–Valsartan/sacubitril earns Class I recommendation
Cardiology groups in the U.S. and Europe have updated their heart failure guidelines to include much-awaited recommendations for Entresto (the combination of valsartan and sacubitril manufactured by Novartis). The new guidelines offer broad support for the new drug. Since its approval last summer Entresto has struggled to gain a foothold in the large and extremely important heart failure marketplace.
One major factor holding back the drug has undoubtedly been the absence of guideline recommendations supporting use of the drug. With the new guideline updates, Novartis and supporters of the drug in the heart failure community may finally have the weapon they need to drive greater usage of the drug.
The European Society of Cardiology (ESC) Guidelines for the diagnosis and treatment of acute and chronic heart failure have now been published in the European Heart Journal and the European Journal of Heart Failure in conjunction with their presentation at the Heart Failure 2016 and the Third World Congress on Acute Heart Failure in Florence, Italy. The 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure has been published in the Journal of the American College of Cardiology, Circulation, and the Journal of Cardiac Failure. The publication of the U.S. update is timed to coincide with the European guideline. The two guidelines are broadly similar in their recommendations regarding Entresto and another new heart failure drug, ivabradine (marketed as Corlanor in the U.S. by Amgen and as Procoralan and other names by Servier in the rest of the world).
The guidelines for Entresto incorporate the major findings of the pivotal PARADIGM-HF trial. The U.S. guideline states that an ARNI (angiotensin receptor-neprilysin inhibitor) should replace an ACE inhibitor or an ARB “when stable patients with mild-to-moderate heart failure on these therapies have an adequate blood pressure and are otherwise tolerating standard therapies well.” Entresto, of course, is the only available ARNI. The guideline warns that it should not be used in addition to an ACE inhibitor or in patients with a history of angioedema.
Piotr Ponikowski, chairperson of the ESC guidelines Task Force, said that there was “a lot of discussion” about how to adopt Entresto into clinical practice. “We recommend that the drug should replace ACEIs in patients who fit the PARADIGM-HF criteria. The Task Force agreed that more data is needed before it can be recommended in a broader group of patients.”
The co-chairperson of the ESC guidelines, Adriaan A. Voors, said that when used in the right patients Entresto “will have a positive effect on prognosis.” Adoption of the drug “may however be a challenge because patients and doctors are usually reluctant to change a drug they have used for decades.”
Addressing the issue of cost, since ACE inhibitors and ARBs are available as inexpensive generics while Entresto is an expensive branded drug, Voors said that “the cost of the swap will be relatively small compared to the new cancer drugs that extend life for just a few months.”
In the U.S. guidelines Entresto gained a class 1 recommendation. Ivabradine gained a class IIa recommendation to reduce heart failure hospitalization for patients with symptomatic heart failure who are already received recommended treatments, “including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest.”
Inside the Guideline Process
Clyde Yancy of Northwestern University, chair of the writing committee for the U.S. guideline, offered a detailed inside look at the process leading up to the simultaneous release of the focused update with the ESC guideline. Yancy’s statement includes an indirect response to a recent editorial by Milton Packer that was highly critical of the guideline process. Here are his comments:
“In the spring of 2015 the still formulated 2013 ACC/AHA heart failure guidelines writing committee was reconvened to discuss the remarkable PARADIGM HF and SHIFT HF data. We began the discussions RE: guideline updating. Coincident with FDA approval, the leadership of the WG committee made formal application to the parent committee — the ACC/AHA Guidelines Taskforce, to request resources needed to begin the process. That request was granted and we were placed in queue. We began our work in earnest in January 2016. What has transpired over the last 5 months has been a due diligent process that has included an evidence review; drafting of guideline statements- especially in the context of pre-existing statements from the 2013 HF guidelines; internal critique and editing; creation of key “knowledge bytes” that further inform the guidelines and will be appropriate for digitization and mobile applications going forward; a definitive and affirmative vote by the WG; external and extensive peer review with all reviewers comments addressed individually by the leadership of the WG; and final approval by the ACC Board of Trustees, AHA Scientific Advisory Coordinating Committee and the HDSA Executive Committee.
“What is now coming forward represents one of the few times where there has been synchrony in the release of guideline statements by all of the leading organizations. Moreover, though each group functioned independently to generate these statements, the final statements are surprisingly similar, (broadly congruent), including a similar adjudication of the levels of evidence. This further drove the desire to orchestrate a simultaneous release. Our goal with the release is to inform best care for patients. The new therapies for heart failure when added to the predicate evidence based therapies create a plethora of choice now and allows the practitioner to develop a regimen uniquely appropriate for a given patient. Having all of the newest statements available concurrently now better informs that decision making process.
“The generation of clinical practice guidelines is pre-eminent in the functionality and responsibility of our leading scientific organizations. The available evidence informs us that our ACC/AHA/HFSA guidelines when implemented correctly reduce the burden of disease. We have not nor would we ever act in response to any given individual or concern, critiques notwithstanding. This is by design a deliberate and focused process conducted briskly and efficiently on this occasion with completion of the current ACC/AHA/HFSA statement in a timeframe that is faster than any prior iteration of the HF guidelines.
“This is only part I of the focused update; part II is forthcoming at a later date as well as additional enhancement tools to facilitate implementation.
“Our hope now is that the path forward for clinicians and the outcomes for our patients will be benefitted by the work done by these four leading scientific organizations. I see this as a bellwether moment in patient care and look forward to the prompt implementation of this new evidence based guideline directed evaluation and management paradigm for patients with heart failure.
“I am confident that these efforts will make a difference in the lives of patients with heart failure.”