Aliskiren fails to show benefit for heart failure patients with diabetes

In continuation of my update on Aliskiren   and  Enalapril

 Enalapril  Aliskiren

A subgroup analysis in heart failure patients with diabetes from the ATMOSPHERE trial has failed to show benefit and signals the end of the road for aliskiren in heart failure. The findings were presented for the first time today in a late breaking trial session at Heart Failure 2016 and the 3rd World Congress on Acute Heart Failure.

"This was a subgroup analysis with the inherent limitations of this type of study. It failed to show superiority or non-inferiority of aliskiren over the angiotensin-converting enzyme (ACE) inhibitor enalapril in heart failure patients with diabetes," said principal investigator Professor Lars Kober, a consultant cardiologist at Rigshospitalet - Copenhagen University Hospital in Copenhagen, Denmark.

He continued: "The result may have been positive had the European Medicines Agency (EMA) not asked us to withdraw patients with diabetes from the trial. We will never know, as the angiotensin receptor neprilysin inhibitor LCZ696 has since emerged and bypassed the need for aliskiren."

Aliskiren is a renin-angiotensin-aldosterone system inhibitor that is used in patients with hypertension. The Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failure (ATMOSPHERE) included 7016 patients with heart failure and reduced left ventricular ejection fraction, of whom 2340 were randomly assigned to enalapril plus aliskiren, 2340 to aliskiren, and 2316 to enalapril. Of these, 1944 (27.7%) had diabetes and 5072 (72.3%) were non-diabetics. The main study results were published in April and showed that aliskiren was not superior or non-inferior to standard treatment with an ACE inhibitor.

Following the results of two separate trials, the EMA requested the withdrawal of all patients with diabetes from ATMOSPHERE. The Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) had been stopped after patients with diabetes and a high risk of cardiovascular events were found to have an excess risk of cardiovascular and renal events with aliskiren. The Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) had found a tendency towards harm in patients with diabetes.

The current study is a prespecified subgroup analysis of ATMOSPHERE according to baseline diabetes status. Due to the premature withdrawal of patients with diabetes from the study drug, median follow-up was shorter in those with diabetes than those without (24.1 months versus 46.0 months; p<0.0001).

The investigators found that the effect of aliskiren on the primary endpoint of cardiovascular death or hospitalisation for heart failure did not significantly differ by baseline diabetes status. In those with diabetes, the primary endpoint occurred in 196 (29.5%) patients in the combination group, compared to 216 (33.1%) in the enalapril group (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.71-1.04; p=0.13), and in 172 (27.4%) patients in the aliskiren group (HR 0.82; 95% CI 0.67-1.00; p=0.053 compared with enalapril).

Regarding the safety of aliskiren in patients with diabetes, compared with enalapril it was associated with a lower risk of symptomatic hypotension (6.7% versus 10.0%; p=0.04). Other adverse events were evenly distributed.

Professor Kober said: "Aliskiren monotherapy looked promising in heart failure patients with diabetes, with an 18% almost significant reduction in cardiovascular death or heart failure hospitalisation compared to enalapril. There was a lower rate of symptomatic hypotension and no increase in other adverse events. This suggests that aliskiren could be an alternative for patients who cannot tolerate an ACE inhibitor."

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."

Drug Gives 'New Hope' Against Heart Failure, Expert Says

In a head-to-head comparison, an experimental drug was more effective than standard treatment at preventing deaths and hospitalizations in heart failure patients.

According to the study authors, the trial was stopped early because of the marked benefit of the new drug, dubbed LCZ696. [LCZ696 is an investigational combination drug consisting of two antihypertensives (blood pressure lowering drugs), valsartan (left below) and AHU-377 (right below), in a 1:1 mixture. It is being developed by Novartis. The combination is often described as a dual-acting angiotensin receptor-neprilysin inhibitor (ARNi)]

In the trial, 26.5 percent of those getting the standard medication, enalapril (Vasotec), either died or were hospitalized due to heart failure, compared with 21.8 percent of those on the new drug. Enalapril belongs to a class of blood pressure-lowering medications known as ACE inhibitors.

"LCZ696 could become the new gold standard, replacing ACE inhibitors," said lead researcher Dr. John McMurray, a professor of cardiology at the British Heart Foundation Cardiovascular Research Center at the University of Glasgow, in Scotland.

LCZ696 combines two blood pressure drugs -- an angiotensin II receptor blocker (ARB) and the neprilysin inhibitor known as sacubitril.

"We found that LCZ696 was superior to the gold-standard ACE inhibitor for heart failure -- an ACE inhibitor being the absolute cornerstone of treatment for this problem," he said.

Not only did LCZ696 beat enalapril, but it did that even when added to other treatments, McMurray noted.

"The new treatment was very well tolerated, with no significant safety concerns," he added.

Drug Gives 'New Hope' Against Heart Failure, Expert Says 

Fixed-dose combination of sacubitril and valsartan for heart failure shows differing added benefit

In continuation of my update on Valsartan and Sacubitril

           Valsartan  Sacubitril 

The fixed-dose combination of sacubitril and valsartan (trade name: Entresto) has been approved since November 2015 for adults with symptomatic chronic heart failure with reduced pump function. In its early benefit assessment, the German Institute for Quality and Efficiency in Health Care (IQWiG) derived an indication of considerable added benefit versus the appropriate comparator therapy enalapril from the data: The positive effects regarding mortality, hospitalizations and quality of life largely outweighed the negative effect in non-severe side effects.

In the following commenting procedure, the drug manufacturer subsequently submitted sensitivity analyses and data, and a possible effect modification by the subgroup characteristic diabetes mellitus was pointed out. IQWiG investigated this in an addendum and concluded that there is an indication of a minor added benefit for diabetes patients. For patients without diabetes, in contrast, an indication of considerable added benefit of the drug combination remains.

