Cardiovascular Safety in Gout: Interpreting Data From the CARES Trial

Individuals with gout have been shown to carry a significantly greater risk for cardiovascular (CV) events and CV-related mortality compared with those without gout. In the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial, investigators conducted a randomized, double-blind study comparing CV outcomes in patients with gout and CV disease (n=6190) who were assigned to take either febuxostat or allopurinol.¹

Patients were followed for up to 85 months, with a median follow-up of 32 months. Rates of premature treatment discontinuation were similar between groups (57.3% for febuxostat and 55.9% for allopurinol), as were the number of participants who discontinued follow-up (45.0% and 44.9%, respectively).

No significant difference was found between groups in terms of the primary end point (a composite of CV death, nonfatal stroke, nonfatal myocardial infarction, or unstable angina with urgent revascularization), which occurred in 10.8% of the febuxostat group and 10.4% of the allopurinol group (hazard ratio [HR], 1.03; upper limit of the one-sided 98.5% CI, 1.23; P =.002 for noninferiority).

However, the febuxostat group showed significantly higher rates of all-cause mortality (HR, 1.22; 95% CI, 1.01-1.47) and CV mortality (HR, 1.34; 95% CI, 1.03-1.73) compared with the allopurinol group.

Ronald Rapoport, MD, chief of rheumatology at Southcoast Health in Massachusetts, and a fellow of the American College of Rheumatology, was one of the investigators involved in the CARES trial. He told Rheumatology Advisor that he and his colleagues were surprised at the results. “None of us were expecting this,” he noted.

The unexpected findings have prompted the publication of several papers exploring the potential reasons for the observed discrepancy. In a recent letter to the editor that was published in Clinical Rheumatology, Jansen and Janssen described multiple factors in the trial design that may have influenced the results, such as the high dropout rate and the lack of a treat-to-target strategy.² “Currently, it is premature to conclude that an increased [CV] or all-cause mortality is associated with febuxostat due to a problematic design and consequently unbalance in the treatment arms of CARES,” they wrote.

Dr Rapoport believes the authors make some reasonable points that are “worth paying attention to,” and that clinicians should await more data on the topic before altering their current approach. He notes that he himself has not yet arrived at a firm conclusion regarding the issue and has not changed his use of febuxostat as a result of the findings.   

“Both of these drugs are excellent drugs for us to use [for different reasons], and it would be a shame if one were pulled — and I don’t think it will be,” he said. “There is room for both medications, with the usual caution” on the part of providers.

For additional perspectives on the CARES trial findings and related implications, Rheumatology Advisor interviewed Theodore R. Fields, MD, FACP, rheumatologist at Hospital for Special Surgery and professor of clinical medicine at Weill Cornell Medical College; and Evelyn R. Hermes-DeSantis, PharmD, BCPS, clinical professor in the department of pharmacy practice and administration at Rutgers Ernest Mario School of Pharmacy, and director of drug information services at Robert Wood Johnson University Hospital.

Rheumatology Advisor: What are your thoughts about the CARES trial results and the points raised in the Jansen and Janssen paper?^1,2

Dr Fields: The points made in the Jansen and Janssen letter to the editor are important and have mostly been made previously, and other points relevant to problems with the CARES study have been noted in other publications. The points are nicely made as well in a letter by Abeles and Pillinger,³ and most were also discussed by Choi, et al.⁴ 

The conclusions of the CARES study are very difficult to interpret because:

• The dropout rate was nearly 60%.
• When the patients who dropped out of the study were tracked, and it was determined which had survived, the increased CV death rate with febuxostat was no longer present.
• Most deaths occurred in patients who were no longer on either allopurinol or febuxostat, raising a question about whether the increased CV death rate in the febuxostat group is a relevant finding.
• The primary end point (the combined major adverse CV event [MACE] end point) was not different in the febuxostat and allopurinol groups, and no mechanism has been proposed for why febuxostat would have an increased cardiac death rate. With no increase in myocardial infarctions, for example, we would need to postulate more sudden death (eg, arrhythmia) in the febuxostat group, but the only mechanism that has been proposed relates to possible risk for more effective urate lowering (discussed by Jansen and Janssen) and is not supported by other literature. As pointed out by Abeles,³ a recent study presented in abstract suggests that febuxostat has CV benefit compared with not receiving it.⁵
• More patients in the febuxostat group were receiving nonsteroidal anti-inflammatory agents, which have been identified as a CV risk factor.
• Subjects in the CARES study did not have different CV mortality  if they were taking aspirin.
• A study of patients with renal disease and preexisting CV disease taking febuxostat had fewer CV events than those starting allopurinol.⁶
• The CARES study did not have a placebo group, so it is possible that both febuxostat and allopurinol were cardiac-protective, for which some of the above is supportive.
• A study of almost 25,000 Medicare patients starting febuxostat compared with almost 75,000 patients starting allopurinol (with or without prior CV history) found no difference in CV outcomes or mortality.⁷

Dr Hermes-DeSantis: [Regarding the primary end point of the CARES trial], febuxostat demonstrated noninferiority compared with allopurinol. In evaluating the secondary end points of CV death and death from any cause, the results did show a significant difference.

