Gout Worsens Heart Failure Outcomes - full text below
Published: August 09, 2010
* Explain that a large Canadian cohort study showed that hospital readmission rates and death were higher for heart failure patients with a history of gout, an acute episode of gout within 60 days, and those within this subgroup on allopurinol.
* Caution that an observational study cannot establish causality.
A history of gout worsens the outlook for patients with heart failure, but its traditional treatment can improve the outcome, a nested case-control study found.
Heart failure patients with a remote history of gout were at increased risk for a composite endpoint of readmission for heart failure or death, with an adjusted rate ratio of 1.63 (95% CI 1.48 to 1.80, P<0.001), according to George Thanassoulis, MD, and colleagues at McGill University in Montreal.
However, they reported in the Aug. 9 issue of Archives of Internal Medicine, allopurinol use was beneficial in those with a history of gout, resulting in:
* Reduced heart failure admission or death, adjusted RR 0.69 (95% CI 0.60 to 0.79, P<0.001)
* Reduced all-cause mortality, adjusted RR 0.74 (95% CI 0.61 to 0.90)
Elevated levels of serum uric acid and increased oxidative stress in patients with heart failure have been linked with increased mortality.
Small clinical studies have suggested potential benefits of the xanthine oxidase inhibitor allopurinol in cardiac function among patients with heart failure. And although a recent clinical trial failed to show benefits for the drug in the overall heart failure population, some positive effects were seen in a subgroup with elevated uric acid levels.
To clarify these conflicting results, Thanassoulis and colleagues analyzed data from a population-based, retrospective cohort of patients ages 66 and older with symptomatic heart failure, using administrative databases from the Quebec universal health insurance program.
The study population of 25,090 patients discharged from the hospital with a diagnosis of heart failure was followed for a median of 2.1 years.
For each case, up to 10 controls were randomly sampled and matched for time of the event.
Among the 25,090 patients included, there were 14,327 events for the composite outcome of heart failure readmission or death, and 11,674 for all-cause mortality.
Not only was a remote history of gout associated with adverse outcomes, so was an acute episode within the previous 60 days, with adjusted relative rates of 2.06 for heart failure readmission or death (95% CI 1.39 to 3.06, P<0.001) and 1.76 for all-cause mortality (95% CI 1.08 to 2.86, P=0.02).
In the overall heart failure population no significant association was seen between allopurinol use and heart failure readmission or death. However, allopurinol was associated with a decrease in the composite outcome for those with a history of gout.
The association of gout and adverse heart failure outcomes seen in this study persisted after adjustment for many potentially important confounders, including prior myocardial infarction, renal failure, and gout treatments such as nonsteroidal anti-inflammatory drugs that can precipitate heart failure.
Possible mechanisms by which allopurinol might be helpful in heart failure patients with a history of gout include improvements in myocardial contractility and endothelial function, while reductions in uric acid may further reduce afterload, according to the investigators.
The authors noted that because their study was observational, the results should be interpreted with caution.
"Given the possible serious adverse events associated with allopurinol, only a large randomized trial among patients with hyperuricemia and [heart failure], both with and without a history of gout, can evaluate the risks and benefits of such a strategy and provide the required evidence for the use of allopurinol in clinical practice," they stated.
Other limitations of the study include its reliance on administrative data with misclassification possible, lack of information on factors such as obesity and alcohol use, and possible confounding by indication.
Nonetheless, they concluded, "Given the limited novel treatment options available for [heart failure] patients, allopurinol may be an important therapeutic consideration in certain subgroups of patients."
The lead author was a recipient of the Fonds de Recherche en Sante du Quebec MSc Award for Medical Professionals, and two coauthors received the FRSQ Chercheur-Boursier Award.
They reported no financial disclosures.
Primary source: Archives of Internal Medicine
Thanassoulis G, et al "Gout, allopurinol use, and heart failure outcomes" Arch Intern Med 2010; 170: 1358-64.
Gout, Allopurinol Use, and Heart Failure Outcomes
George Thanassoulis, MD; James M. Brophy, MD, PhD; Hugues Richard, MSc; Louise Pilote, MD, MPH, PhD
Arch Intern Med. Aug 9/23 2010;170(15):1358-1364.
