A 2022 literature review compared current evidence on cardiovascular and neoplastic risk in patients with rheumatoid arthritis treated with Janus kinase inhibitors (JKIs). Although data from randomized controlled trials and real-world analyses reported conflicting findings regarding the risk of major adverse cardiovascular events (MACE) associated with tofacitinib, a post-marketing ‘ORAL surveillance’ safety study found that tofacitinib missed the trial’s co-primary endpoints to show non-inferiority to TNF inhibitors in risks for MACE and cancer. During a median follow-up of 4.0 years, the incidence of MACE was higher with the combined doses of tofacitinib vs. a Tumor Necrosis Factor inhibitor (3.4% vs. 2.5%; hazard ratio 1.33 [95% confidence interval [CI] 0.91 to 1.94] for MACE). The Food and Drug Administration (FDA) issued an alert and placed warnings on the JKI therapeutic class (including upadacitinib and baricitinib) based on these preliminary results in patients at least 50 years old who had at least one cardiovascular risk factor. [1], [2]

There were fewer safety data overall for MACE with upadacitinib compared to tofacitinib, likely due to its more recent approval. However, most efficacy and safety data of upadacitinib were derived from the SELECT program and reported comparable exposure-adjusted event rates of adjudicated MACE across treatment groups, 1.2 events/100 patient-years (PY) (95% CI 0.2 to 3.4) in placebo, 0.6 events/100PY (95% CI, 0.4 to 1.0) in upadacitinib 15 mg, and 1.0 events/100PY (95% CI 0.5 to 1.6) in upadacitinib 30 mg, respectively. Moreover, the incidence rates of MACE did not increase over time, and there was no pattern in the time onset for MACE. Notably, all patients with MACE during upadacitinib treatment had at least one cardiovascular risk factor at baseline. Thus, using upadacitinib still requires additional caution in at-risk patient populations. However, due to a lack of head-to-head comparisons between tofacitinib and upadacitinib, differing selectivity of the single molecule, and heterogeneous patient cohorts involved in clinical trials, definitive conclusions on comparative risk of MACE associated with each JKI had yet to be established. [1], [2], [3]

A 2019 meta-analysis of 26 randomized controlled studies assessed the incidence of MACE and venous thromboembolism events (VTEs) in patients with rheumatoid arthritis who received a JKI. General use of JKI was not associated with a significant increase in MACE or VTE events. Compared to placebo, MACE incidence risk was not significant for tofacitinib vs. placebo (odds ratio [OR] 0.93; 95% CI 0.18 to 4.67; p= 0.93 [I2= 0%; p= 0.99]) or upadacitinib vs. placebo (OR 1.55; 95% CI 0.16 to 15.15 p= 0.70 [I2= 0%; p= 0.99]). VTE incidence risk also had non-significance for tofacitinib vs. placebo (OR 0.17; 95% CI 0.03 to 1.05; p= 0.06 [I2= 37%; p= 0.21]) and upadacitinib vs. placebo (OR 1.77; 95% CI 0.20 to 16.00; p= 0.61 [I2= 0%; p= 0.99]). There was less data for upadacitinib than tofacitinib, reflected by the wider confidence interval range. Ultimately, although upadacitinib appeared to exhibit a higher risk for MACE and VTE and with insignificant heterogeneity between studies, all studies were placebo-controlled trials without direct comparisons. Follow-up duration was also limited within the studies (median 12 weeks versus placebo and median 24 weeks versus dose comparators). [4]

Rinvoq (Upadacitinib) Warnings: [5]

Mortality:
In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients treated with the JAK inhibitor compared with TNF blockers.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ.

Major Adverse Cardiovascular Events:
In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke was observed with the JAK inhibitor compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue RINVOQ in patients that have experienced a myocardial infarction or stroke.

Thrombosis:
Thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. Many of these adverse events were serious and some resulted in death.

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers.

If symptoms of thrombosis occur, patients should discontinue RINVOQ and be evaluated promptly and treated appropriately. Avoid RINVOQ in patients that may be at increased risk of thrombosis.

Lipids:
Treatment with RINVOQ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Assess lipid parameters approximately 12 weeks after initiation of treatment, and thereafter according to the clinical guidelines for hyperlipidemia. Manage patients according to clinical guidelines for the management of hyperlipidemia.

Xeljanz (Tofacitinib) Warnings: [6]

Mortality:
Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular (CV) risk factor treated with XELJANZ 10 mg twice a day had a higher rate of all-cause mortality, including sudden CV death, compared to those treated with XELJANZ 5 mg given twice daily or TNF blockers in a large, ongoing, postmarketing safety study.

A dosage of XELJANZ/XELJANZ Oral Solution 10 mg twice daily or weight-based equivalent twice daily, or XELJANZ XR 22 mg once daily, is not recommended for the treatment of RA, PsA, or pcJIA.

For the treatment of UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

Thrombosis:
Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions. Patients with rheumatoid arthritis 50 years of age and older with at least one CV risk factor treated with XELJANZ 10 mg twice daily compared to XELJANZ 5 mg twice daily or TNF blockers in a large, ongoing postmarketing study had an observed increase in incidence of these events. Many of these events were serious and some resulted in death.

A dosage of XELJANZ/XELJANZ Oral Solution 10 mg twice daily or weight-based equivalent twice daily, or XELJANZ XR 22 mg once daily is not recommended for the treatment of RA, PsA, or pcJIA.

In a long-term extension study in patients with UC, four cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer.

Promptly evaluate patients with symptoms of thrombosis and discontinue XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients with symptoms of thrombosis.
Avoid XELJANZ/XELJANZ XR/XELJANZ Oral Solution in patients that may be at increased risk of thrombosis. For the treatment of UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

Lipid Elevations:
Treatment with XELJANZ was associated with dose-dependent increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ/XELJANZ XR/XELJANZ Oral Solution therapy.
Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

A search of the published medical literature revealed 1 study investigating the researchable question:

What is the risk of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE) with upadacitinib versus tofacitinib?

D - Case reports or unreliable data  Read more→