Do drugs that suppress the immune system improve outcomes in those with or at risk from atherosclerosis?
Key messages
- We found some limited evidence that some agents may reduce the risk of developing heart failure, but we are very uncertain about the results.
- We found no difference in death rates or any evidence that these agents reduce the risk of heart attack or stroke.
- Due to the limitations of the available studies, more robust research is needed to draw firm conclusions about the effectiveness of these agents in preventing cardiovascular events.
What is atherosclerotic vascular disease?
Atherosclerosis is the process of narrowing and blocking arteries. High blood pressure, high cholesterol, diabetes, and smoking increase the risk of this occurring, as do age and genetic factors. When atherosclerosis develops, arteries can narrow or block, resulting in angina, heart attacks, stroke, and problems with circulation in the feet and legs (peripheral vascular disease). These diseases, which result from narrowing arteries around the body caused by this process, are described broadly as atherosclerotic vascular disease (ACVD). It has also been noted that chronic inflammation can increase the risk too, and many studies have been done to see if drugs which affect the immune system and dampen inflammation can affect this disease process.
What agents have we studied that affect the immune system?
Interleukin-1 (IL-1) is a substance that causes an inflammatory process when it binds to its receptor (IL-1R). Anakinra and canakinumab are drugs which block (“antagonise”) the binding of IL-1 to the IL-1 receptor and are termed IL-1RAs. Anakinra is used, for example, to treat rheumatoid arthritis.
Interleukin-6 (IL-6) is similar, and a drug called tocilizumab blocks the IL-6 receptor to prevent the inflammatory process from developing.
Tumour necrosis factor-alpha (TNF-a) is a cytokine. A cytokine is a small protein. TNF-a is involved in inflammation. Drugs such as infliximab, etanercept, and adalimumab inhibit TNF activity and dampen inflammation.
What did we want to find out?
We wanted to find out if there was any evidence that these drugs, which block inflammation, can affect the progression of ACVD and reduce the risk of dying or having a heart attack, stroke or other complications.
What did we do?
We gathered all the data we could on trials which used these agents and reported on outcomes of death, heart attack, stroke, peripheral vascular disease, heart failure, and also infection and side effects more broadly. We looked at 58 trials with over 20,000 participants. Some of those trials (34) looked at preventing the development of ACVD. The remainder (24) looked at the impact of giving these drugs to people who already had ACVD to see if they could prevent further problems from developing.
What did we find?
We found, broadly, that these agents have a very limited impact, if at all, on the development or progression of ACVD. We found no conclusive evidence of their effect on the risk of death, heart attack, stroke or peripheral vascular disease. They may have some impact on heart failure, but we are very uncertain about the results.
What are the limitations of the evidence?
We found that the trials contained several flaws in the way they were conducted and in the limited number of participants, preventing us from drawing definitive conclusions.
How up to date is this evidence?
We searched for studies that were published up to 20 February 2024.
This Cochrane review assessed the benefits and harms of using interleukin-receptor antagonists and tumour necrosis factor inhibitors for primary and secondary prevention of atherosclerotic diseases compared with placebo or usual care. However, the evidence for the predetermined outcomes was deemed low or very low certainty, so there is still a need to determine whether these interventions provide clinical benefits or cause harm from this perspective. In summary, the different biases and imprecision in the included studies limit their external validity and represent a limitation to determining the effectiveness of the intervention for both primary and secondary prevention of ACVD.
Atherosclerotic cardiovascular disease (ACVD) is worsened by chronic inflammatory diseases. Interleukin receptor antagonists (IL-RAs) and tumour necrosis factor-alpha (TNF) inhibitors have been studied to see if they can prevent cardiovascular events.
The purpose of this study was to assess the clinical benefits and harms of IL-RAs and TNF inhibitors in the primary and secondary prevention of ACVD.
The Cochrane Heart Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, EBSCO CINAHL plus, and clinical trial registries for ongoing and unpublished studies were searched in February 2024. The reference lists of relevant studies, reviews, meta-analyses and health technology reports were searched to identify additional studies. No limitations on language, date of publication or study type were set.
RCTs that recruited people with and without pre-existing ACVD, comparing IL-RAs or TNF inhibitors versus placebo or usual care, were selected. The primary outcomes considered were all-cause mortality, myocardial infarction, unstable angina, and adverse events.
Two or more review authors, working independently at each step, selected studies, extracted data, assessed the risk of bias and used GRADE to judge the certainty of evidence.
