Clyde Yancy, MD: Commentary on PARADIGM HF Study Design

Updated:Aug 31,2014

A Commentary by
Clyde W. Yancy, MD, MSc, FACC, FAHA, MACP
Magerstadt Professor of Medicine, Chief, Division of Cardiology
Northwestern University, Feinberg School of Medicine
Chicago, IL

Congratulations to the investigators, study oversight committees and the nearly 9,000 patients who have helped to further enlighten the field of heart failure.

The Study Design

Context is important: the design is the presage to the presentation of the positive results noted.

Two immediate observations:
  1. This is an excellent study design that has been benefitted not only by the collective experience of the leadership, but also by the many lessons learned from a parade of prior negative/disappointing trials. It is a randomized double blind trial with an open label run – in to insure tolerability of the tested agents. It is appropriately powered and has the strongest possible endpoint.
  2. The design is important as it reinforces the validity of the pending results which for this study is topmost priority. A flawed design would color the results and lead to much less enthusiasm. Because of the magnitude of the findings, we must begin with careful scrutiny of the study design. This is a large multinational study with a well phenotyped patient population. It is appropriately powered and used the most conservative rules for interim analyses and stopping rules for evidence of overwhelming benefit – all of which were pre-specified a priori.

This is a well-designed study and the results must be interpreted as valid. Thus, we are either on the precipice of peril, given the magnitude of anticipated change in the standard of care; or we are at the horizon of a true paradigm change as the name of the study would infer.

The Results

The data are dramatically positive and the data are compelling — nearly meeting the advanced billing we’ve seen.

BUT, there are a few important caveats with needed questions that follow —

  1. 70% had NYHA class II or mild HF and another 5% were asymptomatic or NYHA class I; is this in fact a “mild HF trial”?
  2. Of the 8,399 patients completing the trial, 602 were from North America – is this a sufficient sample size to obviate further study in the U.S.?
  3. Only those able to tolerate a full dose of ACE-inhibitor, enalapril 10 mg twice daily, or LCZ (which includes valsartan 160 mg twice daily) were enrolled- was this trial biased towards healthier patients able to tolerate full doses of RAAS blockers?
  4. Of the 10,000 recruited patients, ~ 2,000 did not qualify during the run-in- can we generate a profile of those patients who are not candidates for LCZ?
  5. Fewer than 500 patients in the entire study were “black”; 213 were on LCZ. Given the earlier risk of angioedema borne by African Americans exposed to an ACE-NI, these limited data do not confirm an absence of risk for this important cohort known to be at higher risk for heart failure; can we comfortably prescribe this therapy for African Americans with heart failure without a further safety study?
  6. As in other principally European heart failure trials, the use of device therapy was < 15% for ICD and ~ 7% for CRT? ICD therapy is associated with a clear survival advantage and CRT, especially for mild HF, has both a morbidity (reduction in hospitalization) and mortality advantage. Would the results seen in PARADIGM - HF be replicated in a patient population exposed to a utilization pattern of device therapy as seen in the U.S.?
  7. One must hesitate when evaluating subgroups and the numbers are smaller but older patients, those with NYHA class III & IV symptoms and Black patients all had trends toward a benefit from LCZ but failed to show a statistically significant benefit. Should we be concerned about these important subgroups or respect the overall study results as absolutely definitive?

So now the big question is — what’s next?

  • Rapid approval in the EU and by the FDA with early and strong adoption?
  • Incorporation immediately into clinical practice guidelines?
  • Specific confirmatory studies in the U.S.?

Here are my answers:

It’s time to be bold and do something disruptive about heart failure; too many patients remain at risk for hospitalization, death and a poor quality of life. Let’s take a patient – centric view, now. My own patients and their families are eager to have more options and hesitant to accept unwarranted delays. We shouldn’t be so intoxicated by our current success in treating heart failure that we take a nihilistic or circumspect view of these data. These data are sufficient. We should begin the conversation about implementation. For the still-pending questions we have the research wherewithal to secure answers.

Let’s disrupt the norm. I vote for early adoption of these results.

Clyde Yancy, MD, is a past president of the American Heart Association.

See a scientific summary and more commentary on the PARADIGM-HF results.

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