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.

New heart failure drug may increase patients' risk of Alzheimer's disease, macular degeneration

In continuation of my update on sacubitril and Valsartan

Patients with mild heart failure stand to benefit from a new drug that can halt the progression of their disease and reduce their risk of cardiovascular-related death. But the drug -- a tablet that combines the agents valsartan and sacubitril, sold under the trade name Entresto by drugmaker Novartis -- may be too good to be true, according to Arthur M. Feldman, MD, PhD, Executive Dean of the Lewis Katz School of Medicine at Temple University (LKSOM), Chief Academic Officer of the Temple University Health System, and Laura H. Carnell Professor of Medicine at LKSOM.

In an article published online December 7th in the Journal of the American Medical Association, Dr. Feldman and colleagues at Thomas Jefferson University and the University of Florida warn that valsartan/sacubitril could theoretically increase patients' risk of Alzheimer's disease and macular degeneration, a blinding condition affecting the retina of the eye. The article raises these concerns about the drug, which was approved by the U.S. Food and Drug Administration in July 2015.

"Basic science data has caused us to speculate that off-target effects of valsartan/sacubitril may cause an exacerbation of Alzheimer's disease and could also exacerbate the course of macular degeneration," Dr. Feldman explained.

Dr. Feldman went on to note that "doctors are prescribing these drugs without knowledge of these theoretical risks."

Valsartan/sacubitril works by inhibiting an enzyme known as neprilysin, which normally plays a critical role in breaking down a wide array of peptides in cells. Among those substances are the so-called natriuretic peptides, which function in regulating scarring and cell growth in the heart when neprilysin is blocked. Because of those activities, valsartan/sacubitril can delay the progression of heart failure in some patients.

Neprilysin, however, also normally degrades amyloid beta, a peptide that can accumulate in the brain, where it contributes to Alzheimer's disease, as well as in the eye, where it is implicated in macular degeneration. The balance between the production and clearance of amyloid beta is crucial to the pathogenesis of Alzheimer's disease and is suspected to influence the development of macular degeneration. In animal models, blocking neprilysin disturbs that balance and exacerbates the development of Alzheimer's pathology.

New heart failure drug may increase patients' risk of Alzheimer's disease, macular degeneration

Entresto drug can be initiated early and safely in heart failure patients with reduced ejection fraction

In continuation of my update on sacubitril/valsartan

Data from the TRANSITION study presented today at the European Society of Cardiology (ESC) Congress in Munich, Germany has shown that Entresto® (sacubitril/valsartan) can be initiated early and safely in a wide range of heart failure patients with reduced ejection fraction (HFrEF) who have been stabilized after hospitalization due to an acute heart failure episode. Patients involved in the study included those with no prior experience of Entresto or conventional HF therapies, as well as those with prior experience of conventional HF therapies.

About half of all heart failure patients have reduced ejection fraction, and optimizing treatment for these patients according to guidelines is critical to reduce the likelihood of another acute episode or dying. However, there is often hesitancy to initiate a new treatment after a hospitalization as these patients are considered 'vulnerable' and unable to tolerate changes in their medication.

"In the weeks following an episode of acute heart failure, patients are very vulnerable and face a high risk of re-hospitalization and death," said Prof. Rolf Wachter, University Hospital Leipzig, Germany and study investigator. "The PARADIGM-HF study showed that sacubitril/valsartan reduces heart failure-related hospitalizations, re-hospitalization and death. TRANSITION shows that sacubitril/valsartan can be initiated early and safely in patients shortly after an acute heart failure episode, providing physicians with added confidence to optimize their care with innovative medicines in heart failure treatment."

In TRANSITION, the safety and tolerability of Entresto were assessed in HFrEF patients after they have been stabilized following an acute heart failure episode. Patients were randomized to initiate Entresto therapy either in the hospital (pre-discharge) or shortly after leaving the hospital (post-discharge). At 10 weeks, more than 86% of patients were receiving Entresto for 2 weeks or longer without interruption and about half of patients in the study achieved the primary endpoint which was a target dose of 200 mg of Entresto twice daily within 10 weeks in both groups. The number of patients who met the primary and secondary endpoints was similar across both treatment arms. The incidence of adverse events and discontinuations of Entresto due to adverse events was also similar in both the in-hospital and the out-patient setting.

"We are encouraged by the findings of TRANSITION which show that Entresto, the new standard of care in heart failure, can be safely initiated in recently hospitalized patients," said Shreeram Aradhye, MD, Chief Medical Officer and Global Head, Medical Affairs, Novartis Pharmaceuticals. "Heart failure is a serious progressive disease with 83% of patients hospitalized at least once for an acute heart failure episode during the course of their condition. Hospitalization provides an opportunity for physicians to optimize heart failure treatment according to guidelines to reduce the likelihood of hospital readmission and death, reduce the burden of hospitalizations, and improve patient outcomes."

Ref : https://www.novartis.com/news/media-releases/novartis-announces-new-data-show-entresto-sacubitrilvalsartan-can-be-initiated-early-safely-hospitalized-patients-after-acute-heart-failure-episode

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