Tailored Immunosuppression in Virus-Negative Inflammatory Cardiomyopathy - TIMIC

Oct 14, 2022
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC; Neil Keshvani, MD
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Italian Ministry of Health
Date Published:
09/21/2022
Date Updated:
10/14/2022
Original Posted Date:
10/13/2022
References

Contribution To Literature:

Among patients with virus-negative inflammatory cardiomyopathy, patients who received the TIMIC immunosuppressive regimen of prednisone and azathioprine for 6 months had improved LV function at 20-year follow-up compared with propensity-matched controls.

Description:

The goal of the trial was to evaluate long-term outcomes of patients enrolled in the original TIMIC trial and the response of relapsing myocarditis to a new TIMIC protocol immunosuppressive cycle.

Study Design

The TIMIC trial was a randomized, double-blind, placebo-controlled trial of oral immunosuppressive therapy (43 patients) of prednisone 1 mg/kg daily for 4 weeks, followed by 0.33 mg/kg for 5 months and azathioprine 2 mg/kg daily for 6 months versus placebo (42 patients) conducted from January 2001 to January 2007. At 6 months, all study patients in the placebo arm showed persistent or worsening cardiac dysfunction and were prescribed the 6-month immunosuppressive regimen.

The current study compares the entire original TIMIC trial group (n = 85) compared in 1:2 fashion to a propensity score-matched group of patients who did not receive immunosuppressive therapy from June 2000 to December 2005 (n = 170).

  • Mean patient age: 44 years
  • Percentage male: 59%
  • Mean left ventricular ejection fraction (LVEF): 26%

Inclusion criteria:

  • Admission for heart failure with biopsy-proven diagnosis of virus-negative chronic inflammatory cardiomyopathy without prescription of immunosuppressive drugs

Exclusion criteria:

  • Refusal to participate in the TIMIC study

Principal Findings:

The primary outcome, composite of cardiovascular death and heart transplantation, for the TIMIC group vs. the matched controls, was: 7.1% vs 41.2% (p < 0.001).

Components of the primary outcome for the TIMIC group vs. matched controls:

  • Cardiovascular death: 4.7% vs. 28.2% (p < 0.001)
  • Heart transplantation: 2.4% vs. 15.9% (p = 0.003)

Secondary outcome for TIMIC group vs. matched controls:

  • Implantable cardioverter-defibrillator (ICD) implantation: 10.6% vs. 42.4% (p < 0.001)
  • Recurrence of myocarditis: 5.9% vs. 8.2% (p = 0.62)

Interpretation:

The results of this trial show that, among patients with virus-negative inflammatory cardiomyopathy, treatment with a protocol of 6 months of immunosuppression with prednisone and azathioprine led to long-term reductions in cardiovascular death or heart transplantation as compared to propensity score-matched controls. Comparison to matched controls allows for better comparison to patients who did not receive the therapy, as all patients in the original TIMIC trial who were randomized to the placebo arm were then treated with immunosuppression after the trial ended. This study suggests persistence of myocardial inflammation that does not improve with supportive heart failure therapy and highlights the potential long-term efficacy of immunosuppressive treatment.

References:

Chimenti C, Russo MA, Frustaci A. Immunosuppressive therapy in virus-negative inflammatory cardiomyopathy: 20-year follow-up of the TIMIC trial. Eur Heart J 2022;43:3463-73.

Editorial Comment: Schultheiss HP, Escher F. Advanced diagnostics in inflammatory cardiomyopathy for personalized therapeutic decision-making. Eur Heart J 2022;43:3474-6.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Implantable Devices, SCD/Ventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Acute Heart Failure, Heart Transplant

Keywords: Azathioprine, Biopsy, Cardiomyopathies, Defibrillators, Implantable, Heart Failure, Heart Transplantation, Immunosuppression, Inflammation, Myocarditis, Prednisone, Prescriptions, Ventricular Function, Left


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