Gout Pharmacotherapy in Cardiovascular Diseases

A Review of Utility and Outcomes

Subuhi Kaul; Manasvi Gupta; Dhrubajyoti Bandyopadhyay; Adrija Hajra; Prakash Deedwania; Edward Roddy; Mamas Mamas; Allan Klein; Carl J. Lavie; Gregg C. Fonarow; Raktim K. Ghosh

Disclosures

Am J Cardiovasc Drugs. 2021;21(5):499-512. 

In This Article

Cardiovascular Outcome and Expanded use of Colchicine

Colchicine

Colchicine is widely used in the management of pericarditis. Colchicine for 3 months is recommended as first-line therapy along with NSAIDs (European Society of Cardiology [ESC] class IA recommendation) for acute pericarditis. The addition of colchicine results in a lower rate of symptom persistence at 72 h, effective reduction in pericarditis recurrence, and rates of hospitalization due to pericarditis. Colchicine is also indicated in the setting of pericardial effusion (with systemic inflammation) and effusive constrictive pericarditis (ESC recommendation class I, level of evidence C).[10]

Recent evidence suggests potential benefit of colchicine in atherogenesis and secondary prevention of CAD via inhibition of cytokine production. The anti-inflammatory action of colchicine is summarized in Figure 4.[11] The COLCOT trial demonstrated a significant reduction in the primary composite endpoint of death from CV causes, resuscitated cardiac arrest, MI, stroke, or urgent rehospitalization for angina leading to coronary revascularization in patients with recent MI (mean of 13.5 days after MI), when treated with low-dose colchicine (0.5 mg once daily) compared with the placebo group (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.61–0.96; p = 0.02) at a median follow-up of 22.6 months.[5] Another study noted colchicine significantly reduced coronary artery plaque volume (− 40.9% vs. − 17.0% in placebo; p = 0.008) and high-sensitivity C-reactive protein (hsCRP; − 37.3% vs. 14.6% in placebo; p < 0.001) in patients with recent acute coronary syndrome (ACS).[12] In contrast, the results of the Low-Dose Colchicine (LoDoCo)-MI trial did not demonstrate a significantly increased likelihood of achieving a CRP level < 2 mg/L or lower absolute levels of CRP 30 days after an acute MI in the colchicine group compared with the placebo group.[13] Emerging evidence is encouraging considering the cost effectiveness and safety profile of colchicine. Larger trials with a longer follow-up period in other patient subgroups could potentially solidify the role of colchicine as add-on therapy in the secondary prevention of MI (Figure 5).

Figure 4.

Schematic representation of the mechanism of the anti-inflammatory effects of colchicine. IL interleukin, MMP matrix metalloproteinase, NLRP3 nucleotide oligomerization domain-, leucine-rich repeat-, pyrin domain-containing protein

Figure 5.

Summary of major cardiovascular outcomes of the drugs. ACS acute coronary syndrome, CAD coronary artery disease, AF atrial fibrillation, MI myocardial infarction, BP blood pressure, CV cardiovascular, SGLT 2 sodium glucose transporter-2

Nascent data on colchicine in ACS are also available; in vitro, colchicine has been shown to have antiplatelet activity, while, in vivo, reduced rates of in-stent stenosis and stabilization of coronary plaques post-ACS have been demonstrated.[14] Use of colchicine in ST elevation MI presenting within 12 h of symptom onset and treated with primary percutaneous coronary intervention (PCI) demonstrated a smaller infarct size (18.3 vs. 23.2 mL/1.73 m[2] in placebo; p = 0.019), lower neutrophil level, and lower hsCRP level.[15] Additionally, decreased cytokine levels in coronary sinus, right atrium, and aortic root was demonstrated in ACS patients (treated with PCI) after administration of colchicine 1.5 mg.[16] In another study evaluating 400 patients undergoing PCI, the administration of colchicine 1.8 mg prior to PCI improved the levels of hsCRP and IL-6 but did not reduce the risk of PCI-induced myocardial injury.[17]

