Aliskiren heart failure trial

Combination therapy with aliskiren and enalapril was associated with more adverse events compared with enalapril alone. As the two drugs together did not produce a better outcome, the trial does not support the combination of an ACE inhibitor and aliskiren. Professor Kober said: "We did a rigorous trial which should have shown that aliskiren is as good as an ACE inhibitor. The drug was never given the chance to demonstrate how good it is because of regulatory interference.

That will never be tested now. This could have been a major problem for patients if the neprilysin inhibitor had not emerged. Use this form if you have come across a typo, inaccuracy or would like to send an edit request for the content on this page.

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Science News. ScienceDaily, 3 September European Society of Cardiology. Aliskiren: Trials on heart failure and acute coronary syndrome. Retrieved January 12, from www. Featured Content. Have High Blood Pressure? Narrowed or blocked coronary arteries can result in a heart attack or sudden cardiac death. A study Continuous data are expressed as mean or median. The all-cause mortality varied between 1. Both all-cause mortality and cardiovascular mortality were slightly higher in intervention group than control group.

The I 2 values of both outcomes were small, indicating low risks of inter-study heterogeneity. To the best of our knowledge, this is the first meta-analysis of aliskiren for heart failure patients. Our results show that aliskiren is not superior to placebo in reducing all-cause mortality or cardiovascular mortality of heart failure patients.

Adverse events are slightly higher in aliskiren group, but the differences have not reached statistical significance. Although RAAS activation is a compensatory action to the decreased cardiac output in heart failure patients and the blockage of RAAS with the drugs such as ACE inhibitor, ARB and MRA have yielded great progresses in the last decades; the direct inhibition of renin does not bring benefits to the heart failure patients who have received optimal medications.

Renin, a amino acid protease polypeptide secreted from renal juxtaglomerular apparatus to blood circulation, serves as the first rate-limiting substance of RAAS [ 13 ]. It is also the first orally active nonpeptide with a plasma half-life of about 24 hours [ 9 ]. Our findings do not support the role of direct renin inhibitor aliskiren as a favourable drug for heart failure patients who have received optimal medications, although some studies do show that it decreases plasma renin concentration and activity.

Aliskiren has also been reported to not decrease the mortality and adverse events of patients with myocardial infarction, prehypertension, or type 2 diabetes mellitus [ 14 — 16 ]. Aliskiren, either used alone or combined with standard medical therapies containing ACE inhibitor or ARB, is associated with more adverse events including hypotension, renal dysfunction, and hyperkalaemia in heart failure patients [ 6 ].

These adverse events such as hypotension seem to be the side effects of excessive inhibition of RAAS.

It appears that there is an unknown upper limit for the benefits of RAAS blockade [ 17 ]. In other words, it's critical to know whether or not there is an optimal inhibition of renin level so as to achieve the best outcomes for heart failure patients.

Another perplexing observation is that although aliskiren decreases the natriuretic peptides level of heart failure patients, it does not reduce the all-cause mortality or cardiovascular mortality.

The results are contradictory to the conventional view on natriuretic peptides which have been widely recognized as one of the most powerful predictors of the prognosis of heart failure patients [ 9 ]. The failure of aliskiren has brought to us some implications for future development of RAAS inhibitors. Firstly, a RAAS inhibitor may not suit all heart failure patients. Since aliskiren has been associated with adverse events such as hypotension and hyperkalaemia, it may be best indicated for the heart failure patients who have a past history of hypertension and laboratory examination of hypokalaemia [ 18 ].

Most studies of our meta-analysis have included heart failure with reduced ejection patients. Nevertheless, a recently published small-scale RCT has preliminarily shown that aliskiren reduce arterial stiffness and left ventricular diastolic function in elderly hypertensive patients during a follow-up of 6 month [ 19 ].

The study indicates that aliskiren is possible to be effective for heart failure with preserved ejection fraction patients, rather than those with reduced ejection fraction. In other words, drug designers should bear in minds that a RAAS inhibitor may be pharmacologically effective for a small proportion of heart failure patients, while trial designers should remember that the inclusion criteria of a RCT should be very carefully designed so that it best covers the most indicated patients.

Secondly, the inhibition of RAAS may suffer from ceiling effects. The direct inhibition of renin is supposed to bring with the most effective inhibition of the RAAS. In fact, the renin concentration and activity do decrease following the use of aliskiren, but this kind of inhibition is seemingly excessive.

Maybe the question that we should keep asking ourselves is that what is the best level of controlling renin and RAAS system, so as to improve the prognosis of heart failure patients to the maximum extent? Thirdly, natriuretic peptides including BNP and NT-proBNP have been extensively recognized as the most important prognostic factor of heart failure patients, but the studies of aliskiren have warned us that this kind of reduction of natriuretic peptides may not be associated with better outcomes in heart failure patients.

Heart failure may be a syndrome that requires a comprehensive management strategy rather than relying on a simple laboratory indicator. Our study is limited by some factors. Firstly, we restricted our publication language to English, so the studies published in other languages were not included in our meta-analysis. Secondly, we identified moderate to high heterogeneity in some adverse events such as renal dysfunction, hypotension and hyperkalaemia, probably attributable to the comparatively low event rates in both intervention group and control group.

In conclusion, our results show that currently available randomized controlled trials do not support a beneficial role of aliskiren in improving the prognosis of heart failure patients. The primary outcomes of this study were all-cause mortality and cardiovascular mortality. We also collected the adverse events reported in the eligible studies. We limited our search to English publications. A study was included if it 1 included heart failure patients 2 administered aliskiren to the intervention group, 3 had a control group, 4 reported all-cause mortality, cardiovascular mortality or adverse events.

Exclusion criteria were as follows: 1 not enrolling heart failure patients, 2 conference abstract, 3 review or editorial articles, 4 trial rationale and design, 5 no control group, 6 not reporting outcome data.

Discrepancies were resolved by consensus. The following basic characteristics of eligible studies were included: first author, publication year, sample size, age, sex, left ventricular ejection fraction LVEF , natriuretic peptide level, estimated glomerular filtration rate eGFR , comorbidities, medication use and follow-up period. All-cause mortality, cardiovascular mortality and adverse events were extracted for meta-analysis.

Heterogeneity across trials was evaluated with Q-statistic and I 2 -statistic [ 7 ]. I 2 represents the percentage of total variation across studies resulting from heterogeneity rather than chance. Begg's test and Egger's test were performed to identify small-study effects. Publication bias was visually estimated by a funnel plot.

All analyses were performed with Stata