Q J Med 2004; 97: 525-535
QJM vol. 97 no. 8 © Association of Physicians 2004; all rights reserved.
Management of tuberculous constrictive pericarditis and tuberculous pericardial effusion in Transkei: results at 10 years follow-up
From the 1Royal Glamorgan Hospital, Ynysmaerdy, Llantrisant, 2MRC Clinical Trials Unit, London, and 3Royal Brompton Hospital, London, UK
Received 26 February 2004 and in revised form 22 April 2004
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Summary |
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Background: Tuberculous pericarditis is common in Transkei (Eastern Cape). Two randomized trials showed benefits at two years for prednisolone in patients with constrictive pericarditis, and open drainage plus prednisolone in patients with pericardial effusion.
Aim: To see whether the advantages of prednisolone and open drainage were maintained up to 10 years.
Design: Follow-up of randomized, double-blind, placebo-controlled trials.
Methods: All 383 patients (143 constriction, 240 effusion) received the same anti-tuberculosis chemotherapy. They were randomized to prednisolone or placebo for the first 11 weeks, and were followed-up over 10 years. Among the 240 with effusion, 122 were also randomized to immediate open surgical drainage of pericardial fluid versus pericardiocentesis as required. Adverse outcomes were: death from pericarditis, pericardiectomy, repeat pericardiocentesis, and subsequent open drainage.
Results: The 10-year follow-up rate was 96%. In constriction patients, adverse outcomes occurred in 19/70 (27%) prednisolone vs. 28/73 (38%) placebo (p = 0.15), deaths from pericarditis being 2 (3%) vs. 8 (11%), respectively (p = 0.098, Fisher's exact test). In effusion patients, adverse outcomes occurred in 14/27 (52%) with neither drainage nor prednisolone, vs. 4/29 (14%) drainage and prednisolone, 4/35 (11%) drainage and placebo, and 6/31 (19%) prednisolone and no drainage (p = 0.08 for interaction). Drainage eliminated the need for repeat pericardiocentesis. In the 176 with effusion and no drainage, adverse outcomes occurred in 17/88 (19%) prednisolone vs. 35/88 (40%) placebo patients (p = 0.003), with repeat pericardiocentesis 20 (23%) placebo vs. 9 (10%) prednisolone (p = 0.025). In a multivariate survival analysis (stratified by type of pericarditis), prednisolone reduced the overall death rate after adjusting for age and sex (p = 0.044), and substantially reduced the risk of death from pericarditis (p = 0.004). At 10 years, the great majority of surviving patients in all treatment groups were either fully active or out and about, even if activity was restricted.
Discussion: In the absence of a clear contraindication, a corticosteroid should be used in addition to antituberculosis chemotherapy in the management of patients with tuberculous pericarditis.
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Introduction |
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It has long been recognized that tuberculous pericarditis is common in Transkei.1,2 It may present either as subacute active constrictive pericarditis or as pericardial effusion. In 1987 and 1988, we published the results, two years from randomization, of two randomized controlled trials in the management of tuberculous pericarditis in Transkei. The first was a double-blind comparison of prednisolone vs. placebo as a supplement to 6 months of antituberculosis chemotherapy in the treatment of active constrictive tuberculous pericarditis.3–5 The results showed that prednisolone increased the rate of clinical improvement, reduced the risk of death from pericarditis and the need for pericardiectomy, and was associated with a higher proportion of patients with an overall favourable status. The second trial compared, in a factorial design: (i) immediate, complete, open surgical drainage of pericardial fluid vs percutaneous pericardiocentesis as required; and (ii) prednisolone vs. placebo, double-blind, as a supplement to 6 months of antituberculosis chemotherapy, in the treatment of tuberculous pericardial effusion.6 Open drainage eliminated the need for repeat pericardiocentesis. Prednisolone reduced the risk of death from pericarditis and the need for repeat pericardiocentesis, and was associated with a higher proportion of patients with an overall favourable status.
