Pravin Manga

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

BACKGROUND Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and reduces levels of low‐density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow‐up was 10 months. RESULTS At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of ‐56.0% in the bococizumab group and +2.9% in the placebo group, for a between‐group difference of –59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower‐risk, shorter‐duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow‐up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher‐risk, longer‐duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow‐up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection‐site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). CONCLUSIONS In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower‐risk patients but did have a significant benefit in the trial involving higher‐risk patients. (Funded by Pfizer; SPIRE‐1 and SPIRE‐2 ClinicalTrials.gov numbers, NCT01975376 and NCT01975389.)

Prednisolone and Mycobacterium indicus pranii in Tuberculous Pericarditis

BACKGROUND Tuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered. We evaluated the effects of adjunctive glucocorticoid therapy and Mycobacterium indicus pranii immunotherapy in patients with tuberculous pericarditis. METHODS Using a 2-by-2 factorial design, we randomly assigned 1400 adults with definite or probable tuberculous pericarditis to either prednisolone or placebo for 6 weeks and to either M. indicus pranii or placebo, administered in five injections over the course of 3 months. Two thirds of the participants had concomitant human immunodeficiency virus (HIV) infection. The primary efficacy outcome was a composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. RESULTS There was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.77 to 1.18; P=0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; hazard ratio, 1.03; 95% CI, 0.82 to 1.29; P=0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; hazard ratio, 3.27; 95% CI, 1.07 to 10.03; P=0.03, and 1.8% vs. 0.5%; hazard ratio, 3.69; 95% CI, 1.03 to 13.24; P=0.03, respectively), owing mainly to an increase in HIV-associated cancer. CONCLUSIONS In patients with tuberculous pericarditis, neither prednisolone nor M. indicus pranii had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. (Funded by the Canadian Institutes of Health Research and others; IMPI ClinicalTrials.gov number, NCT00810849.).

The Drakensberg Declaration on the Control of Rheumatic Fever and Rheumatic Heart Disease in Africa

Bongani Mayosi, Kate Robertson, Jimmy Volmink, Wole Adebo, Kingsley Akinyore, Albert Amoah, Charles Bannerman, Shan Biesman-Simons, Jonathan Carapetis, Antoinette Cilliers, Patrick Commerford, Anne Croasdale, Albertino Damasceno, Jenny Dean, Michael Dean, Robert de Souza, Antonio Filipe, Chris Hugo-Hamman, Sally-Ann JurgensClur, Pierre Kombila-Koumba, Christelle Kotzenberg, John Lawrenson, Pravin Manga, Jonathan Matenga, Tshimbi Mathivha, Phindile Mntla, Ana Mocumbi, Tiny Mokone, Elijah Ogola, Samuel Omokhodion, Chapman Palweni, Adrian Pearce, Avril Salo, Baby Thomas, Kathie Walker, Charles Wiysonge, Salah Zaher

Prognostic Indicators for Recurrent Thrombotic Events in HIV-infected Patients with Acute Coronary Syndromes: Use of Registry Data From 12 sites in Europe, South Africa and the United States

AIMS Limited data are available on prognostic indicators for HIV patients presenting with ACS. METHODS AND RESULTS Data on consecutive patients with HIV infection receiving standard highly active antiretroviral therapy (HAART) presenting with ACS between January 2001 and September 2012 were collected. Cardiac death and myocardial infarction (MI) were the primary end-points. 10,050 patients with ACS were screened, and among them a total of 201 patients (179 [89%] males and a median age of 53 [47-62] years) were included, 48% of them admitted for ST-elevation myocardial infarction and 14% having left ventricular systolic dysfunction (LVSD) at discharge. CD4+ counts less than 200 cells/mm(3) were reported in 18 patients (9%), and 136 patients (67%) were treated with nucleoside-reverse transcriptase inhibitors (NRTI). After a median of 24 months (10-41), 30 patients (15%) died, 12 (6%) for cardiac reasons, 20 (10%) suffered a MI, 29 (15%) a subsequent revascularization, and 7 (3%) a stent thrombosis. Other than LVSD (hazard ratio=6.4 [95% confidence interval [CI]: 1.6-26: p=0.009]), the only other independent predictor of cardiac death was not being treated with NRTI (hazard ratio=9.9 [95% CI: 2.1-46: p=0.03); a CD4 cell count <200 cells/mm(3) was the only predictor of MI (hazard ratio=5.9 [95% CI: 1.4-25: p=0.016]). CONCLUSIONS HIV patients presenting with ACS are at significantly increased risk for cardiac death if not treated with NRTI, and at significantly increased risk of MI if their CD4 cell count is <200 cells/mm(3), suggesting that the stage of HIV disease (and lack of NRTI treatment) may contribute to cardiovascular instability.

Pulmonary arterial aneurysms in Marfan's syndrome

We report the case of a 23-year-old man with Marfans syndrome and saccular aneurysms of the pulmonary arteries. The importance and possible complications of this finding are discussed.

