New Cardio Drugs Off To Very Slow Start

–Heart failure experts divided over how and when to use Entresto

To many long-time observers, the approval last year of two new cholesterol drugs and a heart failure drug appeared to herald a rebirth of the cardiovascular marketplace after a long period of dormancy. But so far in 2016, those new drugs have hardly made a dent in the marketplace. Physicians have been extremely reluctant to prescribe them, despite loads of encouragement from the companies and thought leaders pushing the drugs.

The problem with the two new cholesterol drugs — the PCSK9 inhibitors evolocumab (Repatha) and alirocumab (Praluent), seems clear. The drugs have been shown to dramatically lower cholesterol levels but they are extremely expensive, with a U.S. retail price over $14,000 a year, and have not yet been shown to improve clinical outcomes. Since gaining approval last summer, the two drugs achieved sales of less than $30 million through February.

In most cases, physicians haven’t found it worthwhile to jump through the hoops required to get insurance companies to pay for the drugs. For now, it seems unlikely that this reluctance will change. But the landscape could change dramatically later this year when the initial results from the first large cardiovascular outcomes trial are announced. Until then it’s a waiting game.

Entresto Scrutinized

The situation with heart failure drug valsartan/sacubitril (Entresto) is more complicated. Unlike the PCSK9 inhibitors, there was no early hype or anticipation about this drug. Entresto wasn’t on most people’s radar until after the initial announcement of the large PARADIGM-HF outcomes trial, which showed a large and highly significant clinical benefit in patients taking it.

But initial sales have been far below most expectations. In the first quarter of 2016, U.S. sales of Entresto amounted to only $17 million, an astonishingly small amount for a drug that was widely expected to be a blockbuster.

The reasons for the poor sales of Entresto are not entirely clear. Four papers appearing in the new issue of JACC: Heart Failure provide a current snapshot of the range of views about Entresto.

By far the most positive perspective on Entresto comes from Milton Packer, MD, of Baylor University in Dallas, the prominent heart failure specialist who was the co-principal investigator of PARADIGM-HF trial and has been a leading proponent of the drug. Recently, as I reported, he argued in an editorial that it was imperative for guidelines to promptly incorporate information from important new trials like PARADIGM-HF. In his new editorial in JACC:Heart Failure Packer outlined specific recommendations for how Entresto should be used in clinical practice.

Packer focused on integrating Entresto into existing treatment strategies. One reason Entresto may be underused, he argued, is because clinicians have focused too heavily on first achieving the highest possible dose of an ACE inhibitor or angiotensin-receptor blocker (ARB). He argued that the evidence in support of this strategy is actually quite weak, and, although it may lead to some clinical benefits, it also results in more adverse events.

He proposed that patients should first be introduced to a low-dose ACE inhibitor or ARB. If this is tolerated, then they should be switched to low-dose Entresto, which can then be gradually adjusted to higher levels. Packer wrote that this strategy “is consistent with the totality of evidence we currently have for the use of neurohormone blockers in the management of chronic heart failure,” because this will achieve the largest reduction in cardiovascular death and fewer cases of renal insufficiency and hyperkalemia.

But much of the heart failure community has been reluctant to adopt Entresto so readily. In a second editorial, Arthur Feldman, MD, PhD, of Temple University in Philadelphia, urged caution in adopting Entresto in clinical practice. He repeated concerns he expressed last year in JAMA that sacubitril may increase the risk for macular degeneration and Alzheimer’s disease. Physicians “should be prudent” using Entresto in patients who are at high risk for dementia. Patients and their family “should be informed of the theoretical risks of cognitive and/or visual dysfunction associated with neutral endopeptidase inhibition so that any cognitive or visual changes can be recognized as early as possible.” Feldman also calls for new trials to study the efficacy of Entresto in patients with more advance heart failure and other populations not well studied in PARADIGM-HF.

In a separate editorial statement, Christopher O’Connor, MD, of Duke University in Durham, N.C., and other editors of JACC: Heart Failure took a more neutral position and outlined some of the reasons for the slow adoption of Entresto. They described the results of PARADIGM-HF as a “grand slam” but said that lingering concerns over angioedema in black patients and about cognitive function “could obviously cause some pause in making this change.” They also suggested that drugmaker Novartis may have hindered uptake by failing to support “registries evaluating special populations and populations not studied in the clinical trial, which would provide further evidence both with respect to comfort and training for practicing clinicians in making the switch from ACE inhibitor therapy to Entresto.”

Cost Effectiveness

The JACC:Heart Failure editors also discussed the issue of cost, which is likely the biggest single obstacle to the uptake of Entresto. In a fourth paper in the journal, researchers at the University of Utah reported the results of a study evaluating the cost effectiveness of Entresto. The results of the study were broadly similar to an earlier cost-effectiveness analysis performed by the Institute for Clinical and Economic Review. At a yearly cost of $4,560 dollars a year, both studies found that the cost to save one quality-adjusted life year was about $50,000, which is considered to be on the borderline of cost-effectiveness. O’Connor and colleagues wrote that the cost makes Entresto “one of the most expensive outpatient heart failure drugs to date.” But they gave a positive response to novel arrangements between the company and insurance companies that would link reimbursement to improvements in patient-related outcomes.

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