Acute MI, Stroke Risks Rise in the Months After Gout Flares

Patients with gout flares are at heightened risk of acute MI or stroke—above and beyond their already increased cardiovascular risk—over the following 4 to 6 months, an observational study suggests.

The findings were consistent in two different types of analyses—a nested case-control study and a self-controlled cases series—and held up across multiple sensitivity analyses, lead author Edoardo Cipolletta, MD (University of Nottingham, England), and colleagues report in a study published in the August 2, 2022, issue of JAMA.

Though gout and other inflammatory diseases are known to be associated with increased cardiovascular risk, it hadn’t been clear whether acute flares of inflammation boost that risk even further. These findings suggest that is, in fact, the case.

“In patients with gout who are known to have cardiovascular disease or cardiovascular risk factors, they should be aggressively managed, be it by a cardiologist or by the family doctor, an internist,” senior author Abhishek Abhishek, MBBS, PhD (University of Nottingham), told TCTMD. “People with gout and recurrent flares, if they come in contact with any physician, the physician should be alert to the study findings and should consider either managing them long term with treat-to-target uric acid-lowering therapy or refer them to a local rheumatologist or the patient’s own family doctor for long-term management of gout.”

Managing gout in this way might prevent cardiovascular events, although that wasn’t assessed in the current study, Abhishek noted. Nonetheless, he said, “we should optimize the cardiovascular risk profile for gout patients and manage it aggressively.”

UK Clinical Practice Research Datalink

For the study, the investigators examined electronic health records of patients with gout spanning 1997 to 2020 from the UK Clinical Practice Research Datalink, using two different types of analyses to explore the link between gout flares and CV events (acute MI and stroke).

The nested case-control study included 10,475 patients with subsequent CV events and 52,099 without CV events (overall mean age 76.5 years; 69.3% men). Compared with patients without CV events, those who had an acute MI or stroke were significantly more likely to have had a gout flare in the preceding 60 days (2.0% vs 1.4%; adjusted OR 1.93; 95% CI 1.57-2.38) and 61 to 120 days (1.6% vs 1.2%; adjusted OR 1.57; 95% CI 1.26-1.96), with no significant difference observed 121 to 180 days before the event.

Those findings were supported by the results of a self-controlled case series that included 1,421 patients with a gout flare and a CV event. Compared with risk of acute MI or stroke in the 150 days before or 181 to 540 days after a gout flare, there were heightened risks in the following time periods after a flare:

• 0 to 60 days (adjusted incidence rate ratio [IRR] 1.89; 95% CI 1.54-2.30)
• 61 to 120 days (adjusted IRR 1.64; 95% CI 1.45-1.86)
• 121 to 180 days (adjusted IRR 1.29; 95% CI 1.02-1.64)

Those findings were similar in analyses restricted to patients treated with colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids.

Although the study cannot establish a causal relationship between gout flares and acute cardiovascular events, the researchers point toward inflammation as the likely driving force.

“Gout flares are characterized by neutrophil-rich acute inflammation due to NLRP-3 inflammasome activation,” they explain. “Neutrophilic inflammation is associated with atherosclerotic plaque instability and rupture. Activated intraplaque inflammatory cells upregulate host response proteins, including metalloproteinases and peptidases, and promote an oxidative stress, all of which contribute to plaque destabilization.”

Another potential mechanism, they add, revolves around a possible increase in atrial fibrillation, similar to what has been seen in relation to acute infection or surgery.

Optimize Treatment of CV Risk Factors

Jeffrey Anderson, MD, who wrote an accompanying editorial with Kirk Knowlton, MD (both Intermountain Medical Center, Salt Lake City, UT), told TCTMD that supporting evidence from animal and human studies, as well as intervention trials with anti-inflammatory therapies, makes it reasonable that there is a causal connection between gout flares and acute CV events. He noted that inflammation could precipitate acute MI, for instance, through either prothrombotic or prooxidant pathways, particularly if atherosclerotic disease is already present.

The observed excess risk associated with gout flares was not that great, but “we should be aware that it is a risk factor, and so we ought to optimize treatment of those standard risk factors, including lipids and blood pressure and sugar and weight,” Anderson said.

In addition, patients should be informed about the CV risk associated with flares so they know to seek immediate treatment if they show signs of an acute MI or stroke, he added.

Further studies will be needed, Anderson said, to determine whether any specific treatments administered after a gout flare—colchicine with or without aspirin, for example—can also reduce risks of cardiovascular events.

“More-potent IL-1 inhibitors (eg, rilonacept) and those targeting IL-18, which also is activated by the NLRP-type inflammasome, may be promising future approaches to reduce residual ASCVD risk,” Anderson and Knowlton note in their editorial, concluding, however, that “preventing gout flares with diet and uric acid-lowering likely represents the most important therapeutic opportunity to reduce gout flares and their associated risk of cardiovascular events.”

When a patient with gout is receiving cardiology care and is experiencing recurrent flares, Abhishek said, “it’s really important that the cardiologist links up with the family doctor or the rheumatologist who can then manage gout in the long term with treat-to-target uric acid-lowering therapy, which resolves urate crystal deposits and provides freedom from gout flares.” Further studies will be needed to determine whether this would ultimately result in fewer acute MIs and strokes, he said.

Note: One of the study authors, Mamas Mamas, BMBCh, DPhil, is TCTMD’s Senior Clinical Editor.