EDITORIAL COMMENT
The Ongoing Search for a Stratified Medicine Approach in Heart Failure*
W.H. Wilson Tang, MD, FACC*
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.
* Reprint requests and correspondence: Dr. W. H. Wilson Tang, Section of Heart Failure and Cardiac Transplantation Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, F25, Cleveland, Ohio 44195. (Email: tangw{at}ccf.org).
The mounting challenges to identify effective pharmacologic therapies for heart failure over the past decade have spurred the continued search for newer therapeutic targets (1). Oxidative stress has consistently been associated with poor outcomes in heart failure and cardiac dysfunction. Animal studies in this area have provided consistent mechanistic support for oxidative stress as a risk factor and therapeutic target rather than a risk marker. However, assessing the degree of oxidative stress in patients with heart failure is challenging, because the pathophysiological processes that lead to it are highly complex.
There has been a longstanding recognition that elevated serum uric acid (SUA) is a surrogate marker for xanthine oxidase activity and a marker of chronic inflammation. It is also associated with impaired diastolic performance, hemodynamic alterations, and poorer outcomes in both acute and chronic heart failure settings (2–5). Uric acid is a metabolic byproduct of purine metabolism from xanthine oxidase activity, and increased circulating levels in the setting of heart failure may be due to either increased generation or decreased excretion. This scenario reflects only one of several mechanisms of reactive oxygen species generation that can lead to potential tissue damage and disease progression. Indeed, SUA levels of 9.5 mg/dl (or 565 mmol/l) or above predicted mortality, and appeared synergistic with reduced left ventricular ejection fraction and peak ventilatory oxygen uptake in predicting 12-month mortality (6).
Inhibition of xanthine oxidase by allopurinol has also been shown to improve endothelial function and clinical presentation in several small-scale mechanistic studies (7,8). In addition, these observations are consistent with insights derived from multivariable models of risk stratification such as the Seattle Heart Failure Model, whereby both SUA levels and allopurinol use were variables in the risk prediction (9).
It is in this context that Hare et al. (10) reported their findings of a carefully conducted multicenter study in this issue of the Journal that examined the role of oxypurinol, the active derivative of allopurinol, in symptomatic patients with heart failure. They found no overall difference between 6 months of oxypurinol and placebo in the percentage of patients that improved, were unchanged, or worsened using a composite end point comprised of heart failure morbidity, mortality, and quality of life. Fortunately, the OPT-CHF (Oxypurinol Therapy for Congestive Heart Failure) investigators have the opportunity to pursue mechanistic understanding of the potential of variations in treatment responses. They confirmed that subjects with elevated SUA levels were associated with poorer outcomes, and with a potential corresponding favorable response to oxypurinol in this cohort.
The OPT-CHF investigators are to be congratulated for completing an excellent trial and publishing their data with careful scrutiny of their results. There can be many reasons why this resulted in an overall neutral study. Subjects in the oxypurinol group were older, had higher mean brain natriuretic peptide levels (374 vs. 336 mg/dl), and shorter 6-min walk distance (257 vs. 278 m) at baseline. Furthermore, despite a largely symptomatic population (New York Heart Association functional class III to IV, 6-min walk distance  267 m), the estimated annualized mortality rate was in the modest range of 8%. This is most likely because this ambulatory patient population was well treated (over 90% with evidence-based drug therapy) and in experienced heart failure centers, and the authors have suggested that this may have potentially dampened the response to oxypurinol therapy. The 6-month treatment duration was relatively short, but prior studies have also indicated improvement in surrogate measures within similar or shorter time periods. The appropriateness of the study drug and its dosage can also play a role, although the reduction in SUA is reassuring.
In interpreting results of the OPT-CHF study, it is important to recognize that conclusions based on the subjective clinical definitions of "benefit versus harm" may be premature and may overlook the scientific foundations of sound therapeutic concepts regarding the role of xanthine oxidase inhibition. Nevertheless, this hypothesis-generated analysis supported the broad concept of "stratified medicine" (11), whereby mechanism biomarkers can identify subgroups of patients with differential responses to a specific therapy. This requires the ability to identify a biological characteristic (so-called "mechanism biomarker") with the potential to induce differential patient responses to a therapy. Also, there should be the need for multiple therapeutic options that have sufficiently heterogeneous responses, and the ability to link therapies to a subset of patients that are more likely to show that different response (11). This concept, although common in the treatment of other diseases, such as infection or anemia, is infrequently adopted in the contemporary management of heart failure, due to the mandate of evidence-based medicine and the "one-size fits all" clinical guidelines approach. Furthermore, there have been many cases in cardiology whereby targeting a specific mechanism can yield to unanticipated adverse events, and many of the current drugs do not provide a clearly defined, mechanistic understanding to demonstrate significant clinical benefits. Therefore, the OPT-CHF investigators have made an important and bold step forward, supporting a stratified medicine approach to heart failure management by suggesting the possible role of SUA as a potential mechanism biomarker.
