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Treatment of Tuberculous
Pericarditis
Bongani M Mayosi
Department of Medicine
GROOTE SCHUUR HOSPITAL AND
UNIVERSITY OF CAPE TOWN
Copyright ©2004 BMJ Publishing Group Ltd.
George, S et al. Heart 2004;90:1338-1339
Figure 1 Apical four chamber view of a two dimensional echocardiogram of a patient with tuberculous pericardial effusion showing multiple fibrin strands as linear or band like structures
crossing the pericardial space or protruding from the epicardium or parietal pericardium and exudates. LA, left atrium; LV, left ventricle; Per eff, pericardial effusion; RA, right atrium; RV, right
ventricle.
Alfieri, O., Mayosi B.M. et al. (2014) Exploring unknowns in cardiology
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2014.123
Pericarditis is an important cause of acute heart failure in Africa
Mayosi BM et al. S Afr Med J 2008; 98:36-40
Low Survival Despite TB Rx
0
.25
.5.7
5
1
Cu
mula
tive P
ropo
rtio
n S
urv
ivin
g
0 50 100 150 200Survival time (days)
Clinical HIV No clinical HIV
Overall
17%
26%
40%
Relative risk (95%CI) of death for individuals treated with adjuvant prednisolone or placebo.
Ntsekhe M et al. QJM 2003;96:593-599
© Association of Physicians 2003; all rights reserved
Contemporary Use of Adjunctive
Steroids in TB Pericarditis
Wiysonge C et al. Int J Cardiol 2008; 124:388-390
17
0
21
0
22
13
4
19
10
48
2
29
0
10
20
30
40
50
60
Number of
participants
Cameroon Gauteng W Cape KZN E Cape Nigeria
No adjunctive corticosteroids Adjunctive steroids
The Investigation of the
Management of Pericarditis
Trial
The IMPI Trial
(Pronounced ‘ee-mp-ee’ for Zulu Warriors)
IMPI Trial: Hypothesis
•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 are uncertain.
IMPI Trial: 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 PROBABLE TUBERCULOUS 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 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 Trial: 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. w
IMPI Trial: 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 TBP % 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
Death
Tamponade
Constriction
Hospitalization
Opportunistic infection
Malignancy
AE, Not Hospitalized
Injection 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 ) 0.01
146 (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 ) 0.03
171 (24.2) 149 (21.5 ) 1.15 (0.93 - 1.44 ) 0.20
140 (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
Death
Tamponade
Constriction
Hospitalization
Opportunistic infection
Malignancy
AE, Not Hospitalized
Injection 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 ) 0.89
152 ( 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 ) 0.03
148 ( 23.7) 149 (23.8) 1.00 ( 0.79 - 1.25 ) 0.97
259 ( 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
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.