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.

Abstract and Introduction

Abstract

Hyperuricemia and gout have been linked to an increased risk for cardiovascular (CV) disease, stroke, hypertension, heart failure, and chronic kidney disease, possibly through a proinflammatory milieu. However, not all the drugs used in gout treatment improve CV outcomes; colchicine has shown improved CV outcomes in patients with recent myocardial infarction and stable coronary artery disease independent of lipid-lowering effects. There is resurging interest in colchicine following publication of the COLCOT, LoDoCo, LoDoCo2, LoDoCo-MI trials, and COLCORONA trial which will shed light on its utility in COVID-19. Our aim is to review the CV use of colchicine beyond pericardial diseases, as well as CV outcomes of the available gout therapies, including allopurinol and febuxostat. The CARES trial and its surrounding controversies, which lead to the US FDA 'black box' warning on febuxostat, in addition to the recent FAST trial which contradicts this and finds febuxostat to be non-inferior, are discussed in this paper.

Introduction

Gout is a chronic inflammatory arthritis that affects 9.2 million adults in the US and is characterized by monosodium urate crystal deposition in the joints, secondary to elevated urate levels.^[1] Evidence suggests that hyperuricemia and gout are independently linked to an increased risk of coronary artery disease (CAD), heart failure (HF), and cardiovascular (CV) mortality.^[2] Patients with recent myocardial infarction (MI) and active gout have worse survival compared with patients with MI who are receiving treatment for gout.^[3] Interestingly, not all urate-lowering therapies (ULTs) improve CV outcomes. The URic acid Right for heArt Health Study Group (URRAH) confirmed the independent association of serum uric acid levels and fatal MI. Indeed, they demonstrated a prognostic uric acid cut-off of 5.26 as a predictor for fatal MI in women.^[4] Colchicine, which is a commonly used gout medication, has long been used in various pericardial diseases, including pericarditis, pericardial effusion, and effusive constrictive pericarditis. It has shown reductions in long-term CV adverse events in patients with recent MI and stable ischemic heart disease (SIHD). While the outcomes of the COLCOT (Colchicine Cardiovascular Outcomes Trial) trial generated interest, more research is required to fully incorporate colchicine into clinical practice.^[5–7] Similarly, allopurinol and febuxostat have shown conflicting evidence with respect to CV outcomes.

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Abstract and Introduction
Literature Search
Inflammation and Uric Acid in Atherosclerosis
Management and Pharmacotherapies in Gout
Cardiovascular Outcome and Expanded use of Colchicine
Future Directions
Conclusion
References
Sidebar

Table 1. Pharmacology of colchicine ^a
Drug for acute flare^a	Colchicine
Route of administration	Oral
Metabolism and excretion	Metabolized by CYP3A4 to 2- and 3-demethylcolchicine; gastrointestinal absorption is limited by enterocyte P-glycoprotein; renally excreted
Dosing	1.2 mg at onset of gout flare, followed by 0.6 mg after 1 h For prophylaxis: 0.6 mg once to twice daily The dose used in the COLCOT trial was 0.5 mg once daily
Important adverse effects	Gastrointestinal, most commonly diarrhea, in up to 10%. Other important adverse effects are myelosuppression and neuromuscular toxicity
Important drug interactions	Avoid coadministration with P-glycoprotein or CYP3A4 inhibitors (such as cyclosporine or clarithromycin, respectively) as they inhibit colchicine metabolism
Monitoring	Blood counts, and liver and renal function
Contraindications	Patients with liver or renal dysfunction should not be administered colchicine along with CYP or P-glycoprotein inhibitors

CYP cytochrome P450 enzyme, COLCOT Colchicine Cardiovascular Outcomes Trial
^aNSAIDs and glucocorticoids are also first-line agents that are not included here

