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Association of colchicine use for acute gout with clinical outcomes in acute decompensated heart failure

Abstract Background Gout is a common comorbidity in heart failure (HF) patients and is frequently associated with acute exacerbations during treatment for decompensated HF. Although colchicine is often used to manage acute gout in HF patients, its impact on clinical outcomes when used during acute decompensated HF is unknown. Methods This was a single center, retrospective study of hospitalized patients treated for an acute HF exacerbation with and without acute gout flare between March 2011 and December 2020. We assessed clinical outcomes in patients treated with colchicine for a gout flare compared to those who did not experience a gout flare or receive colchicine. The primary outcome was in‐hospital all‐cause mortality. Results Among 1047 patient encounters for acute HF during the study period, there were 237 encounters (22.7%) where the patient also received colchicine for acute gout during admission. In‐hospital all‐cause mortality was significantly reduced in the colchicine group compared with the control group (2.1% vs. 6.5%, p = .009). The colchicine group had increased length of stay (9.93 vs. 7.96 days, p < .001) but no significant difference in 30‐day readmissions (21.5% vs. 19.5%, p = .495). In a Cox proportional hazards model adjusted for age, inpatient colchicine use was associated with improved survival to discharge (hazards ratio [HR] 0.163, 95% confidence interval [CI] 0.051−0.525, p = .002) and a reduced rate of in‐hospital CV mortality (HR 0.184, 95% CI 0.044−0.770, p = .021). Conclusion Among patients with a HF exacerbation, treatment with colchicine for a gout flare was associated with significantly lower in‐hospital mortality compared with those not treated for acute gout.


| INTRODUCTION
Gout is a common comorbidity in heart failure (HF) patients and is the result of monosodium urate crystal deposition in joints and periarticular tissues. 1 Gout is associated with significant morbidity, mortality, and healthcare costs. [1][2][3] Diuretics are known to precipitate hyperuricemia and increase the risk of gout flares through mechanisms related to decreased uric acid secretion and increased uric acid reabsorption. 4,5 Studies have estimated the prevalence of gout in HF patients to be approximately 16%−40%, and one study found that 56% of hospitalized HF patients had hyperuricemia. [6][7][8][9] The therapeutic agents commonly used for an acute gout flare include colchicine, steroids, and nonsteroidal anti-inflammatory drugs (NSAIDs). However, steroids and NSAIDs are often avoided in HF because of the legitimate concerns of fluid retention and HF exacerbation. 10 In addition to its role in gout, colchicine's antiinflammatory effects are also highly beneficial in the treatment and prevention of other cardiac conditions such as pericarditis. 11 Colchicine has also recently shown broader cardiovascular (CV) outcomes benefit in high-risk patients, particularly those with coronary artery disease (CAD) or history of myocardial infarction (MI). However, the impact of colchicine use during gout flares on outcomes in patients with acutely decompensated HF is unknown.
The purpose of this study was to assess clinical outcomes in patients treated for an acute HF exacerbation and receiving colchicine for an acute gout flare.

| Study design
This single center, retrospective cohort study compared clinical outcomes in those receiving colchicine for the treatment of an acute gout flare versus those without a gout flare among patients with an acute HF exacerbation at an academic medical center.

Adult patients (age ≥ 18 years) admitted between March 2011 and
February 2020 with an acute HF exacerbation who received initial intravenous (IV) diuretics were eligible for inclusion. Patients were identified using ICD 9 and ICD 10 codes for acute HF exacerbation. Patients treated with colchicine during the admission for a documented acute gout flare were included in the treatment group, while those not given colchicine during the admission were presumed not to have had a gout flare and were included in the control group. Patients were excluded if they had end-stage renal disease on hemodialysis, any history of transplantation or underwent transplantation during the admission, and any history of left ventricular assist device (LVAD) or LVAD implantation during admission. Patients receiving colchicine for indications other than acute gout or admitted for reasons other than acute decompensated HF were also excluded. All patients were included for analysis on an intention-to-treat basis. The study was approved by the Institutional Review Board before data collection. Study covariates were collected from the electronic medical record and data warehouse of medical records.

| Outcomes
The primary outcome was in-hospital all-cause mortality. Secondary outcomes included hospital length of stay (LOS), 30-day readmissions, and time to death. This study also compared the primary and secondary outcomes between patients with a prior history of gout, a first diagnosis of gout, and the control group. A post hoc analysis was completed to evaluate in-hospital CV mortality and time to CV death. Baseline characteristics included age, gender, and ejection fraction (on the most recent imaging including echocardiogram, nuclear stress test, or angiography), comorbidities, and home HF and gout medications.

| Statistical analysis
The primary outcome of in-hospital all-cause mortality and secondary outcome of 30-day readmissions were compared using the Pearson χ 2 test, while LOS was assessed using the Mann−Whitney U test. Multivariable logistic regression was performed to assess the association of in-hospital colchicine with survival to discharge with adjustment for key covariates. Multivariable Cox proportional regression was used to assess differences in time to death with adjustment for age. The α value for all statistical tests was set at .05. R and SPSS statistical software were used in the analysis.

