Tailored Immunosuppression in Inflammatory Cardiomyopathy - TIMIC

Jun 29, 2009
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Trial Sponsor:
Italian Ministry of Health
Date Presented:
01/01/2008
Date Published:
01/01/2009
Date Updated:
06/29/2009
Original Posted Date:
06/29/2009
References

Description:

There is currently no consensus on the management of patients with chronic inflammatory dilated cardiomyopathy, other than the use of standard heart failure medications. The role of immunosuppressive therapy in these patients, both pediatric and adult, remains controversial. The goal of this trial was to evaluate the efficacy of immunosuppressive therapy in adult patients with virus-negative inflammatory cardiomyopathy.

Hypothesis:

Immunosuppressive therapy would be associated with improved left ventricular (LV) function at 6 months compared with placebo in patients with virus-negative inflammatory cardiomyopathy.

Study Design

Study Design:

Patients Screened: 137
Patients Enrolled: 85
NYHA Class: II (56.4%), III (31.7%), IV (11.8%)
Mean Follow Up: 6 months
Mean Patient Age: 42.7 years
Female: 40
Mean Ejection Fraction: 27.1 ± 6.5%

Patient Populations:

  • LV dilatation, with an LVEF <45%
  • Age 18-75 years
  • Chronic heart failure unresponsive to standard heart failure management
  • Negative PCR for cardiotropic viruses such as EBV, HHV6, and HSV-12
  • Absence of congenital, valvular, or ischemic causes of cardiomyopathy
  • Histologic and immunohistochemical evidence of active lymphocytic myocarditis

Exclusions:

  • Recent onset (<6 months) of heart failure
  • Known etiology for heart failure
  • Steroid use in the 6 months preceding therapy
  • Contraindications to steroids or azathioprine
  • Pregnancy or lactation

Primary Endpoints:

Change in LVEF from baseline at 6 months, as assessed by echocardiography

Secondary Endpoints:

  • Change in LV dimensions
  • Presence of inflammation on biopsy at 6 months

Drug/Procedures Used:

Patients were randomized to receive either immunosuppressive therapy with prednisone (1 mg/kg daily for 1 month, followed by 0.33 mg/kg daily for 5 months), and azathioprine (2 mg/kg daily for 6 months), or matching placebo.

Concomitant Medications:

Digitalis, angiotensin-converting enzyme inhibitors, diuretics, carvedilol

Principal Findings:

A total of 85 patients were randomized, 43 to the immunosuppressive therapy arm and 42 to the placebo arm. There were no significant differences in the baseline characteristics between the two groups. The mean LV ejection fraction (LVEF) at baseline was 27.1 ± 6.5%, and most patients had New York Heart Association (NYHA) class II symptoms. Diagnostic angiography, biventricular angiography at baseline, and endomyocardial biopsy at baseline, 1 month, and 6 months were performed in all patients.

There was a significant improvement in LVEF in the immunosuppressive therapy arm compared with placebo at 6 months. In particular, 88% of the patients in the treatment arm showed an improvement in LVEF (26.5 ± 6.7 to 45.6 ± 9.6%) and LV end-diastolic diameter (LVEDD) (68.4 ± 7.0 to 54.4 ± 7.4 mm). None of the patients in the placebo arm improved, with 83% of the patients demonstrating further reduction in LVEF (27.7 ± 5.6 to 21.3 ± 5.3%) and further LV dilatation (68.8 ± 7.5 to 74.0 ± 7.6) (p < 0.001 for all comparisons). Symptomatically, there was a significant decrease in the number of patients reporting class III/IV symptoms in the treatment arm (p = 0.01).

Endomyocardial biopsy in the immunosuppressive therapy arm showed a marked improvement in inflammation, with disappearance of inflammatory infiltrates (responders) or reduction/disappearance of inflammation with degeneration of myocytes (nonresponders). Biopsy of the placebo arm demonstrated persistent myocardial inflammation and cell necrosis, with expansion of fibrosis.

There were no cardiac deaths or transplants in either arm at 6 months. Minor side effects such as weight gain and elevated plasma glucose were noted in the treatment arm.

Interpretation:

The results of this small randomized trial indicate that in adult patients with proven inflammatory, virus-negative, dilated cardiomyopathy, immunosuppressive therapy with prednisone and azathioprine for 6 months results in a significant improvement in the LVEF and LVEDD at 6 months, compared with placebo. There were no cardiac deaths or transplants at 6 months.

These results are certainly interesting, and large multicenter studies to corroborate these findings are necessary. If borne out by future studies, this could represent a novel approach to the management of heart failure in this subgroup of patients with chronic heart failure.

References:

Frustaci A, Russo MA, Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study. Eur Heart J 2009;Jun 25:[Epub ahead of print].

Randomized Study on the Efficacy of Immunosuppressive Therapy in Patients With Virus-Negative Inflammatory Cardiomyopathy: The TIMIC Study. Presented by Dr. Andrea Frustaci at the European Society of Cardiology Congress, Munich, Germany, August/September 2008.

Keywords: Prednisone, Azathioprine, Ventricular Function, Left, Pediatrics, Biopsy, Heart Failure, Myocarditis, Weight Gain, Cardiomyopathy, Dilated, Glucose


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