JAMA: A gout attack or a heart attack alarm! Data from more than 60,000 patients with gout show that gout attacks are associated with an increased risk of cardiovascular events in the short term

*For medical professionals only

Gout is a common, recurrent acute inflammatory arthritis[1] and the incidence of gout increases
year by year as living standards improve and dietary structure changes.

Gout is common in patients with cardiovascular disease, and a large number of studies have proved that gout is associated with cardiovascular disease, including myocardial infarction, heart failure, hypertension, etc.
, and is a risk factor
for cardiovascular disease.
Colchicine, originally a common drug used in gout, has been found in recent studies to prevent cardiovascular events in patients with inflammatory heart disease such as pericardial disease, coronary artery disease and atrial fibrillation, and further demonstrates the correlation between gout and cardiovascular events [2].

However, the short-term correlation between a gout attack and cardiovascular events is not known
.

Recently, the Edoardo Cipolletta team of the University of Nottingham published important findings in JAMA on the short-term correlation between gout and cardiovascular events[3], and found that gout attacks are associated with an increase in the incidence of short-term cardiovascular events, providing important theoretical support
for the early prevention of cardiovascular events after gout attacks in clinical work.

Screenshot of the first page of the paper

Let's take a look at how this retrospective observational study was conducted
.

Gout episodes are determined
by inpatient information, primary care clinics, and prescriptions (NSAIDs, glucocorticoids, or colchicine).
Cardiovascular events are defined as acute myocardial infarction or stroke (ischemic or hemorrhagic
).

The studies included gout patients aged ≥18 years in the data chain of clinical practice studies in England between 1 January 1997 and 31 December 2020, excluding patients who had been registered in the database for less than one year before the first diagnosis of gout, and patients whose first gout consultation was recorded on the same date as the cardiovascular event, analysed
using nested case-control studies and self-controlled case series (SCCS).

A total of 62,574 patients with gout were enrolled in the nested case-control study, and 1421 patients with gout episodes and cardiovascular events were included in the self-controlled case series to assess whether the gout episode was associated
with an increase in the incidence of cardiovascular events in the near term.

Nested case-control study cohorts

The results found that in the nest case-control study, 10,475 patients with newly diagnosed gout had at least one cardiovascular event following the gout attack, while 52,099 patients did not have related cardiovascular events
.

Patients with cardiovascular events had a significantly higher chance of having a gout attack in the first 60 days compared with patients who did not have a cardiovascular event (2.
0% vs 1.
4%; adjusted OR，1.
93）
。 In the period 61 to 120 days before the cardiovascular event, patients also had a higher rate of gout attacks than those who did not have a cardiovascular event (1.
6% vs 1.
2%; adjusted OR，1.
57）
。 Pushing back the clock, 121 to 180 days before the cardiovascular event, no significant difference was found in
the rate of gout attacks between the two groups.

Association between cardiovascular events and pre-event gout episodes (nest case-control study)

The self-controlled case series was observed for up to 720 days, and overall, the incidence of cardiovascular events after the gout attack gradually decreased
.
On the 0-60th day after the onset of gout in patients, the incidence of cardiovascular events is 2.
49 per 1000 people / day; Between 61 and 120 days, the incidence is 2.
16 per 1000 people/day; 121-180 days, the incidence rate is 1.
70 per 1000 people/day
.

The association between a gout attack and the occurrence of cardiovascular events gradually weakens
over time.
The incidence of cardiovascular events was 1.
32 per 1000 people/day
for the period 150 days before the onset of gout or 181 days to 540 days after the onset.
The final findings showed that in patients with gout, gout attacks were associated
with an increased short-term risk of cardiovascular events.
The self-controlled case series controlled all fixed confounding variables using themselves as controls, further confirming the results of the nested case-control studies and increasing the credibility
of the findings.

Correlation analysis of first gout attack with cardiovascular events (self-controlled case series)

Gout attacks are characterized by acute neutrophil-dominated inflammation caused by the activation of NLRP3 inflammasome [4
].
Neutrophil inflammation is associated with plaque instability and rupture in atherosclerosis[5].

Inflammatory cells that activate plaques upregulate reactive proteins, including metalloproteinases and peptidases, and promote oxidative stress, all of which exacerbate plaque instability [6
].
This may partly explain the link
between a gout attack and the risk of subsequent short-term cardiovascular events.

Of course, since this is an observational study, we cannot get a causal relationship between gout attacks and cardiovascular events, and secondly, due to the lack of clinical data, the severity of gout is not controlled
in the analysis.
However, this research result still provides important tips for the research work and clinical practice related to gout and cardiovascular disease, emphasizing that clinicians need to pay attention to the risks associated with gout attacks and cardiovascular events in patients and take preventive measures
in advance.
We can also optimize patient management processes by stratifying the risk of recent cardiovascular events and enabling more precise interventions based on different stratifications
.

References:

[1] Dalbeth N, Gosling AL, Gaffo A, Abhishek A.
Gout [published correction appears in Lancet.
2021 May 15; 397(10287):1808].
Lancet.
2021; 397(10287):1843-1855.
doi:10.
1016/S0140-6736(21)00569-9

[2] Nidorf SM, Fiolet ATL, Mosterd A, et al.
Colchicine in Patients with Chronic Coronary Disease.
N Engl J Med.
2020; 383(19):1838-1847.
doi:10.
1056/NEJMoa2021372

[3] Cipolletta E, Tata LJ, Nakafero G, Avery AJ, Mamas MA, Abhishek A.
Association Between Gout Flare and Subsequent Cardiovascular Events Among Patients With Gout.
JAMA.
2022; 328(5):440-450.
doi:10.
1001/jama.
2022.
11390

[4] Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J.
Gout-associated uric acid crystals activate the NALP3 inflammasome.
Nature.
2006; 440(7081):237-241.
doi:10.
1038/nature04516

[5] Ionita MG, van den Borne P, Catanzariti LM, et al.
High neutrophil numbers in human carotid atherosclerotic plaques are associated with characteristics of rupture-prone lesions.
Arterioscler Thromb Vasc Biol.
010; 30(9):1842-1848.
doi:10.
1161/ATVBAHA.
110.
209296

[6] Musher DM, Abers MS, Corrales-Medina VF.
Acute Infection and Myocardial Infarction.
N Engl J Med.
2019; 380(2):171-176.
doi:10.
1056/NEJMra1808137

Responsible editorWang Xuening