Regular follow-up of all patients continued, with an exceptionally high follow-up rate at ten years, largely owing to the dedication of the two nurses and three home visitors.7 Accordingly, we undertook an analysis 10 years from randomization to determine whether the early benefits were maintained, and to study any further differences emerging after the first two years.
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Methods |
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Details of the patients, their treatment and their assessments up to two years from randomization were given in the previous reports.3,6 In summary, they were from Transkei, of Xhosa ethnic origin, aged 5 years or more, with active non-calcific tuberculous constrictive pericarditis or pericardial effusion. They had received no previous antituberculosis chemotherapy, or no more than 2 weeks of treatment during the previous year. Those consenting to take part were all prescribed the same 6-month standard antituberculosis regimen of streptomycin, isoniazid, rifampicin, and pyrazinamide daily for 14 weeks as an in-patient, followed by isoniazid and rifampicin daily up to 6 months.
All patients were allocated at random to receive either prednisolone or matching placebo, on a double-blind basis, for the first 11 weeks of antituberculosis chemotherapy (Table 1).
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Among the patients with pericardial effusion, those who were willing, if allocated, to undergo complete open surgical drainage of pericardial fluid were allocated at random, in a factorial design, to (i) prednisolone or placebo and (ii) complete drainage by substernal pericardiotomy followed by continuous drainage,8 or percutaneous pericardiocentesis, as indicated clinically. Patients who were unwilling to undergo open drainage were treated by pericardiocentesis as required.
After the follow-up at 2 years from randomization, patients were asked to attend for assessment annually. Those who did not attend were visited or information on their status was obtained from their relatives, friends, headman or employer.7 Data were collected on treatment given, level of physical activity, and evidence of constriction and of tuberculosis. Level of physical activity was recorded as: 1 = activity unrestricted, 2 = out and about but activity restricted, 3 = confined to home or hospital, or 4 = bedridden. For patients who died, information was obtained on cause of death from hospital records, relatives, or other contacts. All the deaths were reviewed by an independent assessor without knowledge of the treatment group, and where possible, he classified the cause.
Statistical analysis
The previously reported analyses at two years were per-protocol analyses. Of the 143 patients with constriction, 29 (17 prednisolone, 12 placebo) were excluded from that analysis (7 incorrect diagnosis; 4 died of causes unrelated to pericarditis; 7 missed >6 weeks of antituberculosis chemotherapy; 11 could not be assessed owing to default). Of the seven misdiagnoses, five were considered subsequently to have chronic constriction and one each restrictive cardiomyopathy and liver failure. Thus, 114 (53 prednisolone, 61 placebo) were assessed at 2 years. Of the 240 patients with effusion, 42 (8 drainage, prednisolone, 8 drainage, placebo, 12 no drainage, prednisolone, 14 no drainage, placebo) were excluded from analysis (2 incorrect diagnosis; in 8 the allocated open drainage could not be done; 1 refused any treatment; 2 died before treatment could be started; 4 died of causes unrelated to pericarditis; 7 missed more than 21 days of antituberculosis chemotherapy in the first 3 months, or more than 42 days altogether; 18 could not be assessed owing to default). Thus, 198 (21 drainage, prednisolone, 27 drainage, placebo, 76 no drainage, prednisolone, 74 no drainage, placebo) were assessed at 2 years. Of the two misdiagnoses, one had amoebic pericarditis and the other myocardial disease with renal failure.
