome ACE inhibition but should be blocked by a direct renin inhibitor. We studied the effects of adding the direct renin inhibitor aliskiren to an ACE inhibitor in patients with heart failure.
Patients with New York Heart Association class II to IV heart failure, current or past history of hypertension, and plasma brain natriuretic peptide (BNP) concentration >100 pg/mL who had been treated with an ACE inhibitor (or angiotensin receptor blocker) and beta-blocker were randomized to 3 months of treatment with placebo (n=146) or aliskiren 150 mg/d (n=156). The primary efficacy outcome was the between-treatment difference in N-terminal pro-BNP (NT-proBNP). Patients' mean age was 68 years, mean ejection fraction was 31%, and mean+/-SD systolic blood pressure was 129+/-17.4 mm Hg. Sixty-two percent of the patients were in New York Heart Association functional class II, and 33% were taking an aldosterone antagonist. Plasma NT-proBNP rose by 762+/-6123 pg/mL with placebo and fell by 244+/-2025 pg/mL with aliskiren (P=0.0106). BNP and urinary (but not plasma) aldosterone were also reduced by aliskiren. Clinically important differences in blood pressure and biochemistry were not seen between aliskiren and placebo.
Addition of aliskiren to an ACE inhibitor (or angiotensin receptor blocker) and beta-blocker had favorable neurohumoral effects in heart failure and appeared to be well tolerated.
- SourceAvailable from: Adrian Covic
[Show abstract] [Hide abstract]
- "Initially used as antihypertensive agents, DRIs have more recently been tested in patients with HF. In the ALOFT (Aliskiren Observation of Heart Failure Treatment) study, which included 302 patients with stable HF, adding the DRI aliskiren to ACEIs or ARBs appeared to be safe and effective in decreasing plasma BNP and urinary aldosterone levels . Two other large trials are underway using aliskiren in HF patients. "
ABSTRACT: Introduction. Heart failure (HF) is highly prevalent in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) and is strongly associated with mortality in these patients. However, the treatment of HF in this population is largely unclear. Study Design. We conducted a systematic integrative review of the literature to assess the current evidence of HF treatment in CKD patients, searching electronic databases in April 2014. Synthesis used narrative methods. Setting and Population. We focused on adults with a primary diagnosis of CKD and HF. Selection Criteria for Studies. We included studies of any design, quantitative or qualitative. Interventions. HF treatment was defined as any formal means taken to improve the symptoms of HF and/or the heart structure and function abnormalities. Outcomes. Measures of all kinds were considered of interest. Results. Of 1,439 results returned by database searches, 79 articles met inclusion criteria. A further 23 relevant articles were identified by hand searching. Conclusions. Control of fluid overload, the use of beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and optimization of dialysis appear to be the most important methods to treat HF in CKD and ESRD patients. Aldosterone antagonists and digitalis glycosides may additionally be considered; however, their use is associated with significant risks. The role of anemia correction, control of CKD-mineral and bone disorder, and cardiac resynchronization therapy are also discussed.BioMed Research International 05/2014; 2014. DOI:10.1155/2014/937398 · 2.71 Impact Factor
[Show abstract] [Hide abstract]
- "Aliskiren suppresses the RAAS by directly inhibiting plasma renin activity (PRA).11 Recently, evidence has accumulated suggesting that aliskiren is effective for blood pressure (BP) control and inhibits the progression of CKD and cardiovascular disease in patients with hypertension and CKD;12–16 however, its effects on elderly CKD patients have not been fully elucidated because most clinical trials have excluded the elderly and few studies have targeted elderly CKD patients. In the present study, we assessed the efficacy of aliskiren on BP control, renoprotection, and cardioprotection in elderly CKD patients with hypertension. "
