Melissa Walton-Shirley, MD


November 09, 2015

I have the same thoughts at every presentation on heart failure with preserved ejection fraction (HFpEF). "Do we really know who or what we are studying?" Just because the patient is female, has an EF of 70%, experiences dyspnea on exertion, and has big ankles (that no one can explain) doesn't always indicate the ever-elusive diagnosis of HFpEF. When a therapy such as isosorbide mononitrate studied in the NEAT trial doesn't work, and even worse, made some patients feel poorly, did nitrates really fail HFpEF? Or did it fail something else?

Only one of four features of HFpEF was required for enrollment in NEAT: HFpEF:[1] HF hospitalization, elevated BNP, increased resting and/or exercise-induced elevation in pulmonary capillary wedge pressure (PCWP), or abnormal diastolic echo features. These good enrollment criteria (but not good enough) still don't boost confidence in the diagnosis. During my 20 years in the cath lab, it was a coin toss as to who would actually have an elevated left ventricular end-diastolic pressure (LVEDP) in the face of normal LVEF when I put them on the table. An occasional diagnosis wound up to be COPD or asthma when I would have bet my 15-lb lead suit on HFpEF.

Here were my succinct thoughts during the press conference and again during the formal presentation of NEAT:

Exercise intolerance is a cardinal feature of HFpEF. Absolutely.

The hemodynamic effects of nitrates may attenuate pulmonary congestion with exertion and improve exercise capacity. Plausible.

Patient-worn accelerometers provide continuous assessment of activity, which may or may not accurately reflect the impact of therapy on a patient's daily life. Seems like a NEAT gadget—pun intended. Seriously, it seems to be an excellent objective measure of exercise tolerance, and I hope to see more data from it in future trials.

The primary end point chosen for this trial was a tally of daily average accelerometer units while the patient was on the maximum treatment dose of daily 120 mg of long-acting mononitrate. Intuitive.

Study design: There was an initial accelerometer observation period for 2 weeks prior to therapy, then accelerometer monitoring on maximum nitrate therapy followed by a 2-week washout period, then more accelerometer monitoring off therapy. In my humble opinion, this was an ingenious trial design. Okay, I admit that sometimes my opinion might not be quite so humble, so sorry for that—kinda.

At the 120-mg isosorbide mononitrate dose, patients were active for fewer hours during the day and also at all doses. Disappointing with a capital D.

There was no effect on the 6-minute-walk or dyspnea scores. Disappointing with a "double" D.

Nitrate use produced a decrease in peripheral blood pressure. Predictable, and the lack of increased deaths or indirect deaths from falling down is always a plus.

More patients discontinued the study drug during the nitrate phase. Again, predictable.

These data do not support the use of long-acting nitrates in HFpEF. DISAGREE: These data conclude that nitrate use is not beneficial in patients with chronic hypertension, obesity, poor conditioning, and shortness of air who suffered hypotension from a combination of diuretics and preload reduction.

Shout it out load: Only when we measure intracardiac pressures in 100% of cohorts to know exactly whom we are testing and then evaluate them on and off therapy will we really know if our findings are related to the cardiovascular system at all or if they are true, true, and unrelated.


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