The LoDoCo trial studied the effect of low-dose colchicine as an add-on therapy to statins and antiplatelet agents in 532 patients with stable CAD followed for a median of 3 years. A significant reduction in the primary outcome (ACS, cardiac arrest, and ischemic stroke) was observed in the colchicine group compared with the placebo group (HR 0.33, 95% CI 0.18–0.59; p < 0.001).[18] The potential benefit of colchicine in the prevention of future ischemic events was confirmed by the results of the LoDoCo2 trial. The trial randomized 5522 patients with catheterization or imaging-proven chronic CAD to receive daily colchicine or placebo and followed them for a median of 28.6 months. They demonstrated a significant reduction in primary outcome measures, including CV mortality, MI, ischemia-driven revascularization and stroke, for colchicine compared with placebo (6.8% vs. 9.6%; HR 0.69, 95% CI 0.57–0.83; p < 0.001). The caveat is a trend towards increased non-cardiac mortality in the colchicine group that warrants further investigation.[19] Two retrospective observational studies found a significantly lower risk of CV events in people with gout treated with colchicine compared with those who did not receive colchicine.[20,21]

In addition, colchicine is efficacious for prophylaxis in postoperative or postablative atrial fibrillation (AF).[22] A meta-analysis evaluated five RCTs with 1412 patients and found that compared with placebo, prophylactic colchicine reduced the incidence of postoperative AF by 30%, as well as decreased the length of stay.[23] Colchicine is also beneficial in postpericardiotomy syndrome, with supportive evidence from major trials.[24,25] Furthermore, Colchicine Coronavirus SARS-CoV2 Trial (COLCORONA) is an ongoing phase 3 RCT with an aim to evaluate the effect of 30-day treatment with colchicine on the mortality rate and pulmonary complications of COVID-19. The results of this trial would shed light on the potential utility of colchicine in the pandemic.[26] COVID-19 is associated with elevated inflammatory mediators, including IL-6, IL-8, IL-10 and tumor necrosis factor-α.[27] In addition, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) virus is thought to stimulate NLRP3 inflammasome activation, and the anti-inflammatory action of colchicine has been hypothesized to be from NLRP3 inhibitions. Previous studies have demonstrated a beneficial effect of colchicine on CRP, IL-1b, and IL-6 in chronic inflammatory conditions.[27] An open-label RCT evaluated the role of colchicine in COVID-19 patients by assessing time to clinical deterioration, time to CRP elevation, and differences in maximum high-sensitivity cardiac troponin (hs-cTn) recorded in the control and colchicine groups. They found that hs-cTn and CRP levels were comparable in the two groups, however time to clinical deterioration was improved (14% in controls vs. 1.8% in colchicine; odds ratio [OR] 0.11, 95% CI 0.01–0.96; p = 0.046). Major study limitations were the open-label design and a small population size.[28]

Xanthine Oxidase Inhibitors

Allopurinol. This urate-lowering agent has several observed CV effects. In an RCT in 65 patients with CAD, allopurinol resulted in increased exercise capacity, time to ST depression, and time to chest pain.[29] In another trial, allopurinol reduced the left ventricular mass by a mean of 5.2 g, compared with 1.3 g in the placebo group.[30] Larger population-based and case–control studies have corroborated these findings, indicating a possible cardioprotective benefit of allopurinol. The study by de Abajo et al. found that the protective effect of allopurinol appeared to increase with greater duration of treatment and higher dose (> 300 mg compared with < 300 mg).[31–33] The observational study by Singh et al. also found increasing duration of colchicine to be protective for MI in the elderly, as seen from analysis of Medicare claims.[34] In addition to its protective role in CAD, allopurinol has also been shown to reduce blood pressure. In a meta-analysis including 738 participants, the allopurinol group had significantly lower systolic and diastolic blood pressure (by 3.3 mmHg and 1.3 mmHg, respectively) compared with controls.[35] Another meta-analysis compared XO inhibitors with placebo/no treatment and found that allopurinol ≤ 300 mg daily did not significantly reduce the risk of major adverse cardiovascular events (MACE) and mortality, but reduced the risk of hypertension (OR 0.54, 95% CI 0.37–0.80) and total events (OR 0.60, 95% CI 0.44–0.82).[36] Moreover, it is suggested that XO inhibition with allopurinol may improve endothelial function, leading to vasodilation and improved blood flow in HF. Since this effect is seen in patients with both hyperuricemia and normouricemia, it may be related to a direct reduction in XO-mediated oxidative stress rather than its hypouricemic effect.[37] The ALL HEART trial is a current trial studying MACE in 5215 patients in the UK with IHD treated with allopurinol 600 mg daily compared with the placebo group, and will further help determine the role of allopurinol in CV disease.[38]