In contrast, the present analysis at 10 years was performed on an intention-to-treat basis. We also reanalysed all the 2-year data to compare findings with the original per-protocol analysis. In the analysis at 10 years, all randomized patients were included in the analysis of survival, patients with <10 years of follow-up being censored at the last date they were known to be alive. Those censored before 9 years, 10 months were considered lost to follow-up. The analysis of factors associated with death was performed using Cox proportional hazards regression models, separately for patients with effusion and patients with constriction, and for both groups combined. The following baseline variables, as measured in the previous reports,3,6 were included in an initial univariate analysis: age, gender, pulse rate, systolic pressure, diastolic pressure, pulse pressure, jugular venous pressure (JVP), degree of arterial paradoxus, liver enlargement, degree of ascites, degree of peripheral oedema, presence of tamponade, ECG voltage, cardiothoracic ratio, and level of physical activity. Variables that showed any evidence of association with death (p < 0.1) were entered into multivariate analyses along with treatment group.
The proportions of patients within each treatment group with adverse outcomes were compared using the 
2 test. The proportion of patients dying of pericarditis or postoperatively in all patients combined was tested using the Mantel-Haenszel test. Perioperative deaths were those occurring during or within 30 days after pericardiectomy. Adverse outcomes were defined as death from pericarditis, pericardiectomy, repeat pericardiocentesis, and subsequent open drainage of pericardial fluid.
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Results |
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Patients assessed
Between July 1980 and September 1984, a total of 383 patients (143 with constrictive pericarditis, 240 with pericardial effusion) were randomized (Figure 1); 122 with effusion were randomized, in a factorial design, to both comparisons and the remaining 118 to prednisolone vs. placebo. The characteristics of the patients on admission are shown in Table 2. In the constriction group, the great majority had evidence of severe constriction, with tachycardia, low pulse pressure, raised JVP, enlarged liver, ascites, oedema and restricted physical activity. In the effusion group too, most patients had substantial cardiac embarrassment with restricted physical activity; 10% had tamponade.
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In the intention-to-treat analysis using 2-year data, 17 more patients (6 with constriction, 11 with effusion) were assessable than in the previously published reports.3,6 However, their inclusion made no difference to the outcomes, and this analysis is not reported further.
Adverse outcomes
In patients with constriction, adverse outcomes of any type during the 10 years (Table 3) were less frequent in the prednisolone than in the placebo group, occurring in 19/70 (27%) vs. 28/73 (38%), respectively (2 = 2.04, p = 0.15). The difference was largely accounted for by deaths from pericarditis, which occurred in two (3%) and eight (11%) of the respective groups (p = 0.098, Fisher's exact test), although pericardiectomy was also required more often in the placebo group.
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In patients with pericardial effusion, repeat pericardiocentesis was less common in patients who underwent open drainage, occurring in 3/64 (5%) vs. 12/58 (21%) patients who did not have this procedure (
2 = 7.23, p = 0.007). It was also less common in those who were allocated prednisolone, occurring in 4/60 (7%) vs. 11/62 (18%) of those allocated placebo (2 = 3.47, p = 0.06). For any adverse outcome, there was, however, evidence of a treatment interaction between open drainage and prednisolone. Adverse outcomes of any type were more frequent in the group of patients who received no drainage and no prednisolone than in any other group, occurring in 14/27 (52%) patients in this group compared with 4/29 (14%) who received both drainage and prednisolone, 4/35 (11%) drainage and placebo, and 6/31 (19%) prednisolone and no drainage. The test for interaction between open drainage and prednisolone was of borderline significance (p = 0.08).
In the no drainage-placebo group there were more deaths, more pericardiectomies and more repeat pericardiocenteses than in the other three groups. Open drainage reduced greatly the need for repeat pericardiocentesis and eliminated the need for subsequent open drainage.
In the comparison of prednisolone vs. placebo in patients with effusion, the 118 who declined to participate in the drainage comparison were combined with the 58 who were allocated no drainage. Adverse outcomes of any type were substantially less frequent in the prednisolone than the placebo group, occurring in 17/88 (19%) compared with 35/88 (40%), respectively (2 = 8.84, p = 0.003; difference 21%, 95%CI 7%–34%). Prednisolone greatly reduced deaths from pericarditis and the need for repeat pericardiocentesis, which was required in 9 (10%) prednisolone and 20 (23%) placebo patients (2 = 5.00, p = 0.025). The deaths attributed to pericarditis all occurred during the first 24 months, 18 of them during the first 3 months. All but one of the 58 pericardiectomies were undertaken during the first 24 months.