However, there are a number of issues with the CARES trial that should be taken into consideration:

• A large proportion of the excess in mortality occurred after discontinuation. The median duration of drug therapy was about 2 years. Looking at the Kaplan-Meier curves for mortality up to the 2-year mark shows no difference, the lines do not start separating until later. Additionally, in a post‐hoc analysis including data on as many of the participants who dropped out of the study as could be identified, the adverse CV signal for febuxostat was no longer significant. Therefore, any conclusion about a causative role of febuxostat is premature.
• Secondary end points were not powered to truly detect a difference and should have been held as exploratory end points.
• The lack of a placebo group confounds the discussion as to whether febuxostat may adversely affect mortality or whether allopurinol may exert beneficial effects on death — or both.
• Other drug therapy and impact:

• Lipid-lowering therapy: Overall, 74% of the patients were on lipid-lowering therapy, but low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were not reported, so it is unclear whether this had any impact.
• Antihypertensive therapy: The CARES authors do not mention which renin-angiotensin blockers were used or whether some patients were also taking calcium channel blockers.
• Antidiabetic therapy: Although 39% of the patients in the CARES trial had type 2 diabetes mellitus with small vessel disease, antidiabetic treatment was not reported.

Rheumatology Advisor: What are the clinical implications of these findings?

Dr Fields: Overall, my impression is that we need to interpret the CARES data very carefully. I believe the CARES study should not eliminate febuxostat from availability, as supported by the vote of the US Food and Drug Administration committee. As Choi, et al has suggested, there is reason to use allopurinol as a first-line agent even in patients with decreased renal function, especially in view of recent data supporting the safety and effectiveness of escalating allopurinol doses in patients with decreased renal function.

For patients with allopurinol allergy or insensitivity, or ineffectiveness despite appropriate dose escalation, I believe febuxostat should remain an option. The studies with opposite results from CARES, and the limitations of the CARES study, suggest that its conclusions should be accepted with significant caution.

Dr Hermes-DeSantis: As a clinician, I would lean toward allopurinol as first-line therapy with febuxostat considered when allopurinol is not tolerated, not achieving normalized uric acid levels, and in the case of renal failure.

Rheumatology Advisor: What should be next steps in terms of research in this area?

Dr Fields: Ideally, future studies should correct for use of nonsteroidal anti-inflammatory drugs and aspirin and attempt to obtain equivalent levels of urate lowering. As Jansen and Janssen proposed, investigators could match 300 mg allopurinol with 40 mg febuxostat and 600 mg allopurinol with 80 mg febuxostat. The CARES study is important, but we must keep in mind that the MACE outcomes were the same in both groups, and that many problems with the study exist.  

Interviews were lightly edited for style and clarity.

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References

1. White WB, Saag KG, Becker MA, et al; CARES Investigators. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018;378(13):1200-1210.
2. Jansen TLTA, Janssen M. Gout lessons from 2018: CARES, a direct comparison of febuxostat vs allopurinol, and CANTOS, IL1 blocker for cardiovascular risk minimisation. Clin Rheumatol. 2019;38(1):263-265.
3. Abeles AM, Pillinger MH. The CARES scare: febuxostat and the risk of cardiovascular disease [published online January 18, 2019]. Arthritis Rheumatol. doi:10.1002/art.4083
4. Choi H, Neogi T, Stamp L, Dalbeth N, Terkeltaub R. Implications of the cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular morbidities trial and the associated Food and Drug Administration public safety alert. Arthritis Rheumatol. 2018;70(11):1702-1709.
5. European Society of Cardiology. Gout drug reduces adverse events in patients with hyperuricaemia [press release]. https://www.escardio.org/The-ESC/Press-Office/Press-releases/gout-drug-reduces-adverse-events-in-patients-with-hyperuricaemia. Published August 28, 2018. Accessed January 30, 2019.
6. Foody J, Turpin RS, Tidwell BA, Lawrence D, Schulman KL. Major cardiovascular events in patients with gout and associated cardiovascular disease or heart failure and chronic kidney disease initiating a xanthine oxidase inhibitor. Am Health Drug Benefits. 2017;10(8):393-401.
7. Zhang M, Solomon DH, Desai RJ, et al. Assessment of cardiovascular risk in older patients with gout initiating febuxostat versus allopurinol: population-based cohort study. Circulation. 2018;138:1116-1126.