Febuxostat. In animal studies, another XO inhibitor, febuxostat, demonstrated potential scavenger-like activity for oxidative radicals, with improvement in myocardial structure and a reduction in the expression of inflammatory markers on myocytes.[39] Pretreatment with febuxostat was noted to interrupt mitochondria-dependent apoptosis and subsequent cardiomyocyte injury with reduced endothelial dysfunction in the left atrium.[40] However, Hays et al. found no benefit on coronary endothelial function in patients with prior CAD after 6 weeks of treatment with febuxostat.[41]

In the early trials that compared febuxostat and allopurinol for the treatment of gout, there were a numerically greater incidence of CV events in the febuxostat arms compared with the allopurinol arms, although the differences were not statistically significant.[42–45] As a result, the US FDA mandated the CARES trial, a postmarketing RCT in which 6190 patients were randomized to either febuxostat or allopurinol, and followed for a median of 32 months. Although the primary endpoint of composite of CV death, non-fatal MI, non-fatal stroke, and unstable angina requiring revascularization was similar in both groups (10.8% in the febuxostat group and 10.4% in the allopurinol group), CV mortality was significantly higher in the febuxostat group (HR 1.34, CI 95% 1.03–1.73).[46] In response to these observations, the FDA issued a black-box warning that restricted the use of febuxostat to people with gout who have failed or cannot tolerate maximally titrated allopurinol doses. It is essential that health care professionals counsel patients about CV risk with febuxostat prior to prescribing.[47] However, the CARES trial had several limitations that make interpretation challenging; for example, a high attrition rate (45%), high medication discontinuation rate (57%), lack of a placebo-control group, and the majority of deaths (85%) occurred after study medication had been discontinued. Rheumatologists have commented that the findings of the CARES trial do not support first-line use of febuxostat, and remind practitioners that there is evidence to support efficacy of both allopurinol dose escalation in the majority of patients with gout and uricosuric therapy.[48] The biological plausibility of the febuxostat increasing risk has also been questioned and raises the possibility that the findings could be explained by allopurinol reducing risk rather than febuxostat increasing risk. In a recently published European trial—the Febuxostat versus Allopurinol Streamlined Trial (FAST)—6128 patients followed for a median period of 1467 days were randomized to either allopurinol or febuxostat to study the primary endpoint of major adverse cardiovascular events. In contrast to the CARES trial, febuxostat was found to be non-inferior to allopurinol (HR 0·85; 95% CI 0.70–1.03; p < 0.0001).[49]

Some of the subsequent studies however have shown variable outcomes. A recent observational study comparing febuxostat and allopurinol with controls showed a similar incidence of major adverse CV events in both groups, while patients receiving febuxostat had a lower incidence of HF hospitalization.[50] Further information from the LEAF-CHF (Effect of urate LowEring Agent Febuxostat in Chronic Heart Failure patients with hyperuricemia) trial, in which patients with HF (left ventricular ejection fraction < 40%) and hyperuricemia (7.0–10.0 mg/day) are randomized to febuxostat or placebo, with a primary endpoint of difference in plasma B-type natriuretic peptide (BNP) from baseline to 24 weeks, may help elucidate the effect of febuxostat in HF.[51] A population-based cohort study evaluated febuxostat versus allopurinol in 99,744 elderly patients (≥ 65 years of age) and found that the primary outcome of composite of hospitalization for MI or stroke was similar in both groups at 1 year. However, there was a trend towards increased all-cause mortality in the group that used febuxostat for more than 3 years.[52] Additionally, a meta-analysis in a Taiwanese population showed no significant difference in CV outcome and mortality with febuxostat versus allopurinol.[53] In a recent study, febuxostat failed to show a halt in the progression of atherosclerosis, as measured by the carotid intimal thickness, after 24 months of treatment.[54]

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