ABSTRACT: We investigated the effects of aliskiren in terms of its inhibition of the renin-angiotensin-aldosterone system (RAAS) as well as that on blood pressure (BP), and renal and cardiac protection in elderly chronic kidney disease (CKD) patients with hypertension. Nineteen elderly CKD patients (nine males, ten females, aged 74.6 ± 5.8 years) were assigned to receive 150 mg/day of aliskiren added to existing antihypertensives for 6 months. Changes in plasma renin activity (PRA), angiotensin I (Ang I), angiotensin II (Ang II), aldosterone (Ald), BP, estimated glomerular filtration rate (eGFR), urine albumin/creatinine ratio (UACR), left ventricular ejection fraction (LVEF), interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), and plasma brain natriuretic peptide (BNP) levels were evaluated. ALISKIREN SUPPRESSED THE RAAS AS FOLLOWS: PRA 1.3 ± 1.0 to 0.3 ± 0.3 ng/mL/hour, P < 0.05; Ang I 59.5 ± 32.1 to 26.0 ± 17.3 pg/mL, P < 0.05; Ang II 58.4 ± 62.1 to 14.3 ± 9.0 pg/mL, P < 0.05; and Ald 86.1 ± 38.3 to 80.1 ± 52.6 pg/mL, not significant (NS). Aliskiren reduced BP (153.6/77.2 ± 14.9/10.4 to 130.9/72.2 ± 15.6/9.9 mmHg, P < 0.05). It also reduced UACR (747.1 ± 1121.4 to 409.6 ± 636.8 mg/g, P < 0.05), whereas it did not change eGFR (52.1 ± 29.2 to 51.2 ± 29.3 mL/min/1.73 m(2), NS), LVEF (66.8 ± 7.9 to 66.5% ± 6.8%, NS), IVST (10.1 ± 1.8 to 9.9 ± 1.8 mm, NS), LVPWT (10.0 ± 1.6 mm to 10.0 ± 1.4 mm, NS), or BNP (48.2 ± 46.0 to 54.9 ± 41.1 pg/mL, NS). Aliskiren was effective for BP control and reduced UACR while maintaining eGFR and heart function in elderly CKD patients with hypertension.International Journal of Nephrology and Renovascular Disease 09/2012; 5:125-32. DOI:10.2147/IJNRD.S36451
[Show abstract] [Hide abstract]
- "Direct renin inhibitors can reduce renin activity, even in the presence of elevated renin activity induced by ACE inhibitors or AT1 receptor antagonists. Direct renin inhibitors not only lower blood pressure but also have renoprotective effects and reduce the risk of heart failure (McMurray et al., 2008; Parving et al., 2008). These findings suggest that renin plays a critical role in blood pressure regulation. "
ABSTRACT: The renin-angiotensin system (RAS) is critical for the control of blood pressure by the CNS. Recently, direct renin inhibitors were approved as antihypertensive agents. However, the signalling mechanism of renin, which regulates blood pressure in the nucleus tractus solitarii (NTS) remains unclear. Here we have investigated the signalling pathways involved in renin-mediated blood pressure regulation, at the NTS. Depressor responses to renin microinjected into the NTS of Wistar-Kyoto rats were elicited in the absence and presence of the endothelial nitric oxide synthase (eNOS)-specific inhibitor, N(5)-(-iminoethyl)-L-ornithine, Akt inhibitor IV and LY294002, a PI3K inhibitor and GP antagonist-2A [G(q) inhibitor]. Lisinopril (angiotensin converting enzyme inhibitor), losartan, valsartan (angiotensin AT(1) receptor antagonists), D-Ala7-Ang-(1-7) (angiotensin-(1-7) receptor antagonist) were used to study the involvement of RAS on renin-induced depressor effects. Microinjection of renin into the NTS produced a prominent depressor effect and increased NO production. Pretreatment with G(q) -PI3K-Akt-eNOS pathway-specific inhibitors significantly attenuated the depressor response evoked by renin. Immunoblotting and immunohistochemical studies further showed that inhibition of PI3K significantly blocked renin-induced eNOS-Ser ¹¹⁷ and Akt-Ser⁴⁷³ phosphorylation in situ. In addition, pre-treatment of the NTS with RAS inhibitors attenuated the vasodepressor effects evoked by renin. Microinjection of renin also increased Ras activation in the NTS. Taken together, these results suggest renin modulated blood pressure at the NTS by AT₁ and Mas receptor-mediated activation of G(q) and Ras to evoke PI3K-Akt-eNOS signalling.British Journal of Pharmacology 08/2012; 166(7):2024-35. DOI:10.1111/j.1476-5381.2012.01832.x · 4.84 Impact Factor