Background Hyperuricemia is associated with reduced survival among patients with heart failure (HF), but the effect of gout on HF outcomes is unknown. A recent randomized trial suggested that allopurinol may reduce adverse outcomes among patients with hyperuricemia and HF. Our objective was to determine whether gout and allopurinol use are associated with HF outcomes.
Methods Time-matched, nested case-control analysis of a retrospective cohort of patients with HF who were 66 years or older using health care databases in Quebec, Canada. The primary outcome measure was a composite measure of HF readmission and all-cause mortality. The secondary outcome measure was all-cause mortality. Rate ratios were calculated using conditional logistic regression and adjusted for known prognostic factors.
Results Of the 25 090 patients in this cohort, 14 327 experienced the primary outcome. Both a remote history of gout and an acute episode of gout (within 60 days of the event date) were associated with an increased risk of HF readmission or death (adjusted rate ratio, 1.63; 95% confidence interval, 1.48-1.80; P < .001 and 2.06; 1.39-3.06; P < .001, respectively). Continuous allopurinol use (>30 days of continuous use) was not associated with the primary outcome among the overall population with HF (adjusted rate ratio, 1.02; 95% confidence interval, 0.95-1.10; P = .55) but was associated with reduced HF readmissions or death (0.69; 0.60-0.79; P < .001) and all-cause mortality (0.74; 0.61-0.90; P < .001) among patients with a history of gout.
Conclusions Patients with HF and a history of gout represent a high-risk population. Among such patients, the use of allopurinol is associated with improved outcomes.
Among patients with heart failure (HF), elevated serum uric acid levels1-3 and increased oxidative stress4-6 have been associated with increased mortality, implicating xanthine oxidase as a possible therapeutic target.7-9 Elevated serum uric acid levels predispose patients to gout, which has been shown to be an independent risk factor for ischemic heart disease and mortality.10-11 Whether a similar association exists between gout and HF mortality is unknown.
Allopurinol, an inhibitor of xanthine oxidase, may be a novel therapeutic agent for HF. Allopurinol reduces uric acid levels, prevents acute gout, and acts as an antioxidant, which could be beneficial among HF patients.8 In animal models of HF, allopurinol has been shown to improve cardiac function,12-15 reduce left ventricular dimensions,16-18 and reduce mortality.19 Small clinical studies with allopurinol have demonstrated improvements in cardiac function,20-21 reductions in endothelial dysfunction,22-23 reductions in oxidative stress,24 and improvements in surrogate outcomes among HF patients.25 Although a recent clinical trial failed to demonstrate any improvement among the overall HF population, it suggested possible benefits among the subgroup with elevated uric acid levels.26
Given the potential of xanthine oxidase inhibition in HF and the conflicting reports regarding the benefits of this strategy, we conducted a large, population-based observational cohort study using a nested case-control analysis to evaluate the effect of a remote history of gout, episodes of acute gout, and allopurinol use on HF readmission and mortality among HF patients. Because of the recently suggested benefits among patients with hyperuricemia, we specifically evaluated the effect of allopurinol in patients with a history of gout.
In this population-based study of 25 090 symptomatic HF patients, we have shown that a remote history of gout and an acute episode of gout are risk factors for HF readmission and/or death. The association with gout and adverse HF outcomes persisted despite adjustments for many important confounders such as prior myocardial infarction, renal failure, daily diuretic dose, and gout treatments known to precipitate HF such as NSAIDs and corticosteroids. In addition, among patients with HF and a history of gout, allopurinol use was strongly associated with improved outcomes.
Our results are consistent with those of a multicenter, masked, placebo-controlled randomized trial addressing the use of oxypurinol, the active metabolite of allopurinol, in HF.26 This trial, conducted in 405 patients, showed that the addition of oxypurinol to standard HF therapy did not produce clinical improvements in HF status after 24 weeks in the overall cohort, but did demonstrate a trend toward improved outcomes among patients with elevated serum uric acid levels. However, because of the small number of patients, these subgroup analyses did not reach the threshold for statistical significance. In our study, using remote history of gout as a surrogate for symptomatic elevations in uric acid levels, we found that allopurinol use was associated with clinically and statistically significant reductions in HF readmission or death. Our population-based study adds important evidence that allopurinol may be beneficial in a subset of patients with HF, symptomatic hyperuricemia, and gout.
