AIRTRIP

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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.
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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 patients with colchicine-resistant, steroid-dependent recurrent pericarditis, the IL-1B antagonist anakinra administered for 6 months after remission resulted in a 70% absolute reduction (2% incidence rate reduction) in recurrent pericarditis at 14 months. Notably, open-label use of anakinra prior to randomization also resulted in complete remission of pericarditis with successful weaning of both NSAID and steroid therapy in all patients treated. Patients assigned to anakinra did not reach median flare-free survival during this period while those assigned to placebo had a median flare-free survival of 72 days.

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[1]. 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, randomization to continued anakinra use was associated with a 70% absolute reduction in recurrent pericarditis (2% absolute incidence rate decrease) as well as a significant increase in median time to recurrence (which was achieved at 72 days in the placebo group and never achieved in the anakinra group). The continued use of colchicine therapy (which was optional in both arms) did not appear to modulate treatment effect. Side effects associated with anakinra were relatively modest (nearly all treated patients had a transient skin reaction and 14.3% of patients had significantly elevated transmmonases that resolved with dose reduction or temporary discontinuation), with no patients discontinuing the drug permanently due to adverse effects.

Given its small size, the results of AIRTRIP require further prospective validation in a larger RCT, but these are highly encouraging results both in terms of achievement of remission in patients with refractory recurrent pericarditis on maximal medical therapy with ability to wean off steroids and NSAIDs with anakinra, as well as maintenance of remission in these patients when anakinra is continued after achievement of remission. These results suggest that anakinra may be a safe and effective "bailout" therapy for patients with refractory recurrent pericarditis with an inability to wean off steroid therapy.

Guidelines

As of December 2016, 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

  • Study consisted of 2 phases
    • Phase 1: open-label treatment with anakinra administered daily for 60 days
    • Phase 2: double-blind withdrawal period in which patients who had a sustained complete response in part 1 were then randomized to anakinra or placebo
  • Sustained complete response defined as a reduction of 30% or more from baseline pericardial pain on a 21-circle visual analog scale, a 30% or greater decrease in CRP, and no increase in pericardial effusion on echocardiogram
  • Responders began to withdraw from steroids (over 6 weeks) and NSAIDs (over 15 days) at day 8 of Phase 1 before entry into Phase 2. Colchicine discontinuation was optional.
  • Patients could enter the study while taking whatever medications they were using to treat pericarditis (with the exception of IL-1 antagonists)
  • A clinical, laboratory, and echocardiographic assessment was performed at study day 1, day 4, and day 8 during Phase 1
  • Patients underwent clinical and laboratory evaluations at months 1, 2, 4, 6, 8, and at time of recurrence (if present) during Phase 2
  • 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
  • Study ended at the earlier of the end of Phase 2 or time of recurrence
  • Outcomes assessment was blinded to study treatment assignment

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

  • Very small trial which is underpowered to detect subgroup effects including effect modification by other pericarditis treatments such as colchicine
  • Open-label nature of anakinra use in Phase 1 (to induce remission) allows for possible bias
  • Exclusion of patients without complete response during Phase 1 prior to Phase 2 selects for anakinra responders, potentially overestimating the benefits of this therapy. However, all patients achieved complete response in Phase 1 making this criticism irrelevant
  • Relatively short duration of follow up limits conclusions regarding the long-term efficacy and/or 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

Further Reading

  1. Imazio M et al. Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial. Lancet 2014. 383:2232-7.