Sensitivity analyses did not change assessment of the added benefit

The PARADIGM-HF study, on which the dossier was based, contained a so-called run-in phase to ensure that the participants tolerated the target dose of the study medication. About 20 per cent of the participants dropped out of the study in this phase. As noted by IQWiG in its dossier assessment, the rate of adverse events may be underestimated as a result, and more so under the drug combination than in the comparator arm.

To account for this, the manufacturer now presented sensitivity analyses. However, these analyses neither considered the outcomes of interest nor were methodologically adequate to remedy this deficiency. They did therefore not change the assessments from the dossier assessment.

Quality of life: indication of added benefit confirmed

Regarding health-related quality of life and health status, the manufacturer subsequently submitted analyses that increase the certainty of conclusions in comparison with the dossier assessment. For quality of life, there is now an indication of an added benefit both for clinically relevant improvement and for clinically relevant worsening. For health status, there is still no advantage of sacubitril/valsartan. Hence there is still no hint of an added benefit for this outcome.

Diagnosis of diabetes as relevant subgroup characteristic

There was proof of an effect modification in the outcome "mortality": Whereas there was an indication of an added benefit of sacubitril/valsartan in comparison with enalapril for patients without diabetes mellitus, there was no hint of an added benefit for patients with diabetes.

Overall, there were therefore still both positive effects and a negative effect. Due to the effect modification by the characteristic "diabetes", an indication of minor added benefit remains for patients with this disease, whereas there is still an indication of considerable added benefit for patients without diabetes.

Entresto drug shows added benefit in symptomatic chronic heart failure

In continuation of my update on sacubitril and Valsartan   

The fixed-dose combination of sacubitril and valsartan (trade name: Entresto) has been approved since November 2015 for adults with symptomatic chronic heart failure with reduced pump function (ejection fraction). The German Institute for Quality and Efficiency in Health Care (IQWiG) now examined in an early benefit assessment whether this drug combination offers an added benefit for patients in comparison with the appropriate comparator therapy.

According to the findings, the positive effects regarding mortality, necessity of heart failure hospitalizations, and quality of life predominate. These were not put into question by a negative effect in non-severe side effects; hence overall an indication of considerable added benefit can be derived from the data.

Approval study terminated prematurely

In its dossier, the drug manufacturer used data from a randomized controlled trial, which compared sacubitril/valsartan directly with enalapril, each in combination with a beta-blocker. Since a planned interim analysis was able to show after 51 months already that fewer cardiovascular deaths occurred under sacubitril/valsartan, the study was terminated prematurely.

Fewer deaths due to cardiovascular failure

The data from the dossier showed that all-cause mortality was lower under sacubitril/valsartan than under enalapril, which was mainly caused by fewer cardiovascular deaths.

The results regarding the frequency of hospitalizations due to heart failure were also in favour of the new fixed-dose combination; however, these were limited to patients with a lower severity grade (NYHA class I and II). Finally, the data on health-related quality of life also showed an advantage of sacubitril/valsartan.

Entresto drug shows added benefit in symptomatic chronic heart failure: The fixed-dose combination of sacubitril and valsartan (trade name: Entresto) has been approved since November 2015 for adults with symptomatic chronic heart failure with reduced pump function (ejection fraction). The German Institute for Quality and Efficiency in Health Care (IQWiG) now examined in an early benefit assessment whether this drug combination offers an added benefit for patients in comparison with the appropriate comparator therapy.

FDA Approves Qbrelis (lisinopril) Oral Solution for Pediatric Patients 6 Years of Age and Older

We know that,  Lisinopril is a drug of the angiotensin-converting enzyme (ACE) inhibitor class used primarily in treatment of high blood pressure, heart failure, and after heart attacks. It is also used for preventing kidney and eye complications in people with diabetes. Its indications,contraindications, and side effects are as those for all ACE inhibitors.

Lisinopril was the third ACE inhibitor (after captopril and enalapril) and was introduced into therapy in the early 1990s. A number of properties distinguish it from other ACE inhibitors: It ishydrophilic, has a long half-life and tissue penetration, and is not metabolized by the liver.

Now Silvergate Pharmaceuticals, Inc., leader in the development and commercialization of innovative and safe medicines for children, today announced that the United States Food and Drug Administration (FDA) approved Qbrelis (Lisinopril) Oral Solution, the first and only FDA-approved Lisinopril oral solution. Qbrelis is indicated for the treatment of hypertension (high blood pressure) in adult patients and pediatric patients 6 years of age and older, adjunct therapy for heart failure, and treatment of acute myocardial infarction in adults. 

“We are excited to launch our second product focused on pediatric patients and pediatric hypertension” said Frank Segrave, President & CEO, Silvergate Pharmaceuticals, Inc. “Qbrelis provides a ready-to-use oral solution for these children with the additional assurance of an FDA approved medication. As a company, we continue to focus on pediatric medications that are safe, effective, and readily available.”

Qbrelis enables weight-based dosing for children 6 years of age and older who until now have relied on an adjusted adult dose. Qbrelis will be available through an extensive network of pharmacies and a qualified mail order service. For additional information on how to obtain Qbrelis, please call 1-855-379-0382.

About Qbrelis

Qbrelis delivers the trusted efficacy of lisinopril (an ACE inhibitor), the effectiveness of which has been well established in clinical trials.1 As a unique formulation of an oral solution, Qbrelis provides consistent potency and stability in each dose1, in addition to the quality of a product made in accordance with FDA regulations and requirements. People who have trouble swallowing lisinopril tablets may also benefit from Qbrelis.

Qbrelis reduces blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. Control of high blood pressure should be part of a comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

More info @ https://www.drugs.com/history/qbrelis.html