| Baseline characteristics
A total of 5109 patient encounters had an ICD 9 or ICD 10 code for acute HF exacerbation during the study period ( Figure 1). The final cohort included 1047 patient encounters after exclusions as indicated in Figure 1 and was then stratified into colchicine and control groups as determined a priori. Baseline characteristics were similar between groups, with the exception of age, sex, and comorbidities of gout and alcohol use (Table 1)

| Primary outcome analysis
A total of 58 patients (5.5%) died during admission, five in the colchicine group and 53 in the control group (2.1% vs. 6.5%, p = .009), that is, a lower in-hospital all-cause mortality in the colchicine group (Table 2). A subgroup analysis was conducted to assess outcomes with the colchicine group stratified based on prior documented history of gout versus de novo gout presentation. In-hospital all-cause mortality was not significantly different between patients with a new gout diagnosis compared to those with a prior history of gout (3.4% vs. 0.8%, p = .213).

| Secondary outcomes analysis
The 30-day readmissions were not significantly different between the colchicine and control groups (21.5% vs. 19.5%, p = .495) ( Table 2). In the subgroup analysis, 30-day readmissions remained similar when comparing patients with de novo gout to those with a prior history of gout (22.9% vs. 20.2%, p = .611). Mean LOS was significantly increased in the colchicine group compared to the control group (9.93 vs. 7.96 days, p < .001) ( Table 2). In the subgroup analysis, LOS was significantly increased in the de novo presentation of gout group compared to the control group (10.52 vs. 7.96 days, p < .001) and in the prior history of gout group compared to the control group (9.35 vs. 7.96 days, p = .006).
There was no significant difference in LOS between those with a first diagnosis of gout and those with a prior history of gout (p = .272). In a post hoc analysis, in-hospital CV mortality censored at 4 weeks was significantly lower in the colchicine group than the control group (0.89% vs. 3.93%, p = .02).  Figure 3). Home colchicine use was associated with a reduced rate of in-hospital all-cause mortality (log rank p = .037) but no significant difference in the rate of in-hospital CV mortality (log rank p = .14).

| Multivariate logistic regression analysis
A multivariate logistic regression model was performed to evaluate associations of other covariates with in-hospital all-cause mortality.
These covariates included in-hospital colchicine use, home betablocker use, inotrope use, age, and diabetes mellitus. In-hospital Our findings highlight the relative high prevalence of acute gout during treatment with IV diuretics for HF exacerbation.
Colchicine is a potent anti-inflammatory and antiproliferative drug that has been used for both acute gout treatment as well as prevention. 10  arrest, or revascularization. The meta-analysis found that colchicine F I G U R E 3 Inpatient all-cause and cardiovascular (CV) death by home colchicine use. Reverse Kaplan−Meier curves for inpatient all-cause death and inpatient CV death stratified on home colchicine use are shown (p = .037 and p = .14, respectively) use was associated with a 56% decrease in the composite CV outcome (p = .0004), as well as a nonsignificant trend toward reduction in all-cause mortality (relative risk 0.50, p = .08). 11 Several additional retrospective studies have also demonstrated favorable CV outcomes with the use of colchicine. 13,14 Recently, prospective, randomized, and placebo-controlled trials have also examined the potential benefit of colchicine in CV patients.
The Colchicine Cardiovascular Outcomes Trial (COLCOT) evaluated the use of colchicine within 30 days after MI, and the Low Dose Colchicine 2 Trial (LoDoCo2) evaluated colchicine in patients with stable CAD. In COLCOT and LoDoCo2, colchicine resulted in a significant reduction in the primary outcomes, which were a composite of CV death and other clinical outcomes in both trials. 25,26 Additionally, a recent systematic review and meta-analysis assessed the impact of colchicine in patients with CAD in 13 randomized trials, which included a total of 13 125 patients. 15 The study found that treatment with colchicine significantly reduced the risk of MI as well as stroke or transient ischemic attack when compared to placebo or standard care. However, colchicine was not associated with a significant reduction in all-cause or CV mortality. Prior studies have also explored the impact of other gout therapies on HF outcomes. Hyperuricemia has been associated with an increased incidence of HF as well as increased mortality among those with HF. Therefore, uric acid lowering therapies have been considered potential medication candidates for improving HF outcomes. Initial studies demonstrated that allopurinol, a xanthine oxidase inhibitor, was associated with improved endothelial function in HF patients. 17  possible that acute gout could be a surrogate marker for more effective diuresis or renal dysfunction. However, the existing literature demonstrating worsened outcomes associated with gout and hyperuricemia suggests that the presence of gout in the intervention group would skew the results toward the null hypothesis. As this was an observational study, it is possible that there could still be unmeasured confounders even after statistical adjustment.

| CONCLUSION
This study demonstrated that colchicine use for acute gout flare in hospitalized patients with a HF exacerbation was associated with decreased in-hospital all-cause mortality and in-hospital CV mortality compared with the control group. The use of colchicine was also associated with a longer LOS but similar 30-day readmissions. Additional large multicenter retrospective and prospective randomized studies are needed to more fully understand the association of colchicine use with outcomes in patients undergoing treatment for HF exacerbations and explore its role as a potential treatment option in this population.

ACKNOWLEDGMENTS
We would like to thank Terran Rice, PharmD for his assistance in identifying encounters to assess for inclusion from the UVA internal data warehouse of medical records. This study was supported by the analysis and interpretation of data; writing of the report; or decision to submit the article for publication.

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
Data available on reasonable request from the authors.