Table 2. Pharmacology of drugs used for the chronic management of gout
Urate-lowering therapy	Xanthine oxidase inhibitors		Uricosuric drugs		Uricase
Urate-lowering therapy	Allopurinol	Febuxostat	Probenecid	Lesinurad	Rasburicase	Pegloticase
Route of administration	Oral	Oral	Oral	Oral	IV infusion	IV infusion
Metabolism and excretion	Metabolized to oxypurinol, which is excreted renally	Undergoes hepatic metabolism by CYP1A2, CYP2C8, and CYP2C9 to active metabolites; excreted renally	Undergoes oxidation of alkyl side chains and glucuronide conjugation; excreted renally	Moderate CYP3A4 inducer; up to 40% excreted renally	Undergoes peptide hydrolysis	Renal excretion
Dosing	50–800 mg/day	40 or 80 mg once daily	500–1000 mg twice daily	Moderate CYP3A4 inducer; up to 40% excreted renally	0.2 mg/kg as an infusion over 30 min daily for up to 5 days (single course only, not repeated)	8 mg every 2 weeks
Important adverse effects	Rash, allopurinol hypersensitivity and gout flare on initiation of treatment	Liver impairment and gout flare on initiation of treatment. US FDA added a boxed warning for possible increased CV mortality	Kidney stones and gout flare on initiation of treatment	200 mg/day in combination with an xanthine oxidase inhibitor	Headache, abdominal pain, mucositis. Uncommon adverse effects are anaphylaxis, hemolytic anemia, and methemoglobinemia.	Infusion reactions, immunogenic effects and gout flare on initiation of treatment
Important drug interactions	Potentiates action of azathioprine and warfarin	Coadministration with drugs that are xanthine oxidase substrates, azathioprine or mercaptopurine, could increase plasma concentrations with resultant severe toxicity	Can increase methotrexate toxicity	Renal failure and urate kidney stones, more common when used as monotherapy; adverse CV events	Does not have any significant drug interactions Interferes with laboratory measurement of serum uric acid. Therefore, blood is collected in heparinized prechilled tubes, maintained in an ice-water bath and tested within 4 h	Other urate-lowering drugs can mask the absence of response to pegloticase and thus raise the risk of infusion reaction
Monitoring	Renal and liver function and serum urate	Renal and liver function and serum urate	Renal function and serum urate	Renal function	Serum urate	Serum urate
Contraindications	Allopurinol hypersensitivity	1. Ischemic heart disease and cardiac failure 2. Patients taking azathioprine or mercaptopurine	1. Uric acid kidney stones 2. Blood dyscrasias	1. Serum creatinine level < 30 mL/min, or kidney transplant 2. Tumor lysis syndrome 3. Lesh–Nyhan syndrome 4. Prior cardiac disease	1. Hypersensitivity to, or hemolysis/methemoglobinemia with, rasburicase 2. G6PD deficiency	1. G6PD deficiency 2. If serum urate response is absent

CYP cytochrome P450 enzyme, CV cardiovascular, G6PD glucose-6-phosphate dehydrogenase, IV intravenous

Table 3. Recent cardiovascular outcomes trials of drugs used in the management of gout
Drug name	Official title of the trial	Abbreviated name of the trial	Median duration for observed effect	Phase of the trial	NCT identifier	Primary outcomes	Key points
Colchicine (patients who had suffered from an MI in the last 30 days)	Colchicine Cardiovascular Outcomes Trial	COLCOT	22.6 months	III	NCT02551094	CV death, recurrent MI, stroke, resuscitated cardiac arrest and hospitalization for unstable angina requiring coronary revascularization	1. Absolute reduction of 1.6% in ischemic events in the colchicine group compared with placebo (primary endpoint was 5.5% vs. 7.1%, respectively; HR 0.77. 95% CI 0.61–0.96) 2. Pneumonia was higher with colchicine, but diarrhea rates did not significantly differ in either group
Colchicine	Effect of ColchiciNe on the InciDence of Atrial Fibrillation in Open Heart Surgery Patients: END-AF Trial	END-AF	Variable: range was 2–56 days	III	NCT03021343	Rate of AF lasting more than 5 min	1. There was no significant difference in rates of AF in the group administered colchicine prior to cardiac surgery compared with the no colchicine group (overall rates of AF were 14.5% vs. 20.5%, respectively; RRR 29.3%, p = 0.14). No net benefit in composite of primary endpoint 2. Diarrhea lead to colchicine discontinuation in about half of the patients with this adverse effect.
Allopurinol (patients undergoing cardiac surgery and no prior history of AF or supraventricular arrhythmias)	Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients	EXACT-HF	24 weeks	II	NCT00987415	Improvement, worsening, or unchanged clinical status of patients with heart failure	1. There was no significant difference in clinical status or left ventricular ejection fraction between the allopurinol- and placebo-treated patients 2. Rash was more common with allopurinol but there was no significant difference in serious adverse event rates compared with placebo
Febuxostat vs. allopurinol	A multicenter, randomized, active-control, phase 3B study to evaluate the cardiovascular safety of febuxostat and allopurinol in subjects with gout and cardiovascular comorbidities	CARES	7 years	III	NCT01101035	Percentage of patients with a composite of non-fatal MI, non-fatal stroke, CV death, and unstable angina requiring coronary revascularization	1. A primary endpoint event occurred in 10.8% in the febuxostat group compared with 10.4% in the allopurinol group 2. All-cause and CV mortality were higher in the febuxostat group than in the allopurinol group