We included 58 RCTs (22,053 participants; 21,308 analysed), comparing medication efficacy with placebo or usual care. Thirty-four trials focused on primary prevention and 24 on secondary prevention. The interventions included IL-1 RAs (anakinra, canakinumab), IL-6 RA (tocilizumab), TNF-inhibitors (etanercept, infliximab) compared with placebo or usual care. The certainty of evidence was low to very low due to biases and imprecision; all trials had a high risk of bias.
Primary prevention:
IL-1 RAs
The evidence is very uncertain about the effects of the intervention on all-cause mortality(RR 0.33, 95% CI 0.01 to 7.58, 1 trial), myocardial infarction (RR 0.71, 95% CI 0.04 to 12.48, I² = 39%, 2 trials), unstable angina (RR 0.24, 95% CI 0.03 to 2.11, I² = 0%, 2 trials), stroke (RR 2.42, 95% CI 0.12 to 50.15; 1 trial), adverse events (RR 0.85, 95% CI 0.59 to 1.22, I² = 54%, 3 trials), or infection (rate ratio 0.84, 95% 0.55 to 1.29, I² = 0%, 4 trials). Evidence is very uncertain about whether anakinra and cankinumab may reduce heart failure (RR 0.21, 95% CI 0.05 to 0.94, I² = 0%, 3 trials). Peripheral vascular disease (PVD) was not reported as an outcome.
IL-6 RAs
The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.68, 95% CI 0.12 to 3.74, I² = 30%, 3 trials), myocardial infarction (RR 0.27, 95% CI 0.04 to1.68, I² = 0%, 3 trials), heart failure (RR 1.02, 95% CI 0.11 to 9.63, I² = 0%, 2 trials), PVD (RR 2.94, 95% CI 0.12 to 71.47, 1 trial), stroke (RR 0.34, 95% CI 0.01 to 8.14, 1 trial), or any infection (rate ratio 1.10, 95% CI: 0.88 to 1.37, I 2 = 18%, 5 trials). Adverse events may increase (RR 1.13, 95% CI 1.04 to 1.23, I² = 33%, 5 trials). No trial assessed unstable angina.
TNF inhibitors
The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.78, 95% CI 0.63 to 4.99, I² = 10%, 3 trials), myocardial infarction (RR 2.61, 95% CI 0.11 to 62.26, 1 trial), stroke (RR 0.46, 95% CI 0.08 to 2.80, I² = 0%; 3 trials), heart failure (RR 0.85, 95% CI 0.06 to 12.76, 1 trial). Adverse events may increase (RR 1.13, 95% CI 1.01 to 1.25, I² = 51%, 13 trials). No trial assessed unstable angina or PVD.
Secondary prevention:
IL-1 RAs
The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.94, 95% CI 0.84 to 1.06, I² = 0%, 8 trials), unstable angina (RR 0.88, 95% CI 0.65 to 1.19, I² = 0%, 3 trials), PVD (RR 0.85, 95% CI 0.19 to 3.73, I² = 38%, 3 trials), stroke (RR 0.94, 95% CI 0.74 to 1.2, I² = 0%; 7 trials), heart failure (RR 0.91, 95% 0.5 to 1.65, I² = 0%; 7 trials), or adverse events (RR 0.92, 95% CI 0.78 to 1.09, I² = 3%, 4 trials). There may be little to no difference between the groups in myocardial infarction (RR 0.88, 95% CI 0.0.75 to 1.04, I² = 0%, 6 trials).
IL6-RAs
The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.09, 95% CI 0.61 to 1.96, I² = 0%, 2 trials), myocardial infarction (RR 0.46, 95% CI 0.07 to 3.04, I² = 45%, 3 trials), unstable angina (RR 0.33, 95% CI 0.01 to 8.02, 1 trial), stroke (RR 1.03, 95% CI 0.07 to 16.25, 1 trial), adverse events (RR 0.89, 95% CI 0.76 to 1.05, I² = 0%, 2 trials), or any infection (rate ratio 0.66, 95% CI 0.32 to 1.36, I² = 0%, 4 trials). No trial assessed PVD or heart failure.
TNF inhibitors
The evidence is very uncertain about the effect of the intervention on all-cause mortality (RR 1.16, 95% CI 0.69 to 1.95, I² = 47%, 5 trials), heart failure (RR 0.92, 95% 0.75 to 1.14, I² = 0%, 4 trials), or adverse events (RR 1.15, 95% CI 0.84 to 1.56, I² = 32%, 2 trials). No trial assessed myocardial infarction, unstable angina, PVD or stroke.
Adverse events may be underestimated and benefits inflated due to inadequate reporting.