The Investigation of the Management of Pericarditis The

The Investigation of the Management of Pericarditis The IMPI Trial (‘ee-MP-ee’ means Warriors in Zulu)

Duality of interests B. M. Mayosi has received research grants from Astra. Zeneca, Cadila Pharma, Novartis, Pfizer, Roche, and Servier

Background • Tuberculous (TB) pericarditis affects a million people per year. • The case fatality rate is 26% despite anti-TB treatment. • Hypotheses: – Anti-inflammatory effect of Steroids may reduce morbidity (i. e. , cardiac tamponade and constrictive pericarditis) and mortality in TB pericarditis. – Immunotherapy with Mycobacterium indicus pranii (Mw), a nonpathogenic environmental organism, may enhance cure of TB. • However, the effectiveness and safety of Steroids and Mw in TB pericarditis in uncertain.

IMPI: Primary Objectives To assess the effect of Prednisolone and Mw in definite or probable TB pericardial effusion on: (1)The composite outcome of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis; (2)The incidence of opportunistic infection and malignancy.

IMPI Trial: Study Design PATIENTS WITH DEFINITE OR PROBABLE TUBERCULOUS PERICARDIAL EFFUSION RANDOMIZATION M. w X 5 Doses PREDNISOLONE PLACEBO X 6 weeks Placebo X 5 Doses M. w X 5 Doses Follow-up data at hospital discharge, at weeks 2, 4 and 6, and months 3, 6 and thereafter 6 monthly for 2 years, and annually up to 4 years Placebo X 5 Doses

IMPI: Trial Interventions • Prednisolone or placebo – 120 mg/day in 1 st wk, followed by 90 mg/day in 2 nd wk, 60 mg/day in 3 rd wk, 30 mg/day in 4 th wk, 15 mg/day in 5 th wk, and 5 mg/day in 6 th wk. • M. w injection or placebo – 5 doses of 0. 1 ml intradermal injection at enrolment, then 2 wks, 4 wks, 6 wks, and 3 mo.

IMPI: Organization 19 centres, 8 countries African Coordinating Center University of Cape Town South Africa International Coordinating Center Population Health Research Institute HHS and Mc. Master University, Hamilton, Canada Sponsors: Canadian Institutes for Health Research, Cadila Pharma, South African Medical Research Council, Lily and Ernst Hausmann Trust

IMPI: Target Population Inclusion Criteria • • Age ≥ 18 years Pericardial effusion on echocardiography Evidence of definite or probable TB pericarditis Within 1 week of starting of anti-TB treatment • • Exclusion Criteria Presence of an alternative cause of pericardial disease Pregnancy Use of corticosteroids in the previous month Allergy to the M. indicus pranii

IMPI : Baseline Characteristics N Age in yrs Female % HIV positive % Centesis done % Definite TB % Probable TB pericarditis % Non-TB cause % On anti-retrovirals % Prednisolone 706 38. 8 44. 9 67. 1 60. 6 26. 7 71. 7 1. 5 14. 0 Placebo 694 38. 5 43. 1 67. 0 60. 4 26. 7 72. 9 0. 4 15. 0

IMPI Prednisolone: Time To Constriction

IMPI Prednisolone: Hospitalization

IMPI: Time To Malignancy

IMPI: Conclusions In those with definite or probable TB pericardial effusion: 1. Prednisolone for 6 weeks and M. w for three months had no significant effect on the combined outcome of death from all causes, cardiac tamponade requiring pericardiocentesis or constrictive pericarditis. 2. Both therapies were associated with an increased risk of HIVassociated malignancy. 3. However, use of prednisolone reduced the incidence of constrictive pericarditis and hospitalization. 4. The beneficial effects of prednisolone on constriction and hospitalization were similar in HIV-positive and HIV-negative patients.