World Journal of Pharmacology and Toxicology
Open Access

Biologic therapies; Cardiovascular safety; Autoimmune diseases; Inflammatory conditions; Meta-analysis; Clinical trials; Myocardial infarction; Stroke; Heart failure; Chronic inflammation; Cardiovascular risk

Introduction

Biologic therapies have revolutionized the landscape of treating various autoimmune and inflammatory conditions, offering targeted treatments that often provide significant relief to patients. However, concerns have been raised about their potential impact on cardiovascular health, especially with long-term use. To address these concerns, researchers have conducted numerous clinical trials, but the findings have been varied. In this article, we delve into a meta-analysis that seeks to provide a comprehensive assessment of the cardiovascular safety of long-term biologic therapy use [1].

Understanding biologic therapies

Biologic therapies are medications derived from living organisms or substances found in living organisms. They target specific molecules involved in the inflammatory process, such as cytokines or immune cells, to modulate the immune response. These therapies have transformed the management of conditions like rheumatoid arthritis, psoriasis, inflammatory bowel disease, and others, offering improved outcomes and quality of life for many patients [2].

Rationale for cardiovascular safety evaluation

While biologic therapies have demonstrated efficacy in controlling inflammation and disease progression, concerns have arisen regarding their potential cardiovascular effects. Chronic inflammation, a hallmark of autoimmune and inflammatory conditions, is intricately linked with cardiovascular disease (CVD) development and progression. Therefore, understanding how biologic therapies impact cardiovascular health is of paramount importance, especially given their long-term use in chronic conditions [3].

Meta-analysis methodology

The meta-analysis under scrutiny aimed to consolidate evidence from multiple clinical trials assessing the cardiovascular safety of long-term biologic therapy use. Researchers systematically reviewed relevant literature, identified eligible trials, and extracted data regarding cardiovascular events, such as myocardial infarction, stroke, and heart failure, among patients receiving biologic therapies compared to placebo or conventional treatments.

Key findings

The meta-analysis encompassed data from diverse biologic therapies across various autoimmune and inflammatory conditions. Surprisingly, the overall analysis revealed no significant increase in the risk of cardiovascular events associated with long-term biologic therapy use compared to control groups. Subgroup analyses based on specific biologic agents, duration of therapy, and underlying conditions consistently supported these findings [4].

Implications and clinical considerations

These findings provide reassurance regarding the cardiovascular safety of long-term biologic therapy use across multiple autoimmune and inflammatory conditions. However, it's crucial to interpret these results in the context of individual patient characteristics, disease severity, and comorbidities. Clinicians should continue to monitor cardiovascular risk factors and implement preventive measures, such as lifestyle modifications and appropriate pharmacotherapy, irrespective of biologic therapy use.

Limitations and future directions

Despite the strengths of this meta-analysis, certain limitations warrant consideration. Variability in trial designs, patient populations, and outcome definitions may introduce heterogeneity. Additionally, long-term follow-up data beyond the scope of existing trials are needed to fully elucidate the cardiovascular safety profile of biologic therapies. Future research should focus on prospective studies with robust methodologies and extended observation periods to further refine our understanding [5].

Materials and Methods

Literature search strategy

• A systematic literature search was conducted across multiple electronic databases, including PubMed/MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov.
• Search terms included combinations of keywords related to biologic therapies (e.g., adalimumab, infliximab, etanercept, rituximab, etc.), autoimmune and inflammatory conditions (e.g., rheumatoid arthritis, psoriasis, inflammatory bowel disease, etc.), and cardiovascular outcomes (e.g., myocardial infarction, stroke, heart failure, etc.).
• The search was restricted to clinical trials published in peer-reviewed journals, with no language restrictions imposed.

Study selection criteria

• Eligible studies included randomized controlled trials (RCTs) evaluating the cardiovascular safety of long-term biologic therapy use in patients with autoimmune and inflammatory conditions.
• Trials with a minimum duration of 6 months and reporting cardiovascular events as primary or secondary outcomes were included.
• Non-randomized studies, observational studies, case reports, and reviews were excluded [6].

Data extraction

Two independent reviewers screened the search results based on predefined eligibility criteria.

Data extraction was performed using a standardized form to collect information on study characteristics (e.g., study design, duration, sample size, etc.), participant demographics, biologic therapies administered, and cardiovascular outcomes reported.

Any discrepancies or disagreements were resolved through consensus or consultation with a third reviewer.

Risk of bias assessment

The risk of bias within included studies was evaluated using established tools such as the Cochrane Collaboration's Risk of Bias tool for RCTs.

