Real-World Challenges to Prescribing Sacubitril/Valsartan for Patients with Heart Failure

At HFSA 2016, Eiran Z. Gorodeski, MD, MPH, director of the Center for Connected Care at the Cleveland Clinic, elegantly presented how his institution implemented the new heart failure therapy sacubitril/valsartan in the real world.

He started by noting that for, patients with chronic symptomatic heart failure with reduced ejection fraction (HFrEF) NYHA class II or III, who can tolerate an ACE inhibitor or angiotensin receptor blocker (ARB), the ACC/AHA/HFSA HF 2016 guidelines recommended replacement by an angiotensin receptor-neprilysin inhibitor (ARNI; sacubitril within entrust) to further reduce morbidity and mortality.

In the presentation, Gorodeski addressed the following questions: How do you implement these guidelines in the real world? How do you navigate the insurance barriers, which are very real? How do you up-titrate the medication?

He described the three packages of Entresto: (1) as 24/26 for 50 mg of sacubitril/valsartan respectively, (2) 49/51 for 100 mg, and (3) 97/103 for 200 mg total. Gorodeski reminded the audience that you can never cut the pills in half because these tablets are not proportionately the same.

Because it is common to switch a patient from an ACE inhibitor to an ARNI, it is important that physicians are aware that patients should never take an ARNI within 36 hours of taking an ACE inhibitor, as this can increase the risk for angioedema.

Gorodeski said cardiologists have been spoiled with powerful and cheap drugs. By making use of the GoogleRx database, he found that you can get furosemide for $4 per month in most places, valsartan for $10 per month, lisinopril for $3 per month, or spironolactone for $4 per month. However Entresto is $12 per day! Almost universally, patients will not be able to afford paying for this out of pocket. This introduces the insurance companies into the situation. Insurance coverage frequently requires prior authorization. He said the drug is 57% covered by Medicare part D and Medicare advantage plans. For those whose insurance does cover it, there tends to be a copay ranging from 0 to $200 per month. However, there are assistance programs available.

Gorodeski then described two Entresto implementation approaches: an aggressive approach and a more cautious approach. In the aggressive approach, physicians just prescribe the drug and in the best case scenario it goes through. Sometimes insurance rejects it, but more commonly a prior authorization is requested. This involves more forms, and hopefully treatment gets approved and the patient can afford the copay and gets the medication.

The more cautious approach is what they have been doing at the Cleveland Clinic. This involves first sending applications to Entresto Central, an entity set up by Novartis that is designed to help with some of these prescribing barriers. Physicians fill out an online form and fax it in, then wait for 2 weeks to find out how much it will cost for the given patient. If prior authorization is required, then Entresto Central will fax the form for the prescriber’s office to fill out and fax back. If the patient finds it unaffordable, then Entresto Central can help refer to various assistance programs.

Gorodeski also elaborated on the topic of up-titration of Ernesto. He described the TITRATION trial, which compared a “conservative” to a “condensed” arm. The conservative arm was up-titrated to 200 mg twice daily over 6 weeks, while the condensed arm was done over 3 weeks. Primary outcome was tolerability, as pre-defined by adverse events: hypotension, renal dysfunction, hyperkalemia, and/or edema. No statistical difference was seen between these two different titration protocols for hypotension, renal dysfunction, hyperkalemia, or angiodema. Further stratification revealed that there as a great likelihood for therapeutic benefit if the drug was up-titrated slowly.

In conclusion, physicians now have a powerful tool at their disposal, but real-world implementation is complex. Careful patient selection, education, and navigation of insurance presents many challenges. Trial data indicates that slowly up-titrating the drug over 6 weeks may be the preferred approach.