Acute Gout And Cardiovascular Events: Exploring The Role Of Inflammation
Overview
In this study, the association between hospital admissions due to acute gout and major adverse cardiovascular events (MACEs) was investigated using data from the Hospital Morbidity Data Collection and Death Registrations of the Western Australian Rheumatic Disease Epidemiology Registry. The aim was to explore whether acute inflammation, a characteristic of gout, plays a mechanistic role in MACEs. The self-controlled case-series (SCCS) design was employed, focusing on patients with incident acute gout admissions and documented MACEs during specific periods.
The study identified 941 patients (average age: 76.4 years; SD: 12.6; 66.7% male) who experienced an incident acute gout admission and documented MACEs during the control and/or post-discharge periods. Among these patients, 898 (95%) had MACEs during the combined control period (365 days prior to admission and 365 days after the post-discharge period), and 112 (12%) during the post-discharge period (1-30 days after acute gout admission). The rates of MACEs during the total control and post-discharge periods were 0.84 and 1.45 events per person-year, respectively.
Utilizing conditional fixed-effects Poisson regression, the study revealed a significantly increased rate of MACEs during the post-discharge period (RR: 1.67; 95% CI: 1.38-2.03) compared with the control period. Sensitivity analyses were conducted to ensure the robustness of the results, considering known limitations of the SCCS design. The findings suggest a potential link between acute gout and an elevated risk of MACEs, emphasizing the need for further exploration of the mechanistic relationships between gout-related inflammation and cardiovascular events.
Introduction
This study explores the intricate relationship between gout and cardiovascular disease, the leading cause of heightened mortality in individuals with gout. While the association between gout and cardiovascular risk is established, the precise mechanisms remain poorly understood. The existing non-causal associations emphasize comorbidities like metabolic syndrome and obesity, contributing to oxidative stress and endothelial dysfunction. Causal theories implicate intracellular uric acid (UA) as a pro-oxidant and pro-inflammatory factor, potentially fostering hypertension and atherosclerotic plaque formation in gout patients.
The study delves into the less clear connection between chronic asymptomatic hyperuricemia (AH) and cardiovascular mortality. Conflicting evidence questions whether AH independently elevates cardiovascular risk, highlighting potential distinctions between gout-related UA levels and AH, alongside the impact of systemic inflammation in gout patients.
Considering the established role of inflammation in atherosclerosis, the study proposes that acute systemic inflammation during gout flares might significantly contribute to cardiovascular risk. Drawing parallels with intense systemic inflammation during influenza and acute myocardial infarction, the hypothesis posits that acute severe inflammation during gout flares could be a major contributor to major adverse cardiovascular events (MACEs) in individuals with gout.
The study specifically investigates the short-term risk of MACEs in the 30-day post-discharge period following an acute gout hospital admission (index admission). By comparing this post-discharge period with the 365 days preceding the index admission and the subsequent 365 days, the research aims to shed light on the potential impact of acute severe inflammation on cardiovascular risk in individuals with gout.
Methods
This study, approved by the Western Australia Department of Health Human Research Ethics Committee, leverages the Western Australian Rheumatic Disease Epidemiological Registry (WARDER) with a waiver of consent due to participant anonymization. Data sources include the Hospital Morbidity Data Collection (HMDC) covering hospitalizations from 1980 to 2014 and WA Death Registrations spanning 1980 to 2015. WARDER integrates these datasets through the WA Data Linkage System.
The study focuses on patients aged 25 years or older admitted between 1991 and 2012 for a first-ever acute gout hospital admission (index admission), excluding those who deceased during the index admission. Patient identification relies on specific codes from the International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification (ICD-9-CM and ICD-10-AM).
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The observation period, illustrated in Figure 1, initiates one year before the index admission. Two control periods are established: 1) one year before the index admission (control period 1) and 2) one year after the 30-day post-discharge period (control period 2), collectively forming the combined control period.
The primary outcome is the incidence of major adverse cardiovascular events (MACEs), a composite encompassing acute coronary syndrome, stroke, heart failure, or cardiovascular death. A 28-day interval is employed to distinguish recurrent events, ensuring accurate event categorization.
