Risk factors

Study clarifies cardiovascular risk for JAK inhibitor


Older patients taking the JAK inhibitor tofacitinib have a higher risk of cardiovascular events compared to those taking TNF inhibitors, according to results from a safety study published in the New England Journal of Medicine.

Findings of the ORAL Surveillance trial indicate that tofacitinib, in comparison with TNF inhibitors, is linked with increased risk of cardiovascular outcomes in subgroup of patients who are aged at least 50 years old and have risk factors or a history of cardiovascular disease, with an even higher risk found in patients aged 65 years or over.

The non-inferiority study was designed to test the hypothesis that the risk of major adverse cardiovascular events (MACE) or cancers (excluding non-melanoma skin cancer) would not be at least 1.8 times higher with tofacitinib than with a TNF inhibitor in this particular cohort of patients.

For the trial, carried out at 323 sites in 30 countries, a research team led by US rheumatologist Dr Steven Ytterberg randomised 4,362 patients (mean age: 61.2 years; 78.2% women; 76.9% White) with active RA to receive treatment with tofacitinib (5 mg or 10 mg twice daily; mean duration around 40 months) or a TNF inhibitor.

According to the data, during a median follow-up of four years, the incidence of MACE was higher with the combined tofacitinib doses (3.4%; 98 patients) than with a TNF inhibitor (2.5%; 37 patients). “Noninferiority was not shown for the combined tofacitinib doses as compared with a TNF inhibitor (hazard ratio, 1.33; 95% confidence interval, 0.91 to 1.94), because the upper boundary of the 95% confidence interval was more than 1.8,” the researchers noted.

Also, over a period of 5.5 years the cumulative estimated probability of MACE was 5.8% with the combined tofacitinib doses and 4.3% with a TNF inhibitor, while that of nonfatal myocardial infarction was 2.2% and 0.7%, respectively.

In a subgroup analysis of the data, the team found that the incidence of MACE was higher across trial groups among patients 65 years of age or older and higher with both tofacitinib doses than with a TNF inhibitor in this older age group.

The estimated cumulative probability of cancers in patients treated with both doses of tofacitinib was 6.1% with the combined tofacitinib doses and 3.8% with a TNF inhibitor. Again, the research found that the incidence rates of cancer were higher among patients 65 years of age or older than those younger.

Overall, the trial reported adverse events in 92% of patients given the 5 mg dose of tofacitinib, 92% of those treated with the 10 mg dose, and 90% of those in the TNF inhibitor group, while the respective incidences of serious adverse events were 24%, 27% and 21%.

“Taken together, these results show the higher risk of MACE and cancers with tofacitinib than with TNF inhibitors,” while “the efficacies of tofacitinib and TNF inhibitors were similar across multiple outcomes,” the authors concluded.

However, the absence of a placebo arm or other control groups in the trial prevented comparison with incidences of MACE and cancers with conventional synthetic DMARDs, other biologic DMARDs, or no treatment, while other important limitations include the study’s open-label design and a high dropout rate (more than 25%).

Implications for practice

An accompanying commentary article in the NEJM noted the FDA had added a safety warning for all JAK inhibitors – including upadacitinib and baricitinib –  considering the increased risks of MACE and cancer to be class effects. The FDA also changed the indications for tofacitinib and upadacitinib from incomplete response to methotrexate to incomplete response to a TNF inhibitor.

It said the implications for practice were that “in patients with RA who have an incomplete response to methotrexate and have active disease, a TNF inhibitor will be preferred to tofacitinib for a new start, especially in persons 65 years of age or older.”

“If patients strongly prefer or are only willing to take an oral DMARD and if the patient is 50 to 64 years of age, a detailed patient–provider discussion of the risks associated with tofacitinib as compared with TNF inhibitors and shared decision making are needed before choosing tofacitinib as the treatment option,” the authors added. “JAK inhibitors are among important oral treatment options for RA.”

Dr Laura Coates, rheumatologist and Associate Professor at University of Oxford, told the limbic: “For now, having a caution around all JAK inhibitors, particularly for patients who have cardiovascular risk, is more sensible,”

However, she also noted that the “lower absolute risk in younger patients potentially means that these drugs are still a reasonable option”.

“We’d like to think that more selective JAK inhibitors will not show the same safety signal but it was not obvious from the initial Phase III trials, so we just don’t know yet.

“I am having a detailed risk/benefit discussion with anyone who I am considering for tofacitinib regardless of indication. I think it’s a particular issue for older patients (>65) and also those with pre-existing cardiovascular risk, [and] in quite a few of our PsA patients given their higher prevalence of metabolic syndrome/diabetes, etc.”

A spokesperson for Pfizer Australia told the limbic: “ORAL Surveillance is the first large-scale, long-term cardiovascular and malignancy outcome clinical trial about JAK inhibitors in the rheumatoid arthritis (RA) patient population. These data make a very important contribution to understanding and advancing JAK science and care for patients with RA.”

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