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McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. Epub 2014 Aug 30 PubMed.
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Johns Hopkins University School of Medicine
I think that certainly the PARADIGM results are very promising, and heart failure is likely an important contributor to cognitive decline, perhaps even independently of the underlying vascular disease that it represents. Some small studies suggest that patients with heart failure, and especially those with lower blood pressures, seem to have worse cognition (I’m actually leading some ongoing studies now, evaluating the cognitive deficits in heart failure). In PARADIGM, the heart failure patients treated with the angiotensin-neprilysin inhibitor did better overall than did participants treated with an ACE-inhibitor, although they actually had lower blood pressures. However, since neprilysin is a major enzyme responsible for the degradation of Aβ, and animal studies have shown that inhibiting neprilyin increases amyloid levels in the brain, this is certainly something that needs to be evaluated for this new heart failure drug. The PARADIGM study was not long enough to detect any differences in cognitive outcomes, nor was it designed to evaluate cognitive outcomes, but I think it will be important to evaluate surrogate outcomes, which might evaluate Aβ levels, as well as longer-term cognitive outcomes, before knowing the true potential utility of this new drug. Any studies taking these outcomes into account may be difficult to interpret since controlling heart failure has the potential to improve cognition, so they will need to be carefully designed.
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