Duality of interests
B.M. Mayosi has received research
grants from AstraZeneca, Cadila
Pharma, Novartis, Pfizer, Roche, and
Servier
Background
• Tuberculous (TB) pericarditis affects up to a million people per year
worldwide.
• The case fatality rate associated with tuberculous pericarditis is as
high as 40% despite anti-tuberculosis treatment.
• The use of adjunctive corticosteroids may reduce the inflammatory
response to tuberculosis and reduce morbidity (i.e., cardiac tamponade
and constrictive pericarditis) and mortality associated with the disease.
• There is also evidence that immunotherapy with Mycobacterium
indicus pranii, a non-pathogenic environmental organism, may reduce
inflammation associated with pulmonary TB.
•However, there is uncertainty about the safety and effectiveness of
adjunctive steroids and Mycobacterium indicus pranii in TB pericarditis
IMPI: Primary Objective
The primary objective of the Investigation of the Management of
Pericarditis (IMPI) Trial was to assess the safety and effectiveness of
oral prednisolone and Mycobacterium indicus pranii immunotherapy in
reducing the composite outcome of death, cardiac tamponade requiring
pericardiocentesis, or constrictive pericarditis in patients with definite or
probable tuberculous pericardial effusion.
IMPI: Study Design
• Randomized double-blind placebo-controlled 2x2 factorial
multi-centre and multi-national trial;
• Enrol 1400 patients with definite or probable TB pericardial
effusion over 36 months, and follow the last patient enrolled
for 6 months;
•Eligible patients were randomly assigned to receive oral
prednisolone or placebo for 6 weeks and Mycobacterium
indicus pranii injection or placebo for 3 months;
• Patients were followed at weeks 2, 4, 6, and months 3 and
6, six-monthly follow-up was performed thereafter for up to
four years.
IMPI: Trial Interventions
• Prednisolone and placebo were supplied as identical
tablets (5mg, 30mg and 40mg) and given at a dosage of
120 mg/day in the first week, followed by 90 mg/day in the
second week, 60 mg/day in the third week, 30 mg/day in the
fourth week, 15 mg/day in the fifth week, and 5 mg/day in
the sixth week.
• Patients enrolled in the Mycobacterium indicus pranii
received 5 doses of 0.1 ml of the vaccine intradermally (on
enrolment, at 2 weeks, 4 weeks, 6 weeks, and 3 months).
Patients in the control arm received a similar regimen of
placebo injections of normal saline in identically packaged
vials.
IMPI: Organization
19 Centers in Africa
African Coordinating Center
University 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
• Confirmed pericardial effusion on echocardiography
• Evidence of definite or probable TB pericarditis (Mayosi BM et al.
Circulation 2005)
• Within 1 week of starting of anti-TB treatment
• Informed consent
Exclusion Criteria:
• Presence of an alternative cause of pericardial disease
• Pregnancy
• Use of corticosteroids within the previous month
• Hypersensitivity or allergy to the Mycobacterium indicus pranii
IMPI Prednisolone: Selected Baseline Characteristics
Characteristics
N=
Age (SD)
Female (n, %)
HIV positive (n, %)
Centesis done (n, %)
Definite TB (n, %)
Probable TB pericarditis
Non-TB cause (n, %)
On anti-retrovirals (n, %)
Prednisolone
706
38.8 (13.5)
317 (44.9)
474 (67.1)
428 (60.6)
189 (26.7)
506 (71.7)
11 (1.5)
99 (14.0)
Placebo
694
38.5 (13.3)
299 (43.1)
465 (67.0)
419 (60.4)
185 (26.7)
506 (72.9)
3 (0.4)
104 (15.0)
IMPI Mycobacterium : Selected Baseline Characteristics
Characteristics
N=
Age (SD)
Female (n, %)
HIV positive (n, %)
Centesis done (n, %)
Definite TB (n, %)
Probable TB pericarditis
Non-TB cause (n, %)
On anti-retrovirals (n, %)
M. Indicus pranii
625
37.7 (12.5)
292 (46.7)
437 (69.9)
372 (59.5)
167 (26.7)
450 (72.0)
8 (1.3)
88 (14.1)
Placebo
625
39.3 (14.1)
263 (42.1)
403 (64.5)
381(61.0)
158 (25.3)
462 (73.9)
5 (0.8)
84 (13.4)
IMPI: Time To Primary Outcome
IMPI Prednisolone: Time To Constriction
IMPI Prednisolone: Hospitalization
IMPI: Time To Malignancy
IMPI Prednisolone: Sub-group analysis
IMPI Prednisolone: Sub-group analysis
IMPI: Conclusions
In those with definite or probable TB pericardial effusion:
1. Adjunctive therapy with prednisolone for 6 weeks and Mycobacterium
indicus pranii for three months did not have a 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 malignancies.
3. However, use of adjunctive steroids reduced the incidence of
pericardial constriction and hospitalization.
4. The beneficial effects of prednisolone on constriction and
hospitalization were similar in HIV-positive and HIV-negative patients.