Doctors urge caution on Novartis’ heart failure drug

The publication of the PARADIGM-HF trial of Novartis LCZ696 has led to suggestions it will transform chronic heart failure treatment, but commentators warn that its benefits may be being trumpeted too early.

PARADIGM-HF was specifically designed to test the hypothesis that adding a neprilysin inhibitor to ACE inhibitor therapy – already a pillar of CHF management – would boost its benefits sufficiently to warrant widespread change in clinical practice.

With the data from the trial suggesting a sizeable improvement with LCZ696 (sacubitril and angiotensin receptor blocker valsartan) over the ACE inhibitor enalapril on cardiovascular mortality, clinicians have already started talking about changing treatment guidelines –  and analysts have predicted multibillion dollar sales for the drug at peak.

Some cardiologists are not quite as convinced, however, and questioned for example why with such a dramatic impact on CHF, LCZ696 did no manage to reduce atrial fibrillation (AF), a key characteristic of worsening heart failure.

Dose discrepancy?

Other questions raised about the trial included that the target dose of enalapril deployed – 10mg twice-daily – was lower than the maximal dose (10mg-20mg twice daily) recommended in guidelines while the valsartan portion of LCZ696 could be pushed to its maximum of 160mg twice-daily.

That could mean that a full dose of valsartan was actually being compared with a moderate dose of enalapril, suggest commentators on the New England Journal of Medicine website, where the results of PARADIGM-HF are published.

Martin Nitschke, a nephrologist from Germany, comments that patients on Novartis’ drug had significantly lower systolic blood pressure than those on enalapril and proper dosing “may be one reason for the better outcome of the LCZ696 arm of the study.”

Run-in, and early termination

Another question raised by cardiologists at the European Society of Cardiology (ESC) meeting in Barcelona this week was how significant a run-in period in the trial – designed to weed out patients who could not tolerate therapies – was in affecting the safety outcomes data.

Patients were switched from their current therapy to enalapril 20mg/day and – if they developed side effects – were dropped. Similarly, patients were switched to LCZ696 therapy and once again were not randomised if they could not tolerate the drugs.

That means that the adverse event rates seem in the study will likely be underestimated compared to what will be encountered in clinical practice, while the patient population is skewed in favour of those who can tolerate valsartan/sacubitril.

“Drug run-in periods are a controversial study-design choice – one that I believe must unequivocally be abandoned,” says physician Vinay Prasad in a blog on the NEJM’s CardioExchange site.

One safety issue raised in the comments by anaesthesiologist William Foster is that sacubitril’s mode of action – inhibiting the neprilysin enzyme – could have some crossover into other metabolic pathways with unintended consequences.

Anaesthesiologist William Foster and physician Ivan Boyadzhiev warn that neprilysin is also elevated in Alzheimer’s and seems to play a role in processing beta-amyloid, which clumps to form the plaques that are characteristic of the disease.

“Knockout mice lacking the gene for neprilysin show an accelerated development of amyloid plaques and neurobehavioral abnormalities,” says Foster, while Boyadzhiev expresses the concern that the enzyme may play a role in regulating arterial tone and cerebral blood flow.

The study was terminated too early to allow for proper monitoring of these and other potential side effects, suggests Foster.

Pricing concerns?

Almost immediately after the results were trumpeted, notes of caution were also being sounded on the impact of LCZ696 on cash-strapped healthcare budgets, given ACE inhibitors are generic medicines and extremely cheap.

The price of LCZ696 is not yet known of course. However, given the ongoing debate about the price of new drugs such as Gilead Sciences’ hepatitis C therapy Sovaldi (sofosbuvir) – and the massive CHF patient population worldwide – any recommendation to switch wholesale from current practice must be done “responsibly”, according to Michel Komajda of Groupe Hospitalier Pitié-Salpêtrière in France, who was the discussant for the PARADIGM-HF results at the ESC meeting.

Health economics studies will be needed to gauge the cost of preventing cardiovascular outcomes with LCZ696, he added.

“The response to PARADIGM-HF has been positive partly because it has been a long time any new drug has been shown to improve mortality in patients with HF,” says Prasad in the blog, which has prompted a vigorous debate with Milton Packer of University of Texas Southwestern, one of the principal investigators in the trial.

“Our desire to find better options for these patients does not mean we should lower the standards for what counts as a good trial.”

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