CARES
PubMed • Full text
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Clinical Question
In patients with gout and cardiovascular disease, is febuxostat noninferior to allopurinol with regards to major cardiovascular events?
Bottom Line
Among patients with gout and cardiovascular disease, febuxostat is noninferior to allopurinol with regard to a primary composite end point of cardiovascular death, nonfatal MI, nonfatal stroke, or unstable angina with urgent revascularization after a median of 32 and maximum of 85 months of follow-up. All-cause and cardiovascular mortality were significantly higher with febuxostat than with allopurinol.
Major Points
Gout is a chronic form of arthritis that is caused by hyperuricemia. It can result in tophi development, kidney stones, and cause pain and swelling in joints. Gout also increases the risk of cardiovascular and chronic kidney disease. Febuxostat and allopurinol are both indicated for long-term management of hyperuricemia in gout patients. Febuxostat is a nonpurine xanthine oxidase inhibitor that decreases uric acid formation by inhibiting both oxidized and reduced forms of xanthine oxidase. Febuxostat is more effective in reducing serum urate levels in gout patients than standard doses of allopurinol, a purine base analogue xanthine oxidase inhibitor. However, during the development of febuxostat, early clinical trials showed a modestly higher rate of cardiovascular events with febuxostat than with allopurinol. The CARES trial was conducted due to FDA mandate to assess whether febuxostat was noninferior to allopurinol in major cardiovascular events among patients with gout and cardiovascular disease.
The CARES trial randomized 6,190 patients with gout and cardiovascular disease to febuxostat 40-80 mg once daily or allopurinol 200-600 mg once daily. At a median of 32 months, febuxostat was noninferior to allopurinol in regards to the composite endpoint of cardiovascular death, nonfatal MI, nonfatal stroke, or unstable angina with urgent revascularization (HR 1.03; 97% CI 0.87-1.23; P=0.002 for noninferiority). However, when the primary endpoints were analyzed individually, febuxostat displayed a higher rate of cardiovascular death than allopurinol (4.3% vs. 3.2% of patients; HR 1.34; 95% CI 1.03-1.73), which also led to a higher all-cause mortality rate compared to allopurinol (7.8% vs. 6.4% of patients; HR 1.22; 95% CI 1.01-1.47).
One of the unexpected results from this study was both febuxostat and allopurinol showing similar rates of non-fatal cardiovascular events but cardiovascular mortality being higher in febuxostat. The increase in cardiovascular mortality in the febuxostat group was caused primarily by sudden cardiac death (2.7% in febuxostat vs. 1.8% in allopurinol). Explanation for these findings is currently unknown and will require further analyses. Even though there was a high discontinuation rate, both the modified intention-to-treat and per-protocol analyses showed similar results for cardiovascular death.
Guidelines
American College of Rheumatology guidelines (2012)
- Xanthine oxidase inhibitor, febuxostat or allopurinol, is recommended as first-line urate-lowering treatment in gout prevention.
- Treat to goal uric acid of <6.0 mg/dl or <5.0 mg/dl in specific patients.
- Start anti-inflammatory prophylaxis when initiating urate-lowering therapy for at least 6 months to prevent acute gout flare. First-line prophylaxis includes low-dose colchine 0.5-0.6 mg once or twice daily or low-dose NSAID (e.g., naproxen 250 mg twice daily).
Design
- Multicenter, randomized, double-blind, noninferiority trial
- N=6,190
- Febuxostat (n=3098)
- Allopurinol (n=3092)
- Setting: 320 sites in North America
- Enrollment: April 2010 - May 2017
- Median follow-up: 32 months
- Analysis: modified intention-to-treat
- Primary outcome: first occurrence of composite of cardiovascular death, nonfatal MI, nonfatal stroke, or unstable angina with urgent revascularization
Population
Inclusion Criteria
- Male (≥ 50 years old) or female (≥ 55 years old) patients with a diagnosis of gout, based on one or more of the American Rheumatism Association criteria for the diagnosis of gout
- History of major cardiovascular or cerebrovascular disease before randomization including at least one of the following:
- Myocardial infarction
- Hospitalization for unstable angina
- Coronary or cerebral revascularization procedure
- Stroke
- Hospitalization for transient ischemic attack
- Peripheral vascular disease (ankle:brachial index ≤ 0.6, peripheral arterial revascularization and/or well-documented history of intermittent claudication)
- Diabetes mellitus with evidence of microvascular or macrovascular disease (retinopathy, neuropathy, nephropathy, and small vessel vascular diseases)
- Serum urate level ≥7.0 mg/dl at screening visit or a serum urate level ≥ 6.0 mg/dl with inadequately controlled gout (≥1 flares in the 12 months prior to screening and/or the presence of a tophus) after a 1 to 3 week washout period from previous gout therapies.
