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Gout Flares Linked to Transient Jump in MI, Stroke Risk

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There is evidence that gout and heart disease are mechanically linked by inflammation, and patients with gout are at increased risk for cardiovascular (CV) disease. But do gout flares per se affect short-term risk of cardiovascular events? A new analysis based on records of British medical practice suggests that this may be the case.

The risk of myocardial infarction (MI) or stroke increased within weeks of isolated gout flares in more than 60,000 patients with a recent gout diagnosis. The risk jump, significant but small in absolute terms, persisted for about 4 months in the case-control study before disappearing.

Similar results were obtained in a sensitivity analysis that excluded patients who already had cardiovascular disease at the time of diagnosis of gout.

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An observational study cannot show that gout attacks per se temporarily increase the risk of myocardial infarction or stroke, but it is enough to send a warning to physicians who treat patients with gout, rheumatologist Abhishek Abhishek, PhD, Nottingham City Hospital, USA. Kingdom, told theheart.org | Medscape Cardiology.

In patients like this who also have conditions like hypertension, diabetes, or dyslipidemia, or a history of heart disease, he says, it’s important to “manage risk factors really aggressively, knowing that when these patients have a gout attack, there’s a temporary increase in risk of cardiovascular disease.

Managing their absolute cardiovascular risk—whether through drug therapy, lifestyle changes, or other interventions—should help limit the transient spike in risk of heart attack or stroke after a gout flare, suggested Abhishek, senior author of the study, published Aug. 2. JAMA edition with lead author Edoardo Cipolletta, MD, also from Nottingham City Hospital.

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The first reliable proof

A case-control study of more than 60,000 patients with a recent diagnosis of gout, some of whom had suffered a myocardial infarction or stroke, examined the frequency of such events at different time intervals after gout flares. Those who experienced such events were more than 90% more likely to have had a gout flare in the previous 60 days, more than 50% more likely to have a gout flare between 60 and 120 days before the event, but there was no increased likelihood until 120 days. days before the event.

Such an association between gout attacks and cardiovascular events was “suspected but never proven,” said rheumatologist Hyun K. Choi, MD, Harvard Medical School, Boston, who was not involved in the analysis. “This is the first time this has actually been shown in a reliable form,” he told theheart.org | Medscape Cardiology.

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The study suggests a “probable causal relationship” between gout attacks and cardiovascular events, but as the published report notes, it has limitations like any observational study, said Choi, who also directs the Center for Gout and Crystal Arthropathy at Massachusetts General Hospital. profile in Boston. “Hopefully this can be replicated in other cohorts.”

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He noted that the analysis took into account a number of relevant potential confounding factors, but could not take into account all the problems that might argue against gout flares as a direct cause of myocardial infarctions and strokes.

Gout attacks are a complex experience with a number of potential indirect effects on cardiovascular disease risk, Choi says. They can immobilize patients, for example, increasing the risk of thrombotic complications. They can be exceptionally painful, stressful, and can lead to frequent or chronic use of glucocorticoids or non-steroidal anti-inflammatory drugs (NSAIDs), which can exacerbate high blood pressure and possibly increase the risk of cardiovascular disease.

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Unique insight

The timing of gout attacks in relation to acute vascular events is not fully understood, notes the accompanying editorial. It states that the “unique insight” of the current study is that disease activity from gout was associated with a gradual increase in the risk of acute vascular events during the time period immediately following a gout flare.

Although the study is observational in nature, “a large body of evidence from animal and human studies, mechanistic insights, and clinical interventions” supports the link between outbreaks and vascular events and “makes causation highly reasonable,” state paper authors Jeffrey L. Anderson. MD, and Kirk W. Knowlton, MD, Intermountain Medical Center, Salt Lake City, UT.

The findings, they write, “should alert clinicians and patients to increased cardiovascular risk in the first weeks after a gout attack and should focus on optimizing preventive measures.” These may include “lifestyle measures and standard risk factor management, including diet, statins, anti-inflammatory drugs (eg, aspirin, colchicine), smoking cessation, control of diabetes and blood pressure, and antithrombotic drugs when indicated.”

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Choi said the current findings favor a more liberal use of colchicine and a preference for colchicine over other anti-inflammatory drugs in patients with gout and traditional cardiovascular risk factors, given the multiple randomized trials supporting the use of the drug in such cases. “If you use colchicine, you cover the risk of heart disease as well as gout. It’s two birds with one stone.”

Nested case-control study

Researchers accessed electronic health records for 96,153 newly diagnosed gout patients in England from 1997 to 2020; the median age of the cohort was about 76 years and 69% of the participants were male. They matched 10,475 patients with at least one CV event and 52,099 others who did not, by age, sex, and time since gout diagnosis. In each matched group of patients, those who did not have a CV event were assigned an interval between exacerbations and events based on their overlap with patients who did experience such an event.

In patients with cardiovascular events, compared with patients without events, the probability of having an exacerbation of gout in the 60 days preceding the disease was more than 90% higher, and the probability of an aggravation was more than 50% higher from 60 to 120. days before the CV event, but no more than 120 days before the event.

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Frequency of gout attacks and their timing in relation to cardiovascular events in the respective cohorts
Flash interval preceding CV event Patients with cardiovascular events, %, n = 10 475 Patients without cardiovascular events, %, n = 52,099 OR (95% CI)*
0-60 days before 2.0 1.4 1.93 (1.57–2.38)
61-120 days before 1.6 1.2 1.57 (1.26–1.96)
121-180 days before 1.4 1.3 1.06 (0.84–1.34)
*Adjusted for demographics, disease duration, body mass index, alcohol consumption, Charlson Comorbidity Index, hypertension, atrial fibrillation, dyslipidemia, previous year’s hospitalizations and primary care visits, cardiovascular drugs, and urate-lowering therapy.

The report noted that a self-controlled case series based on the same general cohort with gout produced similar results while eliminating any possibility of residual confounding, an inherent problem in any case-control analysis. It included 1421 patients with one or more gout flares and at least one MI or stroke after a gout diagnosis.

In this cohort, the ratio of cardiovascular event rates (CVF), adjusted for age and season of the year, as well as the time interval after a gout flare, was:

  • 1.89 (95% CI, 1.54–2.30) 0 to 60 days

  • 1.64 (95% CI, 1.45–1.86) 61 to 120 days

  • 1.29 (95% CI, 1.02–1.64) at 121–180 days

Also, as noted in the report, were the results of several sensitivity analyses, including one that excluded patients with confirmed cardiovascular disease prior to the diagnosis of gout; another that did not include patients with low to moderate cardiovascular risk; and one that only treated gout attacks treated with colchicine, corticosteroids, or NSAIDs.

The additional risks of CV events seen after exacerbations in the study were small, which “has implications for both cost-effectiveness and clinical relevance,” Anderson and Knowlton note.

“An alternative to universally enhancing CV risk prevention with therapy among patients with gout attacks,” they write, “could be “further risk stratification by identifying the group with the highest short-term risk.” Such interventions could potentially be identified by markers of cardiovascular risk, such as, for example, levels of highly sensitive C-reactive protein (hs-CRP) or lipoprotein (a) or plaque on calcium scans of the coronary arteries.

Abhishek, Cipolletta and other authors report no competing interests. Choi reported research support from Ironwood and Horizon; and consulting services from Ironwood, Selecta, Horizon, Takeda, Kowa and Vaxart. Anderson reports that his institution has received grants from Novartis and Milestone.

JAMA. 2022;328:440-450, 425-426. Abstract, Editorial

Follow Steve Stiles on Twitter: @SteveStiles2. Read more at theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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