John Mandrola


August 30, 2014

I could go on and on about the epidemiology of congestive heart failure due to left ventricular dysfunction. It suffices to say it's a huge problem—for patients and healthcare systems. Everyone knows that. Everyone also knows there hasn't been an exciting new therapy in years. This is why there has been great anticipation since the PARADIGM-HF trial,[1] a comparison of the new combination drug LCZ696 (Novartis) with enalapril, was stopped due to benefit early this year.

Today was the big day. PARADIGM-HF was released this afternoon at the European Society of Cardiology2014 Congress . Steve Stiles has the details on heartwire .

Here are some of my early impressions. I see 10 things that make the trial noteworthy and four reasons to pause the celebration.

Here are 10 key features of Paradigm-HF:

  1. It was a well-conceived and legitimate comparison—placing the novel drug against the well-studied ACE inhibitor enalapril given at effective doses.

  2. The novel drug LCZ696 has biologic plausibility for improving outcomes in patients with heart failure.

  3. There were large numbers of patients, more than 4000 in each group, and patients were recruited from across the globe, although only one in five were women.

  4. Enrolled patients were typical of those seen in practice and were well-matched in baseline characteristics. There was a wide range of functional class; average EF was 30%, and 60% of patients had ischemic cardiomyopathy.

  5. Both groups of patients were on good baseline CHF therapy. Beta-blockers were used in approximately 93% of patients in both groups. Other CHF therapies were used in typical proportions.

  6. The primary outcome of death from cardiovascular cause or first hospital admission for worsening heart failure occurred in 914 of 4187 (21.8%) of patients on LCZ696 and 1117 of 4212 (26.5%) patients on enalapril. The absolute difference was 4.7%, the number needed to treat 21, and the percent same result was 95.3%.

  7. Importantly, although the primary outcome was a composite (always a cautionary note), the hard end point of death from cardiovascular cause drove the significance as much as the softer end point of first hospitalization for worsening heart failure.

  8. The secondary outcome of death from any cause seems most notable: 711 of 4187 (17%) of patients on LCZ696 died during follow-up compared with 835 of 4212 patients (19.8%) on enalapril. The absolute difference 2.8%, the number needed to treat 35, and the percent same result was 97.2%.

  9. Quality of life and functional status also improved significantly on LCZ696, which is remarkable given the double-blinded nature of the trial.

  10. On safety, LCZ696 held up well. There were no differences in drug discontinuation, creatinine levels, hyperkalemia, and cough. The LCZ696 group had 5% more patients with symptomatic low blood pressure.

That's a lot of upside. Given the millions of patients with heart failure and its associated morbidity and mortality, absolute differences in the 3% to 5% range add up to a great benefit.

Here are some thoughts that might give one pause.

  1. The FDA has not reviewed this data. Yes, the trial results were impressive and there is no reason to question data integrity, but the past has shown that things sometimes change with more scrutiny. I doubt it; but you don't know yet.

  2. From a pragmatic patient-level view of the absolute differences, the question of value will come to the fore. Namely, how much will Novartis charge, how much will insurers pay, and when patients are faced with higher costs, how will each person judge NNTs of 21 to 35? I don't know the answer to that question, but the fact that the percent same result is greater than 95% will factor in. Four dollars per month is much different from hundreds per month, especially when you consider that these patients have many other meds to take.

  3. The blood-pressure difference does not seem like much, but it is. Here is why: Hype will propel this drug into widespread use. This means LCZ696 will be extended to patients outside the study's inclusion criteria, such as the elderly and frail. In the real world, the facts that the mean age of enrolled patients in PARADIGM-HF was 64 years and that the enrolling process excluded patients who would not tolerate such drugs will not be emphasized. Trust me . . . hype has incredible power.

  4. The final thing that worries me is that the excitement over this pill will take our eyes off the treatment of the entire person with heart failure. I see this all the time. Doctors get busy adjusting hordes of medicines and do not see the 18-in neck of sleep apnea, the wasting skeletal muscles of deconditioning, or the frown of depression. Improving outcomes in people with heart failure is about caring for all associated diseases. But this isn't the drug's fault; it's just a fact of clinical practice.

That said, it is exciting to have a new drug that works by novel and plausible mechanisms. The science is nifty, even if it's not electrophysiology.



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