Exclusion Criteria
- Secondary hyperuricemia (e.g. due to a myeloproliferative disorder)
- History of xanthinuria
- Received a urate-lowering therapy (i.e. allopurinol, febuxostat, probenicid) or other excluded medication less than 7 days prior to randomization
- Known hypersensitivity to febuxostat or allopurinol or any components of their formulations
- Active peptic ulcer disease
- History of cancer (other than basal cell carcinoma of the skin) within 5 years prior to the first dose of study medication
- Myocardial infarction or stroke within 60 days prior to screening
- Liver transaminases greater than 2 times the upper limit of normal during the screening period
- Alcohol or substance abuse/dependence within the 5 years prior to screening
- Investigational drug within the 30 days prior to the screening or has previously received study drug for the present study
- Estimated CrCl is < 30 ml/min using the Cockcroft and Gault formula based on ideal body weight
- History of infection with hepatitis B, hepatitis C, or HIV
- A study site employee, or is an immediate family member (ie, spouse, parent, child, and sibling) of a study site employee involved in the conduct of this study
Baseline Characteristics
From the Febuxostat group. There were no significant differences between the two groups for any baseline characteristics.
- Median age: 64 years
- Age ≥65 yr: 48.9%
- Male sex: 84.1%
- Duration of gout: 11.8 years
- Baseline serum urate level: 8.7 mg/dl
- Presence of tophi: 21.6%
- Median body weight: 97.7 kg
- Body mass index: 33.6
- Race/ethnic group: White(69.7%), Black(17.8%), Asian(3.0%), American Indian or Alaska Native(8.5%), Native Hawaiian or other Pacific Islander(0.4%), Other(0.6%)
- Cardiovascular risk factors and history: Diabetes mellitus with small-vessel disease(38.5%), Hypertension(92.4%), Hyperlipidemia(86.4%), Myocardial infarction(38.6%), Hospitalization for unstable angina(27.6%), Coronary revascularization(36.4%), Cerebral revascularization(36.4%), Congestive heart failure(20.1%), Stroke(14.8%), Peripheral vascular disease(13.3%)
- Median estimated creatinine clearance: Stage 1 or 2 chronic kidney disease(75 ml/min), Stage 3 chronic kidney disease(46.0 ml/min)
- Stage of chronic kidney disease: Stage 1 or 2(47.1%), Stage 3(52.9%)
Interventions
- Patients randomly assigned to one of two groups:
- Febuxostat 40 mg (or 80 mg starting after 2 weeks of therapy if serum urate level ≥6.0 mg/dl) tablets once daily
- Allopurinol 200 mg up to 400 mg (for eCrCl ≥30 but <60 mL/min) or 300 mg up to 600 mg (for eCrCl ≥60 mL/min) once daily, increased in 100 mg increments each month until serum urate level <6.0 mg/dl or reached top of dose range.
- All patients received colchicine 0.6 mg daily for first 6 months of treatment for gout flare prophylaxis.
- If history of unacceptable adverse effects to colchicine and eCrCl ≥50 mL/min, patients received naproxen 250 mg twice daily with lansoprazole 15 mg once daily.
- Other NSAIDs or prednisone could be used as prophylaxis if patient could not receive colchicine or naproxen.
- Patients followed for median of 32 months
Outcomes
Presented as febuxostat vs. allopurinol
Primary Outcomes
- Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization due to unstable angina
- 335(10.8%) vs. 321(10.4%) [HR 1.03; 97% CI 0.87-1.23; P=0.002 for noninferiority; P=0.66 for superiority]
Secondary Outcomes
- Cardiovascular death
- 134(4.3%) vs. 100(3.2%) [HR 1.34; 95% CI 1.03-1.73; P=0.03]
- Nonfatal myocardial infarction
- 111(3.6%) vs. 118(3.8%) [HR 0.93; 95% CI 0.72-1.21; P=0.61]
- Nonfatal stroke
- 71(2.3%) vs. 70(2.3%) [HR 1.01; 95% CI 0.73-1.41; P=0.94]
- Urgent revascularization for unstable angina
- 49(1.6%) vs. 56(1.8%) [HR 0.86; 95% CI 0.59-1.26; P=0.44]
- Composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke
- 296(9.6%) vs. 271(8.8%) [HR 1.09; 95% CI 0.92-1.28; P=0.33]
- Death from any cause
- 243(7.8%) vs. 199(6.4%) [HR 1.22; 95% CI 1.01-1.47; P=0.04]
Subgroup Analysis
There was no significant difference pertaining to the primary end point for any of the analyzed subgroups.
Adverse Events
Criticisms
- The mechanism behind the increase in cardiovascular mortality seen among the febuxostat group but not in the non-fatal cardiovascular events is currently unknown.
- Patients in this study have high cardiovascular risk but in the febuxostat group at baseline, only 59.4% of patients were on aspirin, 74% were on lipid-lowering treatment, and 58% were on a beta blocker. The question to whether the increase in cardiovascular mortality in the febuxostat group is due to febuxostat or the lack of optimal baseline cardiovascular treatment is unclear.
- Results are limited to patients who have a history of major cardiovascular disease and can’t extrapolate to those who only have cardiovascular risk factors.
- The study did not address patients with eCrCl<30 mL/min (Stage 4 or worse chronic kidney disease).
- There was a high rate of treatment discontinuation(56.6%) and loss in follow-up(45.0%).
Funding
Funded by Takeda Development Center Americas, the manufacturer of Uloric.
Further Reading
Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care and Research. 2012;64:1431-46.
Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: Therapy and anti-inflammatory prophylaxis of acute gouty arthritis. Arthritis Care and Research. 2012;64:1447-61.