A total of eight patients were reported to have a recurrence of their tuberculosis: five pulmonary (one sputum-positive), two pleural and one pericardial effusion, 10 years after entering the trial. Of the eight patients, two (one prednisolone, one placebo) were in the constriction group and six (three prednisolone, three placebo) in the effusion group.
Survival
The survival analysis was based on all 383 randomized patients, only 15 (4%) of whom were lost to follow-up before 10 years (Figure 1); there were 96 deaths in all.
In patients with constriction, the Kaplan-Meier survival plot (Figure 2) suggests improved survival in the prednisolone compared with the placebo group (death rates 27.6 per 1000 person-years prednisolone, 37.3 per 1000 person-years placebo at ten years), although the difference was not significant (2 = 0.70, p = 0.40, log rank test). In the multivariate Cox regression (Table 4), the only baseline variables that affected the death rate significantly were age and gender, with a greater risk for older patients (HR for a one-year increase in age 1.03, 95%CI 1.00–1.06) and males (HR 2.80 for comparison with females, 95%CI 1.39–5.63).
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In patients with effusion not treated with open drainage (Figure 3), there was also a suggestion of improved survival in the prednisolone group (death rates 25.0 per 1000 person-years prednisolone, 41.0 per 1000 person-years placebo at ten years), although the difference was not statistically significant (
2 = 2.46, p = 0.12, log rank test). In the Cox regression (Table 4), the only baseline variables that significantly affected the death rate were, again, age and gender, with a greater risk for older patients (HR for a one-year increase in age 1.06, 95%CI 1.04–1.09) and males (HR 2.72 for comparison with females, 95%CI 1.48–5.02). Combining the two patient groups and stratifying for type of pericarditis, there was evidence (p = 0.044) that, after adjusting for age and sex, prednisolone conferred a significant survival advantage over placebo (HR 0.64, 95%CI 0.41–0.99).
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The causes of death are shown in Table 5. There was strong evidence that the proportion of patients dying from pericarditis or perioperatively was smaller in the prednisolone than in the placebo groups (p = 0.004, Mantel-Haenszel stratified
2 test). Most deaths, however, were from causes unrelated to pericarditis. The perioperative mortality rate for pericardiectomy was 6/58 (10%).
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Levels of physical activity
The analysis of levels of physical activity at 10 years (Table 6), showed that the majority of survivors were out and about, but with some restriction of activity; very few were confined to home or hospital, and none were bedridden. Of the 67 prednisolone and 69 placebo patients with constriction who were assessed, 46 (69%) and 46 (67%), respectively, were out and about, even if with some restriction. The corresponding figures for patients with effusion who did not undergo drainage were 60/84 (71%) and 49/82 (60%) (
2 2.51, p = 0.11).
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Discussion |
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The main reasons for undertaking the present follow-up were to see whether the previously reported advantages of prednisolone and of open drainage were maintained, and to assess the risks of late constriction and of death from pericarditis after 2 years. Follow-up was remarkably complete, and so bias from missing data is very unlikely. Particularly important findings are that the benefits of prednisolone and open drainage were maintained, that no deaths attributed to pericarditis were seen between 2 and 10 years, and that only one patient required pericardiectomy for constriction after 2 years.
