AIRTRIP

Published

Brucato A, et al. "Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence". Journal of the American Medical Association. 2016. 316(18):1906-1912.
PubMed • Full text

Clinical Question

In patients with colchicine-resistant, steroid-dependent recurrent pericarditis, does the IL-1B antagonist anakinra reduce recurrent pericarditis compared to placebo?

Bottom Line

In a small open-label trial, patients with colchicine-resistant, steroid-dependent recurrent pericarditis, the IL-1B antagonist anakinra was associated with a dramatic reduction in the pericarditis recurrence rate. At 14 months, only 2 out of 11 patients on anakinra experienced recurrent pericarditis (18%) compared to 9 out of 10 (90%) in the placebo group.

Major Points

Recurrent pericarditis is a major clinical problem affecting up to 30% of patients after a first episode of acute pericarditis and up to 50% of patients after a first recurrence when colchicine is not used. As shown in the ICAP trial, upfront combined therapy with both colchicine and anti-inflammatory agents is effective in reducing risk of recurrence after acute pericarditis, but even with this therapy recurrence still occurs around 20% of the time. Although oral steroids are often effective in treating recurrent pericarditis, patients who require steroids for this indication often have difficulty with recurrence when steroids are weaned off and are therefore exposed to the myriad side effects of long-term steroid therapy. Whether the addition of more novel anti-inflammatory agents may allow for steroid-sparing therapy in refractory recurrent pericarditis is unclear although there have been suggestions from retrospective studies and case series that anakinra may be effective in this setting.

The 2016 Anakinra-Treatment of Recurrent Idiopathic Pericarditis (AIRTRIP) study investigated whether the addition of anakinra, a selective IL-1B antagonist used primarily in rheumatoid arthritis, after induction of remission in 21 patients with recurrent pericarditis refractory to colchicine and requiring steroids, leads to more sustained remission with the possibility of steroid sparing. Patients with severe recurrent pericarditis (mean 7 previous episodes of pericarditis, all steroid dependent and > 70% on both NSAIDs and colchicine) were treated initially with open-label anakinra in order to induce remission of pericarditis while steroids and NSAID therapy were tapered off. After 60 days of open-label anakinra, patients were randomized to either continued anakinra for 6 months versus placebo. After the initial open-label period of anakinra therapy, all patients achieved complete response to anakinra by day 8 which remained sustained until day 60 (the point of randomization) with successful concomitant discontinuation of both NSAID and steroid therapy.

After median 14 months, only 2/11 (18%) of the anakinra group experienced recurrent pericarditis compared to 9/10 (90%) of the placebo group, a 70% absolute risk reduction, as well as a significant increase in median time to recurrence (72 days vs. unmet). Despite these encouraging results, this study should be interpreted cautiously, as there are many potential sources of error and bias. In addition to being a small, open-label trial subject to publication bias, the definition of recurrent pericarditis allows any fever to define recurrence--the primary outcome could be greatly skewed by fever suppression of unrelated illnesses. Nevertheless, the drug was relatively well tolerated with nearly all treated patients experiencing a transient skin reaction and 14.3% of patients had transaminitis that resolved with dose reduction or temporary discontinuation), with no patients discontinuing the drug permanently due to adverse effects.

The results of AIRTRIP require further prospective validation in a larger RCT, but these results are encouraging that anakinra may prove to be a safe and effective therapy to help achieve remission and prevent recurrence in patients with refractory recurrent pericarditis on maximal medical therapy.

Guidelines

As of December 2017, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, randomized, double-blind, placebo-controlled study
• N=21
  • Anakinra (n=11)
  • Placebo (n=10)
• Setting: 3 centers in Italy
• Enrollment: June 1, 2014 - November 30, 2014
• Median follow-up: 14 months
• Analysis: Intention-to-treat
• Primary outcomes: Recurrent pericarditis, median time to recurrent pericarditis

Population

Inclusion Criteria

• Recurrent idiopathic pericarditis (≥ 3 previous recurrences)
  • Diagnosis of pericarditis made when at least 2 of the following were present:
    • Pericarditic-typical chest pain (sharp and pleuritic, improved by sitting up and leaning forward)
    • Pericardial friction rub
    • Widespread ST-segment elevation or PR depression
    • New or worsening pericardial effusion
• Age > 2 and < 70 years
• CRP increased (> 1mg/dL) both in the first episode of pericarditis and in the following recurrences
• Patient on corticosteroid therapy with demonstrated failure to wean

Exclusion Criteria

• Secondary pericarditis (tuberculous, neoplastic, purulent, postcardiac injury, systemic inflammatory disease)
• Pregnant or lactating
• History of immunosuppression including positive HIV test
• Positive IGRA or PPD after the first attack of pericarditis
• Any live vaccinations within 3 months prior to the trial
• History of malignancy of any organ system within the past 5 years
• History of significant other medical conditions that in the investigator's opinion should exclude the patient from the trial
• History of recurrent or active bacterial, fungal, or viral infection

Baseline Characteristics

All patients

• Demographics: Age 45.4 years, male 33%
• Pericarditis: Duration 27.8 months, pain VAS score 7.7, pericardial effusion 85.7%, previous recurrences 6.8
• Laboratories: CRP 4.2
• Therapies: Corticosteroids 100%, NSAIDs 71.4%, colchicine 85.7%

Interventions

• Phase 1: open-label treatment with anakinra administered daily for 60 days
• Phase 2: complete responders were randomized to anakinra vs. placebo for an observed steroid and NSAID withdrawal period (colchicine discontinuation was optional)
  • Sustained complete response defined as a 30%+ reduction in baseline pericardial pain on a 21-circle visual analog scale, a 30%+ decrease in CRP, and no increase in pericardial effusion on echocardiogram
  • On Day 8 of Phase 1, Responders began to withdraw from steroids (over 6 weeks) and NSAIDs (over 15 days) before entry into Phase 2.
  • Clinical, laboratory, and echocardiographic assessment was performed at scheduled intervals throughout both phases

• Patients were monitored for 14 months or until recurrent pericarditis, defined as 1 or more of the following signs:
  • Fever
  • Pericardial friction rub
  • ECG changes consistent with pericarditis
  • Echocardiographic evidence of new or worsening pericardial effusion

Outcomes

Comparisons are anakinra versus placebo.

Primary Outcomes

Recurrent pericarditis

2 (18%) vs. 9 (90%); Mean difference -0.718 [95% CI -1.01 to -0.42] (P=0.001)

Median flare-free survival

Never achieved vs. 72 days (64-150); (P<0.001)

Adverse Events (Anakinra-treated patients)

Overall adverse events

20 (95.2%)

Local skin reactions

20 (95.2%)

Infection

1 (4.8%)

Elevated LFTs

3 (14.3%)

Ischemic optic neuropathy

1 (4.8%)

Adverse effects requiring permanent drug discontinuation

0 (0%)

Criticisms

• Colchicine use was not standardized and may have explained some of the variation in outcomes
• Weak definition of recurrent pericarditis. Fever alone meets criteria for recurrence. Anakinra may have improved outcomes through fever suppression of unrelated illnesses.
• Small sample size
• High probability of publication bias due to open label trial design
• Duration of follow-up limits conclusions about long-term efficacy and side effects of anakinra therapy

Funding

• SOBI (Sweden) provided anakinra and placebo as part of unrestricted institutional grant
• Authors with multiple ties to industry
• The study funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication