IMPI: No Immunotherapy Benefit in Tuberculous Pericarditis

Marlene Busko

September 08, 2014

BARCELONA, SPAIN — In the large Investigation of the Management of Pericarditis (IMPI) trial of patients with presumed tuberculous pericarditis, neither of two immunotherapies—prednisolone and Mycobacterium indicus pranii—reduced the primary efficacy outcome, a composite of death, cardiac tamponade, or constrictive pericarditis, during a median of close to two years[1].

However, in this trial, in which two-thirds of the participants were HIV-positive, both adjuvant therapies were linked with an increased rate of cancer, largely HIV-related cancers.

Prednisolone therapy was, however, associated with significantly reduced incidences of constrictive pericarditis and hospitalization.

"I think IMPI does give guidance to say that we need to be selective in the use of steroids in these patients [with tuberculous pericarditis], and we need to avoid them in people who are HIV positive . . . but in people who are HIV-negative, we may use them for their benefit on constriction and hospitalization," Prof Bongani M Mayosi (Groote Schuur Hospital and University of Cape Town, South Africa) said in a press briefing at the European Society of Cardiology (ESC) 2014 Congress . IMPI was presented at an ESC hot-line session and simultaneously published in the New England Journal of Medicine, with Mayosi as first author.

This study is important, since it shows that in patients with tuberculous pericarditis, "steroids may have a role in the long-term prevention of constrictive pericarditis—which is a devastating thing once you have it—but they are not to be used in patients with HIV, because of the risk of HIV-associated malignancies," ESC spokesperson Prof Paulus Kirchhof (University of Birmingham, UK) commented to heartwire .

Poor Survival With Current Treatment

Tuberculous pericarditis is a common cause of pericardial effusion, cardiac tamponade, and constrictive pericarditis. As many as 26% of patients with this disease and about 40% of such patients who also have AIDs die within six months despite antituberculosis therapy, pericardial drainage, or pericardiectomy, the researchers write.

A meta-analysis of small trials suggested that glucocorticoids suppress the inflammatory response and improve survival in patients with tuberculosis[2]. Other early evidence suggested that M indicus pranii (formerly known as Mycobacterium w), a rapidly growing nonpathogenic bacteria that simulates the immune system and is widely used to treat leprosy in India, might be effective.

IMPI was a large, 2x2 factorial trial designed to evaluate the efficacy and safety of adjunctive prednisolone and M indicus pranii in patients in Africa who had tuberculous pericarditis.

From January 2009 to February 2014 the trial enrolled 1400 adult patients with pericardial effusion and definite or probable tuberculous pericarditis at 19 hospitals in eight countries.

The patients had a mean age of 39, and 45% were women; they all received antituberculosis treatment and antiretroviral drugs, as needed.

Participants were first randomized to receive placebo or prednisolone tapered from 120 mg/day to 5 mg/day over six weeks. In the second part of the study, they were randomized to receive placebo or five injections of heat-killed M indicus pranii, with the last injection at three months.

The participants were followed for a median of more than 600 days, and adherence was high.

There was no significant difference in the primary efficacy outcome in patients who were treated with prednisolone vs placebo (23.8% vs 24.5%, respectively) or in patients who received M indicus pranii vs placebo (25.0% vs 24.3%, respectively).

"The much-talked-about reduction in [rate of] death with steroids was not observed, [and] surprisingly, steroids did not reduce tamponade," Mayosi noted. Mortality was about 18%, and about 4% of patients had cardiac tamponade.

Compared with placebo, prednisolone was also associated with a clear reduction in the rates of constrictive pericarditis (4.4% vs 7.8%, respectively) and as a result, in the rates of hospitalization (20.7% vs 25.2%, respectively).

However, both therapies were associated with a significant increase in new cancers—mainly Kaposi's sarcoma. Within three months, 1.8% of patients treated with prednisolone and 1.8% of patients treated with M indicus pranii, but only about 0.6% of patients in the placebo groups, had incident cancer.

Patients treated with prednisolone were more likely to develop infections, mostly candida.

More Preventive Efforts, Clinical Studies Needed in Africa

This was a "large, pragmatic trial," DrsRichard E Chaisson and Wendy S Post (Johns Hopkins University School of Medicine, Baltimore) write in an accompanying editorial[3].

In addition to the clinical implications, IMPI also highlights how more efforts are needed to prevent tuberculosis in Africa. The 18% mortality rate "underscores the importance of preventing tuberculosis in sub-Saharan Africa, where HIV fuels the highest global rates of the disease," they write. Diagnosing HIV infection early, initiating antiretroviral therapy early, and providing preventive therapy for tuberculosis are highly effective strategies that can reduce the risks of tuberculosis by up to 90%, they note. This should be a "top priority."

"There's a huge disease burden of unique conditions in Africa, Asia, and South America," IMPI coauthor Dr Salim Yusuf (McMaster University, Hamilton, ON), echoed in a press briefing. "It's fantastic that this huge, high-quality study with very high follow-up was done," he continued. "I can't remember when we had a trial that was entirely conducted in Africa presented at the ESC as a hot line. . . . It's by doing studies in Africa that we are going to solve the problems in Africa."

The study was supported by grants from the Canadian Institutes of Health Research, the Canadian Network and Centre for Trials Internationally, the Population Health Research Institute, the South African Medical Research Council, the Lily and Ernst Hausmann Research Trust, and Cadila Pharma, India. Cadila Pharmaceuticals donated the study drugs but had no role in the study. Mayosi has received research grants from AstraZeneca, Cadila Pharma, Novartis, Pfizer, Roche, and Servier. Disclosures for the coauthors are listed with the article.

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