AF atrial fibrillation, CI confidence interval, CV cardiovascular, HR hazard ratio, LDL low-density lipoprotein, MI myocardial infarction, RRR relative risk reduction

Table 4. Ongoing trials on drugs used in gout and other rheumatological diseases
Drug studied	Official title (acronym)	NCT identifier	Primary outcome measure	Status, expected completion
Colchicine	A 2 × 2 factorial randomized controlled trial of colchicine and spironolactone in patients with ST-elevation myocardial infarction (STEMI)/SYNERGY Stent Registry (CLEAR SYNERGY)	NCT03048825	Major adverse cardiovascular effects	Recruiting, December 2021
	The Canadian study of Arterial inflammation in patients with Diabetes and recent vascular events: EvaluatioN of Colchicine Effectiveness (CADENCE)	NCT04181996	Change in the FDG uptake of tissue-to-blood ratio as a marker of arterial plaque inflammation in the maximally diseased segment of imaged vasculature (carotid or aorta) over a period of 6 months	Not yet recruiting, December 2023
	Impact of Short-course Colchicine Versus Placebo After Pulmonary Vein Isolation: A Pilot Study, (IMPROVE-PVI Pilot)	NCT04160117	Average monthly number of patients enrolled	Recruiting, January 2022
	Colchicine Prevents Myocardial Injury After Non-Cardiac Surgery Pilot Study (COPMAN)	NCT04139655	Number of patients included in 3 months after the run-in period	Recruiting, October 2021
	Colchicine for the Prevention Of Perioperative Atrial Fibrillation in Patients Undergoing Thoracic Surgery (COP-AF)	NCT03310125	Atrial fibrillation within 14 days of randomization	Recruiting, June 2022
Hypouricemic agents	A phase 2, MulticEnter, double-blind, THree-arm, placebo and active control efficacy and safetY STudy to evaluate verinurad combined with allopurinol in heart failure with preserved ejection fraction (AMETHYST)	NCT04327024	Effect of verinurad and allopurinol on exercise capacity by measurement of VO₂ change over 28 weeks	Not yet recruiting, September 2021
Anti-inflammatory agents	Phase 3, double-blind, placebo-controlled, randomized withdrawal study with open-label extension, to assess the efficacy and safety of rilonacept treatment in subjects with recurrent pericarditis (RHAPSODY)	NCT03737110	Time to recurrence of pericarditis	Active but not recruiting, June 2021
Anti-inflammatory agents	Treatment of Acute Pericarditis with Anakinra (none)	NCT03224585	Change in pain, measured by Visual Analog Score, within 6–12 h	Active, not recruiting, March 2021

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Gout Pharmacotherapy in Cardiovascular Diseases

A Review of Utility and Outcomes

Abstract and Introduction

Abstract

Introduction

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Tables

References

Authors and Disclosures

Authors and Disclosures

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