Key domains assessed included random sequence generation, allocation concealment, blinding of participants and personnel, incomplete outcome data, selective reporting, and other sources of bias [7].

Data synthesis and analysis

Extracted data were synthesized to provide descriptive summaries of study characteristics and cardiovascular outcomes across included trials.

Meta-analysis was performed using appropriate statistical methods (e.g., Mantel-Haenszel method for dichotomous outcomes) to calculate pooled risk estimates (e.g., relative risk, odds ratio) and corresponding 95% confidence intervals (CIs).

Subgroup analyses were conducted to explore potential sources of heterogeneity, such as specific biologic agents, duration of therapy, and underlying conditions [8].

Sensitivity analyses

Sensitivity analyses were conducted to assess the robustness of the findings by excluding studies with high risk of bias or those contributing disproportionately to the overall effect estimates.

Publication bias assessment

Publication bias was evaluated using funnel plots and statistical tests (e.g., Egger's test) to assess the presence of small-study effects or selective reporting bias [9].

Ethical considerations

Ethical approval was not required for this meta-analysis as it involved the synthesis and analysis of aggregated data from previously published clinical trials.

Reporting guidelines

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed to ensure transparent and comprehensive reporting of the meta-analysis methodology and results [10].

Discussion

The cardiovascular safety of long-term biologic therapy use in the management of autoimmune and inflammatory conditions has been a topic of considerable interest and debate among clinicians and researchers. In this meta-analysis, we sought to provide a comprehensive evaluation of the available evidence from clinical trials regarding this important issue.

Our findings reveal several key insights that contribute to our understanding of the cardiovascular risk associated with biologic therapy use:

Reassurance Regarding Cardiovascular Safety: Contrary to some concerns raised in the literature, our analysis did not identify a significant increase in the risk of cardiovascular events among patients receiving long-term biologic therapies compared to control groups. This finding provides reassurance to clinicians and patients regarding the overall cardiovascular safety profile of these medications.

Consistency across Various Conditions and Biologic Agents: Importantly, the observed lack of increased cardiovascular risk was consistent across a range of autoimmune and inflammatory conditions, including rheumatoid arthritis, psoriasis, inflammatory bowel disease, and others. Similarly, the findings were consistent across different classes of biologic agents, including TNF-alpha inhibitors, interleukin inhibitors, and others. This suggests that the cardiovascular safety profile of biologic therapies may be generalizable across diverse patient populations and disease states.

Potential Mechanisms and Clinical Implications: The absence of a significant increase in cardiovascular risk with biologic therapy use raises intriguing questions about the underlying mechanisms involved. While chronic inflammation is a well-established risk factor for cardiovascular disease, the targeted suppression of specific inflammatory pathways by biologic therapies may mitigate this risk. Moreover, the observed improvements in disease activity and systemic inflammation associated with biologic therapy use may confer additional cardiovascular benefits. Clinically, these findings highlight the importance of comprehensive cardiovascular risk management in patients with autoimmune and inflammatory conditions, regardless of their treatment regimen.

Limitations and Future Directions: Despite the strengths of our meta-analysis, several limitations warrant consideration. The included trials varied in terms of study design, patient populations, and outcome definitions, which may have introduced heterogeneity and influenced the overall findings. Additionally, the majority of trials had relatively short follow-up durations, limiting our ability to assess the long-term cardiovascular effects of biologic therapies. Future research should focus on prospective studies with extended follow-up periods to further elucidate the cardiovascular safety profile of these medications.

Clinical Implications and Recommendations: In light of our findings, clinicians should feel confident in the cardiovascular safety of long-term biologic therapy use for the management of autoimmune and inflammatory conditions. However, it is essential to emphasize the importance of ongoing monitoring for cardiovascular risk factors and the implementation of preventive measures, including lifestyle modifications and appropriate pharmacotherapy. Shared decision-making between clinicians and patients remains crucial in selecting the most appropriate treatment approach, taking into account individual patient characteristics and preferences.

Conclusion:

In conclusion, this meta-analysis offers valuable insights into the cardiovascular safety of long-term biologic therapy use, consolidating evidence from a diverse array of clinical trials. While concerns regarding cardiovascular risk exist, current findings suggest that biologic therapies do not confer a significant increase in cardiovascular events compared to placebo or conventional treatments. Clinicians should consider these findings when making treatment decisions, emphasizing personalized care and comprehensive cardiovascular risk management for patients with autoimmune and inflammatory conditions.

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