Inhibition of xanthine oxidase has been hailed as a promising therapeutic strategy for HF. Several animal models and subclinical studies have shown clinical benefits using various xanthine oxidase inhibitors including allopurinol. However, results among human subjects have been quite variable with respect to important outcomes such as HF readmission and death. In the Seattle Heart Failure Model,44 allopurinol was associated with an increased risk of death or urgent transplantation. Similarly, a retrospective analysis of a UK cohort with HF demonstrated that high-dose but not low-dose allopurinol was associated with a reduction in HF hospitalization and death.45 Previous analyses of allopurinol use in HF have had several methodologic limitations. Specifically, these studies did not evaluate patients with a documented history of gout and may also have been biased by residual confounding and measurement errors. In our study we carefully defined a history of gout according to comorbidity, physician visits, and anti-inflammatory medications and evaluated drug exposure using a nested case-control approach.
The observed association between allopurinol use and HF outcomes among patients with gout could be mediated by reductions in uric acid levels or by decreases in superoxide anions since these biochemical markers have been associated with adverse outcomes in HF patients.1-3,24 Our observation of a protective association with allopurinol use only among patients with HF and gout indicates that the effects of allopurinol may be evident only in patients with markedly elevated xanthine oxidase activity. In animal models of HF, experimentally induced ventricular dysfunction led to upregulation of xanthine oxidase by 50% to 400% with resulting elevations in superoxide ions.46-48 Increased oxidative stress causes inactivation of nitric oxide, which can worsen endothelial dysfunction and reduce myocardial contractility.14, 17-18 Allopurinol has been reported to reverse many of these adverse effects.12-18,47-48 Allopurinol improves myocardial contractility by restoring myocardial calcium sensitivity and ß-adrenergic responsiveness in HF.49 It may also improve endothelial dysfunction, leading to vasodilatation and reductions in afterload.23-24,45 George et al24 showed that the administration of allopurinol to HF patients led to marked improvements in endothelial function by decreasing oxidative stress. Decreases in uric acid levels may further reduce afterload since uric acid has been shown to stimulate renin release.50 A recent randomized trial in adolescents with hypertension demonstrated lowered plasma renin activity, peripheral resistance, and blood pressure after 4 weeks of treatment with allopurinol.51
On the basis of our results, patients with HF and a history of gout appear to represent a high-risk subgroup owing to elevated xanthine oxidase activity. Therefore, a history of gout among HF patients may be an indication for low-dose allopurinol therapy unless an important contraindication arises (ie, renal failure). Whether asymptomatic patients with hyperuricemia and HF should also be treated with allopurinol to reduce xanthine oxidase activity is unclear. Because of the observational nature of our study, our results should be interpreted with caution and should not be used as evidence supporting the clinical use of allopurinol in HF. Given the possible serious adverse events associated with allopurinol, only a large randomized trial among patients with hyperuricemia and HF, both with and without a history of gout, can evaluate the risks and benefits of such a strategy and provide the required evidence for the use of allopurinol in clinical practice.
Some limitations of our study merit discussion. First, this was an analysis of administrative data, so misclassification of some exposures, covariates, and outcomes is always possible. We used validated end points of HF readmission and death to minimize misclassification of outcomes. The diagnosis of gout using administrative databases may also be prone to misclassification. We chose an inclusive definition of gout that accounted for any primary or secondary diagnosis in an effort to include all patients with a possible remote history of gout. In addition, we performed a sensitivity analysis using variable definitions of gout to ensure that our results were robust to our definition of gout. Nonetheless, despite our efforts, some patients may have been misclassified according to gout status, which could have biased our effect estimates for remote gout and may have led to some residual confounding. Second, despite adjustments in our models for many important confounders such as renal failure, myocardial infarction, history of gout, daily diuretic dose, and comorbidities (using the Charlson index), some degree of confounding may still modify our estimates. We could not adjust for obesity, alcohol use, or socioeconomic status since these variables were not available. We also could not adjust our models for ejection fraction because this covariate was not available. However, on the basis of the pathophysiological mechanisms of allopurinol, which is known to improve endothelial function, allopurinol should have similar benefits in systolic and diastolic HF. Third, because we used prescriptions to assess drug use, we could not account for use of over-the-counter drugs (such as NSAIDs) and could not measure compliance with prescribed drugs. Fourth, because we compared allopurinol users with nonusers, our results may be biased by confounding by indication. Because we were studying the unintended effects of allopurinol use on HF outcomes, our estimates are less likely influenced by such confounding. However, it is possible that in certain patients with HF and gout, lack of allopurinol use (or stopping allopurinol use) may itself represent a risk factor for adverse HF outcomes. Fifth, our analysis of acute gout may be inflated owing to reverse causality. We attempted to limit this problem by adjusting for covariates that suggested a recent worsening in HF (eg, a recent visit to a physician or ED for HF or a recent increase in diuretic dose).