The patients were, in general, in poor clinical condition on entry to the trial. The benefits of treatment were assessed in terms of the avoidance of adverse outcomes (death from pericarditis, pericardiectomy, repeat pericardiocentesis, subsequent open drainage of pericardial fluid). In patients with constriction, prednisolone reduced the proportion of patients with adverse outcomes from 38% to 27%, although this difference was not significant (p = 0.15), reducing pericarditis deaths from 11% to 3% (p = 0.06). In patients with effusion, adverse outcomes were more frequent in patients who received neither prednisolone nor open drainage (52%) than in the other three groups (11–19%) (p = 0.08 for the interaction). Open drainage and prednisolone reduced greatly the need for repeat pericardiocentesis, and eliminated the need for subsequent open drainage, but had no effect on the proportions of patients dying from pericarditis. In patients with effusion but no drainage, prednisolone reduced the proportion of patients with adverse outcomes from 40% to 19% (p = 0.003), this reduction being accounted for largely by a reduction in the need for repeat pericardiocentesis from 23% to 10%.
After adjusting for age and gender, there was evidence of an overall survival advantage in the prednisolone groups (p = 0.044). The higher death rate that was found in older patients might have been expected, but not necessarily that in males. In spite of the poor clinical condition of patients on entry to the trial, at 10 years the great majority of surviving patients were fully active, or were out and about even if activity was restricted. In the constriction and effusion groups combined, prednisolone had a major influence in reducing deaths from tuberculous pericarditis (p = 0.004).
The ability of prednisolone to reduce the need for pericardiectomy is important, because pericardiectomy is a major procedure in a developing country, and carries a risk of perioperative mortality (10% in the current study).
The standard treatment for pericardial effusion is pericardiocentesis, which is safe, especially if echocardiography is available. However, open drainage on admission proved to be more effective; indeed, it virtually eliminated the need for repeat pericardiocentesis, which was necessary to relieve tamponade in 21% of patients who did not have open drainage. Therefore, when available, open drainage should be done. It is a minor procedure for a surgeon, can be done under local anaesthesia, and avoids entering the pleural space. It is also particularly valuable when the diagnosis is uncertain and an open diagnostic biopsy is necessary.8
An arguable limitation of the present study might be the accuracy of diagnosis. However, as reported previously, there was evidence of tuberculosis in 84% of patients with constriction (this being histological in 40% of those with specimens available) and in 73% of patients with effusion (this being bacteriological in 57%).3,6 Examination of pericardial fluid may be considered unnecessary in areas where tuberculous pericarditis is common and when another diagnosis is unlikely.9 In the present study, the diagnosis of effusion was made on clinical grounds, but was confirmed in all cases by aspiration of pericardial fluid. Two-dimensional echocardiography with an ATL 100 sector scanner became available during the intakes to the trials. With no change in entry criteria, echocardiography confirmed the nature of the pericardial disease in all the patients so studied.3,6 Echocardiography is the definitive investigation for pericardial effusion, and is particularly valuable for distinguishing effusion from subacute constriction. Subacute active constriction is due to fibrocaseous ‘porridge-like’ material within the pericardium, compressing the heart.
A Cochrane systematic review, last updated in June 2002,10 and a subsequent literature search by us, identified no other randomized trial comparing steroids vs. no steroids in addition to antituberculosis chemotherapy in presumed HIV-negative patients with tuberculous pericarditis. Of the four trials in the Cochrane review, two were the present trials, the third was not randomized,2 and the fourth involved only patients who were HIV-positive.11
The current trial was conducted before the HIV pandemic had affected Transkei. In a literature search, we identified only one randomized trial of the treatment of tuberculous pericarditis in HIV-positive patients.11 This compared prednisolone vs. placebo, double-blind, in addition to antituberculosis chemotherapy in 58 HIV-seropositive patients (29 prednisolone, 29 placebo) with tuberculous pericardial effusion in Zimbabwe. Prednisolone was associated with fewer deaths (5 prednisolone, 10 placebo) during 18 months of follow-up and more rapid clinical improvement, but showed no difference in radiographic or echocardiographic resolution of pericardial effusion. This trial provides additional evidence of benefit from giving a corticosteroid in addition to antituberculosis chemotherapy in patients with tuberculous pericarditis, however, further research to confirm these findings in HIV-infected patients is desirable.
