Oral Rheumatoid Arthritis Trial - ORAL Surveillance

Feb 01, 2022
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC; Neil Keshvani, MD
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
Pfizer
Date Published:
01/27/2022
Date Updated:
02/01/2022
Original Posted Date:
02/01/2022
References

Contribution To Literature:

Among patients with active rheumatoid arthritis despite methotrexate treatment in the ORAL Surveillance trial, incidences of MACE and cancer were higher with tofacitinib compared with a TNF inhibitor.

Description:

The goal of the trial was to assess the noninferiority of tofacitinib compared to a tumor necrosis factor (TNF) inhibitor in patients with active rheumatoid arthritis with regard to major adverse cardiovascular events (MACE) or cancers.

Study Design

Among patients with active rheumatoid arthritis receiving treatment with methotrexate, patients were randomized in a 1:1:1 open-label, noninferiority design to receive oral twice daily tofacitinib 5 mg (n = 1,455 ) or 10 mg (n = 1,456) or subcutaneous TNF inhibitor (n = 1,451). The TNF inhibitor was adalimumab 40 mg every 2 weeks in North America or etanercept 50 mg once weekly in the rest of the world. In February 2019, the 10 mg twice daily dose of tofacitinib was reduced to 5 mg twice daily after the data and safety monitoring board noted a higher frequency of pulmonary embolism compared to TNF inhibitor.

  • Total screened: 6,559
  • Total number of enrollees: 4,362
  • Duration of follow-up: median 4.0 years
  • Mean patient age: 61 years
  • Percentage female: 78%

Inclusion criteria:

  • Active rheumatoid arthritis despite methotrexate treatment
  • Age >50 years
  • Presence of one additional cardiovascular (CV) risk factor (smoking, hypertension, high-density lipoprotein <40 mg/dL, diabetes, family history of coronary heart disease, extra-articular rheumatoid arthritis, history of coronary artery disease)

Exclusion criteria:

  • Current or previous cancer except adequately treated nonmelanoma skin cancer

Other salient features/characteristics:

  • Mean duration of treatment: tofacitinib 5 mg, 41 months; tofacitinib 10 mg, 39 months; TNF inhibitor, 40 months
  • 31% of patients were aged ≥65 years
  • Mean disease duration: 31%
  • 48.2% with smoking history

Principal Findings:

The primary outcome, incidence of MACE (including death from CV causes, nonfatal myocardial infarction, or nonfatal stroke) for tofacitinib (combined doses) vs. TNF inhibitor, was 3.4% vs. 2.5%. Noninferiority was not shown (hazard ratio [HR] 1.33, 95% confidence interval [CI] 0.91-1.94) as upper boundary of the 95% CI was >1.8. Noninferiority was shown for 10 mg tofacitinib compared to 5 mg tofacitinib (HR 1.15, 95% CI 0.77-1.71) as upper boundary of the 95% CI <2.0.

The primary outcome, incidence of cancers for tofacitinib (combined doses) vs. TNF inhibitor, was 4.2% vs. 2.9%. Noninferiority was not shown (HR 1.48, 95% CI 1.04-2.09) as upper boundary of the 95% CI was >1.8. Noninferiority was shown for 10 mg compared to 5 mg tofacitinib (HR 1.0, 95% CI 0.7-1.43) as upper boundary of the 95% CI was <2.0.

Secondary outcomes for tofacitinib vs. TNF inhibitor:

  • Serious adverse event: tofacitinib 5 mg (24.1%), tofacitinib 10 mg (26.8%), TNF inhibitor (21.1%)
  • Serious infection: tofacitinib 5 mg (9.7%), tofacitinib 10 mg (11.6%), TNF inhibitor (8.2%)
  • Efficacy determined through Simplified Disease Activity Index score was similar

Interpretation:

The results of this trial indicate that among patients with active rheumatoid arthritis treated with methotrexate, risk of MACE and cancers was higher with tofacitinib compared to TNF inhibitors and did not meet prespecified noninferiority criteria. Rates of serious adverse events and serious infections were higher with tofacitinib compared to TNF inhibitors. Additionally, the data and safety monitoring board saw a higher rate or pulmonary embolism and mortality with the 10 mg twice daily dose of tofacitinib versus TNF inhibitors, and therefore, the tofacitinib dose of 10 mg twice daily was reduced to 5 mg twice daily partway through the trial.

Use of TNF inhibitors and other biologic disease-modifying anti-rheumatic drugs is associated with reduced risk of MACE. Compared to tofacitinib, efficacy was similar across both groups with sustained improvements noted. However, this study observed elevated risk of MACE and cancers with tofacitinib. The study authors calculate that during 5 years of treatment, 113 and 55 patients would need to be treated with tofacitinib (5 mg twice daily) instead of a TNF inhibitor to have an additional MACE or cancer event.

These findings raise significant concerns for future use of tofacitinib for rheumatoid arthritis and potentially other indications. It is unknown if excess MACE risk is due to greater reductions in MACE with TNF inhibitors or is due to increased risk of MACE with tofacitinib, as there was no placebo comparator arm. Along with the increased risk of cancers and opportunistic infections observed, the study findings indicate that tofacitinib should not be a first-line drug for patients with rheumatoid arthritis.

References:

Ytterberg SR, Bhatt DL, Mikuls TR, et al., on behalf of the ORAL Surveillance Investigators. Cardiovascular and Cancer Risk With Tofacitinib in Rheumatoid Arthritis. N Engl J Med 2022;386:316-26.

Editorial: Risks and Benefits of Janus Kinase Inhibitors in Rheumatoid Arthritis — Past, Present, and Future. N Engl J Med 2022;386:387-9.

Clinical Topics: Acute Coronary Syndromes, Cardiovascular Care Team, Dyslipidemia, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Hypertension, Smoking

Keywords: Acute Coronary Syndrome, Antirheumatic Agents, Arthritis, Rheumatoid, Coronary Artery Disease, Diabetes Mellitus, Hypertension, Lipoproteins, HDL, Methotrexate, Myocardial Infarction, Neoplasms, Primary Prevention, Pulmonary Embolism, Risk Factors, Smoking, Stroke, Tumor Necrosis Factor Inhibitors


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