When Gout Flares, So Does the Cardiovascular System Save

We have spent decades teaching that a gout flare is a joint problem: a hot, swollen, painful joint that we treat with anti-inflammatory drugs and move on from (i.e., the treat to avoid symptoms strategy). The campaign title says it well — gout is more than flares. I would add that a flare is more than a joint problem. It is a transient, systemic inflammatory event and we should consider it as such.

Here are three points I would make to any colleague managing gout.

1. A flare casts a cardiovascular shadow that lasts weeks

In the 30–60 days after a gout flare, the risk of acute cardiovascular events rises. In a UK study, the odds of a recent flare were nearly doubled before a myocardial infarction or stroke (adjusted odds ratio (OR) 1.93, 95%CI 1.57–2.38), and a nearly five-fold rise in fatal cardiovascular events (adjusted OR 4.76, 95%CI 1.69–8.43). This association held in people newly diagnosed with gout and it was confirmed in an independent Western Australian cohort.

This is not limited to major adverse cardiovascular events. We have since seen the same temporal association for venous thromboembolism (adjusted incidence rate ratio 2.31, 95%CI 1.39–3.83), and for new tachyarrhythmia — mainly atrial fibrillation/flutter (adjusted OR 1.41, 95%CI 1.07–1.85). For tachyarrhythmia, the association was replicated in an independent Swedish cohort.

Different outcomes, same time window, same direction of association. Gout flares destabilise the cardiovascular system like any other acute systemic inflammatory insult such as flu and pneumonia.

2. Blame the inflammation, not the urate

This conceptual leap changes the way in which we manage gout. Hyperuricaemia and cardiovascular disease travel together, but Mendelian randomisation studies do not support serum urate as a causal driver of cardiovascular disease, and lowering urate in people without gout produced no cardiovascular benefit despite a large drop in serum urate (ALL-HEART trial). Inflammation is what distinguishes gout from asymptomatic hyperuricaemia. Systemically, NLRP3 inflammasome activation, via IL-1β, drives endothelial dysfunction and recruitment of inflammatory cells into atherosclerotic plaques, where matrix metalloproteinases thin the fibrous cap; the same pathway promotes myocardial dysfuncion, sympathetic activation, and a transient prothrombotic state.

Recent cardiology trials provide additional evidence supporting the link between inflammation and cardiovascular events. The interleukin-1β inhibitor canakinumab (CANTOS trial) and the colchicine, which inhibits the assembly of inflammasome components, trials (COLCOT and LoDoCo2 trials) showed that suppressing inflammation significantly lowers cardiovascular events compared with placebo. A recent Cochrane review of randomised controlled trials found that colchicine significantly reduced myocardial infarction (risk ratio 0.74, 95%CI 0.57–0.96) and stroke (risk ratio 0.67, 95%CI 0.47–0.95).

3. Treating gout properly is cardiovascular prevention

If the inflammation is the link, then good gout care is cardiovascular care. Two practical implications follow.

First, treat-to-target urate-lowering therapy does more than dissolve crystals. The recent GO TEST Overture trial showed that a treat-to-target strategy was associated with improved long-term disease control compared with a treat to avoid symptoms strategy. In addition, an emulated target trial of over 100,000 patients, reaching target urate (<360 µmol/L; 6 mg/dL) within a year was associated with significantly fewer major adverse cardiovascular events at five years (hazard ratio (HR) 0.91, 95%CI 0.89–0.92). In addition, in a separate cohort study, Wheeler and colleagues showed that reaching target serum urate lowered systemic inflammatory markers, including C reactive protein, at 24 and 48 months.

Second, not all medications to prevent gout flares are equal. Patients on NSAID prophylaxis had more cardiovascular events than those on colchicine (HR 1.56, 95%CI 1.11–2.17) in an emulated target trial. Since long-term colchicine reduces cardiovascular events in secondary prevention, we can hypothesise that gout flare prophylaxis with colchicine can reduce cardiovascular risk in people with gout at high cardiovascular risk. Yet mean prophylaxis duration in UK practice is around 45 days, well short of the guideline-recommended 3–6 months. Stopping early leaves patients exposed to recurrent flares and cardiovascular risk that comes with them. 

The bottom line

When a patient presents with a gout flare, you are not just looking at an inflamed joint. You are looking at someone whose cardiovascular risk is transiently elevated for the next month or two. You are also assessing a patient whose overall cardiovascular risk may not be adequately captured by current estimation tools (i.e., QRisk4, ASCVD+, SCORE2). That is the moment to start (or escalate) urate-lowering therapy with adequate prophylaxis, preferring favour colchicine whenever possible, and to carry out a comprehensive cardiovascular risk assessment that many of these patients have never had.

Gout really is more than flares and a flare is more than a painful joint.