the i nvestigation of the m anagement of p er i carditis
DESCRIPTION
The I nvestigation of the M anagement of P er i carditis. The IMPI Trial (‘ ee-MP-ee ’ means Warriors in Zulu). Duality of interests. B.M. Mayosi has received research grants from AstraZeneca, Cadila Pharma, Novartis, Pfizer, Roche, and Servier. Background. - PowerPoint PPT PresentationTRANSCRIPT
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 AstraZeneca, 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 non-pathogenic 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.
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
PATIENTS WITH DEFINITE OR PROBABLETUBERCULOUS PERICARDIAL EFFUSION
RANDOMIZATION
PREDNISOLONE
X 6 weeks
PLACEBO
X 6 weeks
M. w X 5 Doses
Placebo X 5 Doses
M. w X 5 Doses
IMPI Trial: Study Design
IMPI: Trial Interventions
• Prednisolone or placebo
–120 mg/day in 1st wk, followed by 90 mg/day in 2nd wk, 60 mg/day in 3rd wk, 30 mg/day in 4th wk, 15 mg/day in 5th wk, and 5 mg/day in 6th 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 CenterUniversity of Cape Town
South Africa
International Coordinating Center Population Health Research Institute
HHS and McMaster 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
Characteristics Prednisolone Placebo
N 706 694
Age in yrs 38.8 38.5
Female % 44.9 43.1
HIV positive % 67.1 67.0
Centesis done % 60.6 60.4
Definite TB % 26.7 26.7
Probable TB pericarditis % 71.7 72.9
Non-TB cause % 1.5 0.4
On anti-retrovirals % 14.0 15.0
0.5 2Prednisolone
BetterPlacebo Better
Primary efficacy outcome
DeathTamponadeConstrictionHospitalization
Opportunistic infectionMalignancyAE, Not HospitalizedInjection side effect
Prednisolone Placebo Hazard Ratio (95% CI) P
N(%) N(%)
168 (23.8) 170 (24.5 ) 0.95 (0.77 - 1.18 ) 0.66
133 (18.8) 115 (16.6 ) 1.15 (0.90 - 1.48 ) 0.26 22 ( 3.1 ) 28 ( 4.0 ) 0.77 (0.44 - 1.35 ) 0.37 31 ( 4.4 ) 54 ( 7.8 ) 0.56 (0.36 - 0.87 ) 0.01146 (20.7) 175 (25.2 ) 0.79 (0.63 - 0.99 ) 0.04
78 (11.0 ) 68 ( 9.8 ) 1.16 (0.84 - 1.61 ) 0.36 13 ( 1.8 ) 4 ( 0.6 ) 3.27 (1.07 - 10.03 ) 0.03171 (24.2) 149 (21.5 ) 1.15 (0.93 - 1.44 ) 0.20140 (19.8) 137 (19.7 ) 0.98 (0.77 - 1.24 ) 0.84
Effect of Prednisolone on Outcomes
0.5 2Mycbacterium
BetterPlacebo Better
Primary efficacy outcome
DeathTamponadeConstrictionHospitalization
Opportunistic infectionMalignancyAE, Not HospitalizedInjection side effect
Mycobacterium Placebo Hazard Ratio (95% CI) P
N(%) N(%)
156 ( 25.0) 152 (24.3) 1.03 ( 0.82 - 1.29 ) 0.81
119 ( 19.0) 111 (17.8) 1.07 ( 0.83 - 1.39 ) 0.59 22 ( 3.5 ) 22 ( 3.5 ) 0.99 ( 0.55 - 1.79 ) 0.98 36 ( 5.8 ) 37 ( 5.9 ) 0.97 ( 0.61 - 1.53 ) 0.89152 ( 24.3) 141 (22.6) 1.09 ( 0.87 - 1.37 ) 0.46
75 ( 12.0) 61 ( 9.8 ) 1.25 ( 0.89 - 1.75 ) 0.20 11 ( 1.8 ) 3 ( 0.5 ) 3.69 ( 1.03 - 13.24 ) 0.03148 ( 23.7) 149 (23.8) 1.00 ( 0.79 - 1.25 ) 0.97259 ( 41.4) 18 ( 2.9 ) 18.51 (11.47 - 29.87 ) <0.01
Effect of M. indicus pranii on Outcomes
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 HIV-associated 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.