In conclusion, this 10-year follow-up confirms our recommendation that, in the absence of a specific contraindication, a corticosteroid should be prescribed in addition to antituberculosis chemotherapy in the treatment of patients with active subacute tuberculous constrictive pericarditis or pericardial effusion. Also, it shows that a very high rate of follow-up can be achieved in the developing world. Experience in a small number of patients suggested that a higher dose of prednisolone with rapid reduction and shorter duration than in the present study may be more effective,12 and this merits further study.
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Acknowledgments |
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The independent assessors were Guy Scadding (deceased) and Eric Bateman. Between 2 and 10 years, chest radiographs were assessed by H. Goodman and electrocardiographs by B. Green, S. Latouf and B. Levatan. H.H.S. Kakaza (deceased), M. Patten, A.A.J. Aluvadeen, A. Pluta and B. Thomas helped with the follow-up assessments. The staff nurses were Edith Mndayi and Patience Mdlatu, and the home visitors No Amen Qala, Nombeko Ntobongwana, Nosakhele Nongawuza and Nophelo Nongawuza. We are grateful to them and to all the patients who participated. The studies were supported by grant 14290/1.5/BMO/CDJS/slp from the Wellcome Trust. Professor Bateman and Drs Goodman, Green, Latouf and Levatan were staff of the University of Cape Town.
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Footnotes |
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Address correspondence to Dr J.I.G. Strang, Royal Glamorgan Hospital, Ynysmaerdy, Llantrisant CF72 8XR. e-mail: george.strang{at}pr-tr.wales.nhs.uk
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References |
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1. Gelfand M. The sick African, 3rd edn. Cape Town, Juta and Co., 1957:494.
2. Schrire V. Experience with pericarditis at Groote Schuur Hospital, Cape Town: an analysis of 160 cases studied over a six year period. S Afr Med J 1959; 33:810–17.[Medline]
3. Strang JIG, Kakaza HHS, Gibson DG, Girling DJ, Nunn AJ, Fox W. Controlled trial of prednisolone as adjuvant in treatment of tuberculous constrictive pericarditis in Transkei. Lancet 1987; ii:1418–22.
4. Strang JIG. Tuberculous Pericarditis. Review Article. J Inf 1997; 35:215–19.
5. Strang G. Echocardiography in the developing world in Clinical Ultrasound. Wilde P, ed. Churchill Livingstone, Edinburgh, 1993.
6. Strang JIG, Kakaza HHS, Gibson DG, Allen BW, Mitchison DA, Evans DJ, Girling DJ, Nunn AJ, Fox W. Controlled clinical trial of complete open surgical drainage and of prednisolone in treatment of tuberculous pericardial effusion in Transkei. Lancet 1988; ii:759–64.
7. Strang JIG. Tracing patients in rural Africa. Lancet 1996; 348:1083–4.[Medline]
8. Cassell P, Cullum P. Technique of pericardial biopsy. Br J Surg 1967; 54:620–6.[Medline]
9. Maher D, Harries AD. Tuberculous pericardial effusion: a prospective clinical study in a low resource setting—Blantyre, Malawi. Int J Tuberc and Lung Dis 1997; 1:358–64.
10. Mayosi BM, Ntsekhe M, Volmink JA, Commerford PJ. Interventions for treating tuberculous pericarditis (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford, Update Software, 2002.
11. Hakim JG, Ternouth I, Mushangi E, Siziya S, Robertson V, Malin A. Double blind randomised placebo controlled trial of adjunctive prednisolone in the treatment of effusive tuberculous pericarditis in HIV seropositive patients. Heart 2000; 84:183–8.
12. Strang JIG. Rapid response of tuberculous pericardial effusions with high dose prednisone and anti-tuberculous drugs. J Infect 1994; 28:251–4.[CrossRef][Web of Science][Medline]
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