In conclusion, our results indicate that patients with HF and a recent or remote history of gout represent a high-risk subgroup, and in these high-risk patients allopurinol use appears to be associated with important reductions in adverse outcomes. Given the limited novel treatment options available for HF patients, allopurinol may be an important therapeutic consideration in certain subgroups of patients with HF. A randomized trial evaluating allopurinol use among patients with increased xanthine oxidase activity based on elevated serum uric acid levels or increased markers of oxidative stress may help to clarify the role of allopurinol in HF.
The study population consisted of 25 090 patients (mean age, 77 years) discharged from the hospital with a recent diagnosis of HF. Median follow-up was 2.1 years. During cohort follow-up, there were 14 327 events for the composite outcome measure of HF readmission or death and 11 674 events for all-cause mortality. Of the 14 327 events for the composite outcome measure, 7581 (52.9%) were for an HF readmission and 6746 (47.1%) were for mortality.
The baseline characteristics of cases and controls are presented in Table 1. Case patients were older (mean age, 78.7 years) and had a higher burden of comorbidities based on the modified Charlson index, particularly a higher prevalence of renal failure and prior myocardial infarction.
ASSOCIATION BETWEEN HISTORY OF GOUT AND HF READMISSION OR DEATH
For the combined outcome measure of HF readmission or death, a remote history of gout was recorded in 4.6% of controls and 7.3% of cases. Compared with patients without gout, patients with a remote history of gout were at increased risk for the composite outcome of HF readmission or death (adjusted RR, 1.63; 95% CI, 1.48-1.80; P < .001). Because of limitations in the ascertainment of gout in administrative databases, we also evaluated 4 other definitions of gout in varying degrees of stringency to determine the robustness of the association. Irrespective of the definition used to determine a history of gout, there was a marked and statistically significant association between gout and HF outcomes (Table 2).
ASSOCIATION BETWEEN ACUTE GOUT AND HF READMISSION OR DEATH
For the combined outcome measure of HF readmission or death, there were 38 cases (0.4%) and 155 controls (0.1%) with a recent acute episode of gout in the 60 days before the event date. An acute episode of gout was associated with an increased risk of adverse HF outcomes (adjusted RR, 2.06; 95% CI, 1.39-3.06; P < .001 for HF readmission or death; and 1.76; 1.08-2.86; P = .02 for all-cause mortality) (Table 3).
ASSOCIATION BETWEEN ALLOPURINOL USE AND HF READMISSION OR DEATH
In the overall HF patient population, we found no statistically significant association between allopurinol use and the combined outcome of HF readmission or death (adjusted RR, 1.02; 95% CI, 0.95-1.10; P = .55). Results for HF readmission or death are summarized in Table 4. When we limited the outcome measure to all-cause mortality, results were similar (data not shown).
However, among patients with a remote history of gout, allopurinol use was associated with reduced HF readmission or death (adjusted RR, 0.69; 95% CI, 0.60-0.79) and reduced all-cause mortality (0.74; 0.61-0.90) (Table 5). We also found that among allopurinol users, the association between gout and adverse HF outcomes that we observed in the overall HF population was no longer statistically significant (adjusted RR, 0.95; 95% CI, 0.84-1.08 for HF readmission or death). We did not detect any differences in effect among men and women treated with allopurinol (adjusted RR for sex interaction, 0.92; 95% CI, 0.80-1.04).