Major cardiac events not more common in patients receiving JAK inhibitors vs adalimumab
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The risks for major adverse cardiac events and venous thromboembolism in patients with rheumatoid arthritis did not significantly differ between those receiving Janus kinase inhibitors or adalimumab, according to data.
“Embolism and venous thromboembolism events (VTEs) and major adverse cardiovascular events (MACEs) have raised concerns among patients with rheumatoid arthritis (RA) receiving a Janus kinase inhibitor (JAKi) (both tofacitinib [Xeljanz, Pfizer] and baricitinib [Olumiant, Eli Lilly]),” Lea Hoisnard, MD, of the University hospital of Henri-Mondor, in Créteil, France, and co-authors wrote in Annals of the Rheumatic Diseases. “Janus kinase inhibitor (JAKi) agents have constituted a new treatment option for a few years.”
To investigate the impact of JAK inhibitors on the rates of MACEs and VTEs in patients with RA, Hoisnard and colleagues conducted a population-based study using information sourced from the French national health data system. The exposed cohort analysis included patients aged 18 years or older who had received at least one prescription of a JAK inhibitor between July 1, 2017, and May 31, 2021. Meanwhile, unexposed cohort patients — adults who instead received adalimumab (Humira, AbbVie) during the same period — were eligible if their RA symptoms matched the severity of those in the cohort exposed to JAK inhibitors.
The JAK inhibitors included in the analysis were tofacitinib (Xeljanz, Pfizer) and baricitinib (Olumiant, Eli Lilly & Co.). Patients who were JAK inhibitor- or adalimumab-naïve were selected.
To measure exposure duration, discontinuation of therapy was defined as a period of more than 90 days without a dispensation of the same therapy, or when a switch to a different therapy occurred.
The primary outcome was the occurrence of a MACE or VTE during follow-up. For this analysis, MACEs included acute myocardial infarction and ischemic stroke. VTEs included pulmonary embolism and venous thromboembolic events.
The total cohort included 15,835 patients, with 8,481 in the exposed group and 7354 in the non-exposed group. According to the researchers, there were 52 cases of MACEs in the exposed group and 35 in the non-exposed group. Additionally, there were 75 cases of VTEs in the exposed group and 32 in the non-exposed group.
The risk for MACEs among patients who received JAK inhibitors vs. those treated with adalimumab was not significant (HRw = 1; 95% CI, 0.7-1.5). The risk for VTEs in the exposed cohort, compared with the unexposed group, was also not significant (HRw = 1.1; 95% CI, 0.7-1.6). These results were consistent among patients aged 65 years or older with at least one cardiovascular risk factor, the researchers wrote.
“In this nationwide cohort study including 15,835 patients with RA, risk of MACEs and VTEs did not significantly differ between initiating a JAKi and initiating adalimumab,” Hoisnard and colleagues wrote. “Whether the JAKi was tofacitinib or baricitinib, these risks did not significantly differ from initiating adalimumab.
“Similar results were observed in patients with at least one cardiovascular risk factor who were 50 years or older and 65 years or older, whatever the gender was,” they added
References:
O’Shea JJ, et al. Annu Rev Med. 2015;doi:10.1146/annurev-med-051113-024537.
Perspective
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N. Lawrence Edwards, MD, MACP, MACR
This is a large population-based study using the French national health database that looked at the relative safety of Janus kinase inhibitors — tofacitinib (Xeljanz, Pfizer) or baricitinib (Olumiant, Eli Lilly & Co.) — compared with adalimumab (Humira, AbbVie), with respect to major adverse cardiovascular events (MACE) and venous thromboembolic events (VTEs). Adalimumab and JAK inhibitors are indicated for the treatment of moderate-to-severe rheumatoid arthritis and have been shown to have similar efficacy.
However, the FDA mandated additional post-marketing clinical trials to examine potential concerns regarding an increased risk for cardiovascular events and, subsequently, thromboembolic events in patients receiving JAK inhibitors. This current study by Hoisnard and colleagues supports the findings of previous post-marketing trials — the ORALSURV and STAR-RA trials — that JAK inhibitors do not add significant risk for MACE or VTEs in patients with RA even for those older than 65 years.
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David A. McLain, MD, MACR, FACP, FRCP
This study addresses the risk for major adverse cardiovascular events (MACE) and venous thromboembolism events (VTE) in patients with rheumatoid arthritis exposed to either a JAK inhibitor — tofacitinib (Xeljanz, Pfizer) or baricitinib (Olumiant, Eli Lilly) — or adalimumab (Humira, AbbVie). Like malignancy, cardiovascular risk is higher in untreated RA patients vs. the general population, with a pooled analysis demonstrating that CV risk was 48% higher in patients with RA. Studies have also demonstrated that anti-rheumatic treatment in RA with methotrexate and TNF inhibitors lowers CV risk.
All of the JAK inhibitors have been shown to increase HDL and LDL levels in RA patients. Active untreated patients with RA have lower LDL-C and HDL-C levels, which is called the “lipid paradox,” where lower levels of LDL are associated with an increased CV risk. In a study that focused on a detailed lipid analysis with a JAK inhibitor, besides causing an elevation of HDL-C and LDL-C, markers of HDL dysfunction improved after tofacitinib.
So, the relationship of JAK inhibitors and CV risk is complex, as is lipid biochemistry itself. Thrombogenesis is associated with lipids. Elevated triglyceride levels were associated with a doubling of risk for venous thrombosis in postmenopausal women, whereas elevated HDL cholesterol levels were associated with a decreased risk. Triglycerides, for example, seem to increase factor VII levels, plasminogen activator inhibitor (PAI-1) levels, and blood viscosity.
LDL promotes platelet activation and tissue factor expression. HDL has anti-atherothrombotic properties that may result from inhibition of platelet aggregation, reduction of viscosity, suppression of tissue factor activity and PAI-1 activity levels, and enhancement of inactivation of factor Va by activated protein C. So, the change in lipid level with JAK inhibition could influence thrombosis.
The present study found no increase in MACEs or VTEs in those starting JAK inhibitors vs. adalimumab. This was a real-world study and, as such, will not affect the black box warning that the FDA has required of the JAK inhibitors.
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