Risk MACE or Cancers with Tofacitinib verses TNF Inhibitor in RA Patients

Table of Content

Introduction

Tofacitinib is a targeted synthetic disease-modifying antirheumatic drugs (DMARDs) that selectively inhibits Janus kinase (JAK)1, JAK3, and, to a lesser extent, JAK212,13. It is approved for the treatment of rheumatoid arthritis (RA) at doses of 5 mg twice daily or 11 mg once daily.

Aim

To compare the risk of major adverse cardiovascular events (MACE) or cancers with tofacitinib and TNF inhibitor in this patient population.

Patient Profile

Inclusion-exclusion criteria

Patients with active rheumatoid arthritis despite methotrexate treatment who was 50 years of age or older and had at least one additional cardiovascular risk factor (current cigarette smoker, hypertension, high-density lipoprotein cholesterol level of <40 mg per deciliter, diabetes mellitus, family history of premature coronary heart disease, extraarticular rheumatoid arthritis, or history of coronary artery disease).

 A key exclusion criteria was current or previous cancer, except adequately treated nonmelanoma skin cancer.

Methods

  • Randomized, open-label, noninferiority, post authorization, safety end-point trial
  • Patients were randomly assigned in a 1:1:1 ratio to receive tofacitinib at a dose of 5 mg or 10 mg twice daily or a TNF inhibitor

Endpoints

  • The coprimary end points were adjudicated MACE and cancers, excluding nonmelanoma skin cancer
  • The noninferiority of tofacitinib would be shown if the upper boundary of the two-sided 95% confidence interval for the hazard ratio was less than 1.8 for the combined tofacitinib doses as compared with a TNF inhibitor

Results

  • The trial was conducted at 323 sites in 30 countries from March 2014 through July 2020
  • Median follow-up duration was 4.0 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)

  • The most common cases of MACE were nonfatal myocardial infarction with tofacitinib and nonfatal stroke with a TNF inhibitor.
  • 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.
  • The incidence of cancers (excluding nonmelanoma skin cancer) was higher with the combined tofacitinib doses (4.2%; 122 patients) than with a TNF inhibitor (2.9%; 42 patients).
  • The most common cancers were lung cancer with tofacitinib and breast cancer with a TNF inhibitor.
  • Over a period of 5.5 years, the estimated cumulative probability of cancers was 6.1% with the combined tofacitinib doses and 3.8% with a TNF inhibitor.
Figure 1: Incidence rate for MACE and Cancer

  • The hazard ratios were 1.33 for MACE and 1.48 for cancers; the noninferiority of tofacitinib was not shown for the combined tofacitinib doses as compared with a TNF inhibitor
  • The incidence rates of MACE and cancer were higher among patients 65 years of age or older than among those younger than 65 years of age and higher among those in North America than among those in the rest of the world. The incidence rate was higher with tofacitinib than with a TNF inhibitor in North America.
  • The incidences of adjudicated opportunistic infections (including herpes zoster and tuberculosis), all herpes zoster (nonserious and serious), and adjudicated nonmelanoma skin cancer were higher with tofacitinib than with a TNF inhibitor
Table 1: Adverse events (Safety analysis population, 28-Day on-treatment Time) *

Event

Tofacitinib,

5 mg

Twice Daily

(N = 1455)

Tofacitinib,

10 mg

Twice Daily

(N = 1456)

TNF Inhibitor

(N = 1451)

Adverse event — no. (%)

91.6

92.3

90.1

Serious adverse event — no. (%)

24.1

26.8

21.1

 Discontinuation of trial treatment due to adverse event — no. (%)

 

 

 

Permanent discontinuation

14.4

20.9

14.5

Temporary discontinuation§

45.7

50.5

39.7

Adverse events of special interest

 

 

 

Serious infection — no. (%)

9.7

11.6

8.2

Hazard ratio vs. TNF inhibitor

1.17

1.48

Referent

Adjudicated opportunistic infection — no. (%)

39

44

21

Hazard ratio vs. TNF inhibitor

1.82

2.17

Referent

All herpes zoster, serious and nonserious — no. (%)

12.4

12.2

58 (4.0)

Hazard ratio vs. TNF inhibitor

3.28

3.39

Referent

Adjudicated hepatic event — (%)

3.2

4.9

2.4

Hazard ratio vs. TNF inhibitor

1.29

2.14

Referent

Adjudicated NMSC — (%)

2.1

2.3

1.1

Hazard ratio vs. TNF inhibitor

1.90

2.16

Referent

Adjudicated pulmonary embolism — (%)

0.6

1.6

0.2

Hazard ratio vs. TNF inhibitor

2.93

8.26

Referent

Adjudicated DVT — (%)

0.8

1.0

7 (0.5)

Hazard ratio vs. TNF inhibitor

1.54

2.21

Referent

Adjudicated VTE — (%)

1.2

2.3

0.7

Hazard ratio vs. TNF inhibitor

1.66

3.52

Referent

Adjudicated death from any cause — (%)

1.8

2.7

1.2

Hazard ratio vs. TNF inhibitor

1.49

2.37

Referent

  • Efficacy was similar in all three groups, with improvements from month 2 that were sustained through trial completion.

Conclusion

  • The results show that higher risk of MACE and cancers with tofacitinib than with TNF inhibitors and did not meet noninferiority criteria
  • The efficacies of tofacitinib and TNF inhibitors were similar across multiple outcomes
  • Several adverse events   such as serious infections, adjudicated opportunistic infections, adjudicated hepatic events, adjudicated venous thromboembolism were more common with tofacitinib

Reference

N Engl J Med 2022;386:316-26