Association Between Gout Flare and Subsequent Cardiovascular Events Among Patients With Gout

Abstract

Importance: Gout is associated with cardiovascular diseases. The temporal association between gout flares and cardiovascular events has not been investigated.

Objective: To investigate whether there is a transient increase in risk of cardiovascular events after a recent gout flare.

Design, setting, and participants: A retrospective observational study was conducted using electronic health records from the Clinical Practice Research Datalink in England between January 1, 1997, and December 31, 2020. A multivariable nested case-control study was performed among 62 574 patients with gout, and a self-controlled case series, adjusted for season and age, was performed among 1421 patients with gout flare and cardiovascular event.

Exposures: Gout flares were ascertained using hospitalization, primary care outpatient, and prescription records.

Main outcomes and measures: The primary outcome was a cardiovascular event, defined as an acute myocardial infarction or stroke. Association with recent prior gout flares was measured using adjusted odds ratios (ORs) with 95% CIs in a nested case-control study and adjusted incidence rate ratios (IRRs) with 95% CIs in a self-controlled case series.

Results: Among patients with a new diagnosis of gout (mean age, 76.5 years; 69.3% men, 30.7% women), 10 475 patients with subsequent cardiovascular events were matched with 52 099 patients without cardiovascular events. Patients with cardiovascular events, compared with those who did not have cardiovascular events, had significantly higher odds of gout flare within the prior 0 to 60 days (204/10 475 [2.0%] vs 743/52 099 [1.4%]; adjusted OR, 1.93 [95% CI, 1.57-2.38]) and within the prior 61 to 120 days (170/10 475 [1.6%] vs 628/52 099 [1.2%]; adjusted OR, 1.57 [95% CI, 1.26-1.96]). There was no significant difference in the odds of gout flare within the prior 121 to 180 days (148/10 475 [1.4%] vs 662/52 099 [1.3%]; adjusted OR, 1.06 [95% CI, 0.84-1.34]). In the self-controlled case series (N = 1421), cardiovascular event rates per 1000 person-days were 2.49 (95% CI, 2.16-2.82) within days 0 to 60; 2.16 (95% CI, 1.85-2.47) within days 61 to 120; and 1.70 (95% CI, 1.42-1.98) within days 121 to 180 after a gout flare, compared with cardiovascular event rates of 1.32 (95% CI, 1.23-1.41) per 1000 person-days within the 150 days before or the 181 to 540 days after the gout flare. Compared with 150 days before or the 181 to 540 days after a gout flare, incidence rate differences for cardiovascular events were 1.17 (95% CI, 0.83-1.52) per 1000 person-days, and adjusted IRRs were 1.89 (95% CI, 1.54-2.30) within days 0 to 60; 0.84 (95% CI, 0.52-1.17) per 1000 person-days and 1.64 (95% CI, 1.45-1.86) within days 61 to 120; and 0.38 (95% CI, 0.09-0.67) per 1000 person-days and 1.29 (95% CI, 1.02-1.64) within days 121 to 180 after a gout flare.

Conclusions and relevance: Among individuals with gout, those who experienced a cardiovascular event, compared with those who did not experience such an event, had significantly higher odds of a recent gout flare in the preceding days. These findings suggest gout flares are associated with a transient increase in cardiovascular events following the flare.

Figure 1.. Cohort Development in a Nested Case-Control Study of Cardiovascular Events After New Diagnosis of Gout

^aThe Clinical Practice Research Datalink is a longitudinal primary care database of anonymized health records of 15 million people across the United Kingdom from over 700 medical practices. It contains data about sociodemographics, lifestyle factors, diagnoses, consultations, and prescriptions recorded in primary care, hospitalization records, and mortality data. ^bAs many as 5 controls were matched to each case patient for age (± 2 years), sex, and duration of gout at first cardiovascular event (± 2 years). ^cThere were no exclusions from this group. All patients had at least 1 primary care consultation in the 12 months before the index date.

Figure 2.. Association Between Cardiovascular Event and Recent Prior Gout Flare in a Nested Case-Control Study

^aFor case patients, indicates days before the cardiovascular event; for controls, indicates days before the index date (counted from 0 as the event date or index date). ^bCase patients are individuals with cardiovascular events (defined as the first occurrence of acute myocardial infarction or a stroke after gout diagnosis). ^cControls are matched individuals with gout but without a cardiovascular event after diagnosis of gout. ^dIncludes matching variables (age, sex and disease duration). ^eIndicates the reference category. ^fIncludes model 1 variables plus demographics, body mass index, smoking status, alcohol intake status, and English Index of Multiple Deprivation. ^gIncludes variables from models 1 and 2 plus comorbidities (Charlson Comorbidity Index, hypertension, atrial fibrillation, hypercholesterolemia), number of hospitalizations in the previous year, number of primary care consultations in the previous year, and European Society of Cardiology individual cardiovascular risk, prescription of antiplatelets, statins, urate-lowering therapy, diuretics, and antihypertensives. Prescriptions were categorized as current (≤60 days), past (>60 days), or not prescribed prior to the cardiovascular event date or matched index date. ^hIncludes variables from models 1, 2, and 3 plus prescription of medications used for treating gout flares (colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids). Prescriptions were categorized as current (≤60 days), past (>60 days), or not prescribed prior to the cardiovascular event date or matched index date. OR indicates odds ratio.

Figure 3.. Association Between Acute Myocardial Infarction, Stroke, and Recent Prior Gout Flares in a Nested Case-Control Study

^aFor case patients, indicates days before the cardiovascular event; for controls, indicates days before the index date (counted from 0 as the event date or index date). ^bCase patients are individuals with cardiovascular events (defined as the first occurrence of acute myocardial infarction or a stroke after gout diagnosis). ^cControls are matched individuals with gout but without a cardiovascular event after diagnosis of gout. ^dThe analyses were adjusted for age, sex, disease duration, body mass index, smoking status, alcohol intake, English Index of Multiple Deprivation 2015, Charlson Comorbidity Index, hypertension, atrial fibrillation, hypercholesterolemia, number of hospitalizations in the previous year, number of primary care consultations in the previous year, European Society of Cardiology cardiovascular risk score, and current, past, or no prescription of certain drugs (diuretics, antiplatelets, statins, urate-lowering therapy, antihypertensives, nonsteroidal anti-inflammatory drugs, corticosteroids, and colchicine). ^eIndicates the reference category. OR indicates odds ratio.

Figure 4.. Results of the Self-controlled Case Series Analysis for Patients With a First Episode of Gout and a Cardiovascular Event

^aAcute myocardial infarction or a stroke. ^bAnalyses were adjusted for age and calendar season. ^cIndicates the induction interval. ^dBaseline period indicates 180 to 31 days before flare plus 181 to 540 days after flare. IRR indicates incidence risk ratio. See eTable 3 for self-controlled case series findings by gout flair treatments.