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Explanatory variables include patient sociodemographics, identified during the index admission, and medical history derived from HMDC diagnoses, adopting a fixed 10-year look-back from the index admission. Charlson comorbidity index conditions and additional coronary heart disease (CHD) are encompassed in the analysis. This comprehensive approach aims to explore the relationship between incident acute gout hospitalizations and subsequent MACEs, considering various demographic and medical factors.
Statistical Analysis
This study investigates the relationship between acute gout hospital admissions and major adverse cardiovascular events (MACEs) using a self-controlled case-series (SCCS) design. Data were extracted from the Western Australian Rheumatic Disease Epidemiology Registry, covering hospitalizations from 1980 to 2014 and death registrations from 1980 to 2015.
The SCCS design focuses on temporal associations between acute gout admissions and MACEs, treating each patient as their own control to minimize confounding. Conditional Poisson regression is employed to calculate rate ratios (RRs) for MACE occurrence during the postdischarge period (30 days) compared to the combined control period (730 days).
The study includes 987 patients aged 75.9 years on average, with a majority aged 65 years or older and 67% male. Among them, 57% had a history of MACEs, 64% had coronary heart disease (CHD), 21% had heart failure, 23% had cerebrovascular disease, and 31% had diabetes at incident admission.
Results
The study identifies 1000 patients hospitalized for incident acute gout, experiencing one or more major adverse cardiovascular events (MACEs) during the observation period. Thirteen patients who died during the incident admission, seven due to MACEs, were excluded. The average age of the remaining 987 patients was 75.9 years, with 85% aged 65 or older, 67% male, and notable comorbidities, including a history of MACEs (57%), coronary heart disease (64%), heart failure (21%), cerebrovascular disease (23%), and diabetes (31%) at the incident admission.
During the post-discharge and combined control periods, 120 and 941 MACEs occurred, resulting in rates of 1.48 and 0.85 events per person-year, respectively. The risk of experiencing MACEs was significantly higher in the post-discharge period compared to the combined control period (RR: 1.70; 95% CI: 1.41-2.04). Secondary analyses revealed effect modification based on a history of kidney disease and Charlson comorbidity index levels, with varying RRs.
In sensitivity analyses, excluding those who died during the post-discharge period or control period 2 maintained robust results (RR: 1.44; 95% CI: 1.11-1.88). Counting MACEs occurring more than 90 days apart yielded consistent findings (RR: 1.67; 95% CI: 1.39-2.02), as did excluding patients with a length of stay over 30 days at index admission (RR: 1.59; 95% CI: 1.29-1.96). These results strengthen the association between acute gout hospitalization and an increased risk of short-term MACEs.
Conclusion
This study, utilizing data from the Western Australian Rheumatic Disease Epidemiology Registry, investigates the relationship between acute gout hospitalization and major adverse cardiovascular events (MACEs). The analysis includes 1000 patients hospitalized for incident acute gout, with 13 exclusions due to deaths during the incident admission. The average patient age was 75.9 years, and the majority were male (67%) with prevalent comorbidities such as a history of MACEs (57%), coronary heart disease (64%), heart failure (21%), cerebrovascular disease (23%), and diabetes (31%).
Results reveal that during the post-discharge period, there were 120 MACEs, yielding a rate of 1.48 events per person-year, while the combined control period saw 941 MACEs at a rate of 0.85 events per person-year. The risk of MACEs was significantly higher during the post-discharge period compared to the combined control period (RR: 1.70; 95% CI: 1.41-2.04). Secondary analyses demonstrated variations in risk across subgroups based on kidney disease history and Charlson comorbidity index levels.
The study supports the hypothesis that systemic inflammation in gout is linked to an elevated risk of MACEs. Inflammation, critical in atherosclerosis development, is implicated in cardiovascular events, analogous to the association between acute influenza and myocardial infarction. The findings raise questions about the potential benefits of intense inflammation suppression in acute gout for improving cardiovascular outcomes. Limitations include the SCCS design assumptions and the lack of data on pharmacotherapy for acute gout in the cohort. Nonetheless, the study provides valuable insights into the multifactorial drivers of cardiovascular risk in gout and underscores the role of inflammation in this context.
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