The proposition made by the investigations, although attractive, is not without obvious challenges. The general concern is related to the mechanistic justification of the approach with the understanding of the beneficial results to date. Proponents would argue that despite being a post-hoc (albeit pre-specified) analysis in this prospective, randomized, placebo-controlled trial, the reported difference is concordant between the improvement in self-reported quality-of-life measurements and the lower death rates with oxypurinol therapy in the subgroup. Indeed, those who improve on average also have greater mean reduction in natriuretic peptide levels than those with unchanged or worsening status. However, critics may point out that this subgroup represented a little bit more than one-third of the already small sample size, and there were significant concerns regarding the observed increase in heart failure hospitalization rates with oxypurinol in the high SUA subgroup. The discordance between the modest improvements in assigned changes in New York Heart Association functional class and marked improvements in patients' self-perceived clinical status captured by the modified Packer score (the primary driver of the "benefit" of oxypurinol use) were also disturbingly troubling. Even when patients with advanced heart failure may desire better quality than quantity of life, it is equally important to have concordance of data all pointing in the same direction (or at least, neutral). In the end, we are still dealing with potentially positive implications from overanalyzing relatively small subgroups with low event rates, hence with much room for error.
The reliability of SUA as a mechanism biomarker over time also needs further exploration. Clearly, xanthine oxidase inhibitors consistently lower SUA levels and other beneficial drugs that affect other pathways may not (12). However, lowering SUA itself may simply be a marker, and drugs independent of xanthine oxidase inhibition may lower SUA without providing the perceived benefits (3). Furthermore, individual data-points of SUA in the placebo arm of the study illustrated relatively large variability in serial measurements of SUA. This may itself affect their reliability as surrogate markers. After all, the overall predictability of changes in SUA with changes in natriuretic peptide levels or clinical events was modest in this report. Other novel inflammatory and oxidative stress markers have been suggested to provide important prognostic information in the heart failure population (13–15), but their potential as mechanism biomarkers have yet to be tested, since risk prediction studies are largely inadequate for the demonstration of their clinical utility to guide therapy (16). Many of these concerns point to the need for prospective validation with larger sample sizes or longer-term follow-up, most likely with the biomarker as a major inclusion criterion.
Based on the results of the OPT-CHF study, the future of xanthine oxidase inhibition in the treatment of heart failure remains unclear, but the relatively longstanding clinical safety profile with allopurinol and the potential value of SUA testing can be an important reassurance for future investigations. The logical next step is to pursue the next phase of clinical study to examine the effectiveness of xanthine oxidase inhibition in patients with advanced heart failure and elevated SUA. But perhaps the most important lesson to be learned in the OPT-CHF study is the proposal of stratified medicine in heart failure—that we should not abandon such valuable academic pursuits of identifying mechanism biomarkers in therapeutic clinical trials, as they form the basis of understanding the human pathophysiology and refinement of treatment strategies.
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Footnotes
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Supported, in part, by 1UL1RR024989 from the National Center for Research Resources, National Institutes of Health. Dr. Tang has previously received research support from Abbott Diagnostics, Inc.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Mehra MR, Uber PA, Francis GS. Heart failure therapy at a crossroad: are there limits to the neurohormonal model? J Am Coll Cardiol 2003;41:1606-1610.[Abstract/Free Full Text]2. Kittleson MM, St John ME, Bead V, et al. Increased levels of uric acid predict haemodynamic compromise in patients with heart failure independently of B-type natriuretic peptide levels Heart 2007;93:365-367.[Free Full Text] 3. George J, Carr E, Davies J, Belch JJ, 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] 4. Baldus S, Mullerleile K, Chumley P, et al. Inhibition of xanthine oxidase improves myocardial contractility in patients with ischemic cardiomyopathy Free Radic Biol Med 2006;41:1282-1288.[CrossRef][Web of Science][Medline] 5. Leyva F, Anker S, Swan JW, et al. Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure Eur Heart J 1997;18:858-865.[Abstract/Free Full Text] 6. Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging Circulation 2003;107:1991-1997.[Abstract/Free Full Text] 7. 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] 8. Farquharson CA, Butler R, Hill A, Belch JJ, Struthers AD. Allopurinol improves endothelial dysfunction in chronic heart failure Circulation 2002;106:221-226.[Abstract/Free Full Text] 9. Levy WC, Mozaffarian D, Linker DT, et al. The Seattle Heart Failure Model: prediction of survival in heart failure Circulation 2006;113:1424-1433.[Abstract/Free Full Text] 10. 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] 11. Trusheim MR, Berndt ER, Douglas FL. Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers Nat Rev Drug Discov 2007;6:287-293.[CrossRef][Web of Science][Medline] 12. White M, Lepage S, Lavoie J, et al. Effects of combined candesartan and ACE inhibitors on BNP, markers of inflammation and oxidative stress, and glucose regulation in patients with symptomatic heart failure J Card Fail 2007;13:86-94.[CrossRef][Medline] 13. Tang WH, Tong W, Troughton RW, et al. Prognostic value and echocardiographic determinants of plasma myeloperoxidase levels in chronic heart failure J Am Coll Cardiol 2007;49:2364-2370.[Abstract/Free Full Text] 14. Kempf T, von Haehling S, Peter T, et al. Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure J Am Coll Cardiol 2007;50:1054-1060.[Abstract/Free Full Text] 15. Weinberg EO, Shimpo M, Hurwitz S, Tominaga S, Rouleau JL, Lee RT. Identification of serum soluble ST2 receptor as a novel heart failure biomarker Circulation 2003;107:721-726.[Abstract/Free Full Text] 16. Maisel A. Biomarkers in heart failure. Does prognostic utility translate to clinical futility?. J Am Coll Cardiol 2007;50:1061-1063.[Free Full Text]
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