CORRESPONDENCE: LETTER TO THE EDITOR
The OPT-CHF (Oxypurinol Therapy for Congestive Heart Failure) TrialA Question of Dose
Jacob George, MD and
Allan Struthers, MD*
* Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom (Email: a.d.struthers{at}dundee.ac.uk).
We read the OPT-CHF (Oxypurinol Therapy for Congestive Heart Failure) study results with interest (1). We agree with the authors' comments regarding the possible reasons oxypurinol did not lead to clinical benefits. However, the issue of dose needs to be emphasized further, as the urate fall from baseline with 600 mg oxypurinol in the OPT-CHF study was  26% (2.1 mg/dl [0.12 mmol/l]). Our group has previously demonstrated that with allopurinol 300 mg, a urate fall of 44% (3.0 mg/dl [0.18 mmol/l]) can be achieved; with allopurinol 600 mg, we achieved a mean urate fall of 61% from baseline (4.2 mg/dl [0.25 mmol/l]) (2). Crucially, in this head-to-head comparison, there was a steep dose-response curve between the dose of allopurinol and its beneficial vascular effects (2). This dose-response was also seen in an observational study of heart failure patients, looking at 100 mg versus 300 mg allopurinol (3).
These observations and the degree of urate lowering seen in the OPT-CHF study suggest that the dose of oxypurinol used was well below the optimum dose. In fact, at the Arthritis Advisory Committee Meeting of the Food and Drug Administration (FDA) in June 2004, data from the bioequivalence AAI-US-175 study showed that 600 mg oxypurinol had a relative bioavailability equivalent to 81 mg allopurinol (4). That is less than the usual starting dose of 100 mg and 10% of the maximal FDA-allowed dose of 800 mg.
In addition, clinical outcomes in a 6-month trial may be more determined by changes in volume status rather than by improvements in mechanoenergetic uncoupling, left ventricular remodeling, and endothelial function, which would require a longer duration of treatment to change clinical end points, especially in an outcome trial with only 400 patients. Despite these limitations, oxypurinol did appear to benefit high-risk patients with raised urate levels, a finding that underscores the need for larger studies using larger doses.
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1. Hare JM, Mangal B, Brown J, et al. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study. J Am Coll Cardiol 2008;51:2301-2309.[Abstract/Free Full Text]2. George J, Carr E, Davies J, Belch JJF, Struthers A. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid Circulation 2006;114:2508-2516.[Abstract/Free Full Text] 3. Struthers AD, Donnan PT, Lindsay P, McNaughton D, Broomhall J, MacDonald TM. Effect of allopurinol on mortality and hospitalisations in chronic heart failure: a retrospective cohort study Heart 2002;87:229-234.[Abstract/Free Full Text] 4. Villaba L. Oxypurinol for Symptomatic Gout in Allopurinol Intolerant Patients: Arthritis Advisory Committee Meeting www.fda.gov/OHRMS/DOCKETS/AC/04/slides/2004-4044S1_05_FDA-Villalba.ppt 2002Accessed June 2, 2004.[CrossRef][Web of Science][Medline]
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