The FIX-CHF-5 clinical trial has successfully shown significant improvement in heart failure outcome parameters: increase in peak VO2, improvement of quality of life, as well as exercise tolerance. However, it failed to meet the primary endpoint of anaerobic threshold, which was mandated by the FDA in order to eliminate a placebo effect. Dr. Daniel Burkhoff, Impulse Dynamics’ Medical Director was asked to address this issue at the CCM symposium that took part at the 77th Congress of the German Cardiology Society, Mannheim, 2011.
Q: How would you interpret the failure to meet anaerobic threshold as the primary endpoint? Why is demonstrating an effect on anaerobic threshold so difficult?
A: This measurement was an endpoint that was required by the FDA to try to overcome the potential impact of a placebo effect on measures of exercise tolerance. The problem is that this endpoint is difficult to quantify with certainty and with variability in test performance between sites, the problem is compounded. –This problem is not eliminated even with a well performed test and the use of a core lab; we showed in a blinded comparison between 4 readers in 2 core labs that there is very frequently uncertainty in quantifying this parameter. This is because the reader must look at the plots of oxygen consumption versus exhaled CO2 and pick a breakpoint in the line, and it is not always obvious where this breakpoint is.
Requiring use of anaerobic threshold was an attempt by the FDA to provide a theoretical advantage to the study, but using an unproven endpoint.
Many of the people participating in this symposium may also be aware of the HF-ACTION study sponsored by the NIH where they looked the effect of exercise training on exercise tolerance, peak VO2, and also anaerobic threshold. Similar to the FIX-HF-5 study they also experienced a significant amount of missing data for anaerobic threshold. Although we know that peak VO2 increased following exercise training, we do not know if anaerobic threshold changed because, surprisingly, it was not reported in the main papers of the study. Thus, there are many questions about whether or not using this unproven endpoint in a clinical trial really tells you anything about the effectiveness of a therapy.
Q: Is peak VO2 a critical parameter to performance in HF clinical trials?
A: Peak VO2 has been used in many studies, especially in CRT studies, and very successfully. The FIX-CHF-5 clinical trial results show that we have an increase in peak VO2 that’s almost the same as what you see in most of the studies of CRT. Compared to anaerobic threshold peak VO2 is a different parameter of the same test, but it’s easier to quantify, it’s easier to understand, it has a long history, and it’s been used to gage the efficacy of many therapies for heart failure.
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