Mitral valve area calculations immediately after percutaneous balloon mitral valvuloplasty: Effect of the atrial septal defect

OBJECTIVES The aim of this study was to assess the effect of the atrial septal defect on mitral valve area calculations after balloon mitral valvuloplasty. BACKGROUND There is poor correlation between the hemodynamic-derived and Doppler mitral valve area immediately after mitral valvuloplasty. The reasons for this are unclear. METHODS Twenty-five patients with severe mitral stenosis were studied. After balloon mitral valvuloplasty, serial mitral valve area calculations were performed with 1) the mitral dilating catheter across the atrial septum, 2) the 7F catheter across the atrial septum, and 3) with the atrial puncture site occluded with the balloon catheter. RESULTS The mitral valve area determined by the Gorlin formula with balloon occlusion of the atrial septum was smaller than the mitral valve area determined without balloon occlusion (mean +/- SD 1.8 +/- 0.43 vs. 2.24 +/- 0.67 cm2, p < 0.005 for the mitral dilating catheter across the atrial septum and 1.8 +/- 0.43 vs. 2.19 +/- 0.52, p < 0.05 for the 7F catheter across the atrial septum). The mean of the differences between the mitral valve area derived by the Gorlin formula and by the Doppler pressure half-time method was smaller with the atrial septum occluded than when the dilating catheter or the 7F catheter was across the atrial septum (0.12 +/- 0.26 vs. 0.56 +/- 0.48 cm2 [p < 0.005] and 0.12 +/- 0.26 vs. 0.48 +/- 0.55 cm2 [p < 0.05]). Left to right shunting was detected less frequently by oximetry (60%), than by shunt ratios calculated by using the cardiac output measurements with and without balloon occlusion of the atrial septum (84%). CONCLUSIONS The presence of left to right shunts after mitral valvuloplasty may account for some of the discrepancies between mitral valve area found at cardiac catheterization and that by the Doppler pressure half-time method; thus, the latter method may be reliably used to follow up patients in the long term.

HIV and Ischemic Heart Disease

The association of coronary heart disease (CHD) and human immunodeficiency virus (HIV) infection has been well recognized for many years. The etiology of the increased prevalence of CHD in HIV-infected populations is the result of complex interactions among the viral infection, host factors, traditional risk factors, and therapies for HIV. As the HIV population is living longer, largely attributable to combination antiretroviral therapy, there is concern about the effect of the rising prevalence of CHD on morbidity and mortality, as well its effect on health systems around the world. This review will highlight the epidemiological evidence linking HIV infection and CHD. It will also focus on our current understanding of the pathogenesis and factors associated with HIV infection and CHD. In addition, the review will highlight modes of presentation and management strategies for mitigating risk and treatment of HIV-positive patients presenting with CHD.

Rationale and design of the Investigation of the Management of Pericarditis (IMPI) trial: a 2 × 2 factorial randomized double-blind multicenter trial of adjunctive prednisolone and Mycobacterium w immunotherapy in tuberculous pericarditis.

BACKGROUND In spite of antituberculosis chemotherapy, tuberculous (TB) pericarditis causes death or disability in nearly half of those affected. Attenuation of the inflammatory response in TB pericarditis may improve outcome by reducing cardiac tamponade and pericardial constriction, but there is uncertainty as to whether adjunctive immunomodulation with corticosteroids and Mycobacterium w (M. w) can safely reduce mortality and morbidity. OBJECTIVES The primary objective of the IMPI Trial is to assess the effectiveness and safety of prednisolone and M. w immunotherapy in reducing the composite outcome of death, constriction, or cardiac tamponade requiring pericardial drainage in 1,400 patients with TB pericardial effusion. DESIGN The IMPI trial is a multicenter international randomized double-blind placebo-controlled 2 × 2 factorial study. Eligible patients are randomly assigned to receive oral prednisolone or placebo for 6 weeks and M. w injection or placebo for 3 months. Patients are followed up at weeks 2, 4, and 6 and months 3 and 6 during the intervention period and 6-monthly thereafter for up to 4 years. The primary outcome is the first occurrence of death, pericardial constriction, or cardiac tamponade requiring pericardiocentesis. The secondary outcome is safety of immunomodulatory treatment measured by effect on opportunistic infections (eg, herpes zoster) and malignancy (eg, Kaposi sarcoma) and impact on measures of immunosuppression and the incidence of immune reconstitution disease. CONCLUSIONS IMPI is the largest trial yet conducted comparing adjunctive immunotherapy in pericarditis. Its results will define the role of adjunctive corticosteroids and M. w immunotherapy in patients with TB pericardial effusion.

Takotsubo cardiomyopathy post liver transplantation.

Abstract A patient with end-stage liver disease developed stressinduced Takotsubo cardiomyopathy post liver transplantation, with haemodynamic instability requiring a left ventricular assist device. We discuss the diagnosis and management of this condition.

Primary leiomyosarcoma of the pulmonary trunk

An unusual case of leiomyosarcoma of the pulmonary trunk in a 33-year-old woman is described. Angiography suggested a large pulmonary embolus. The patient was referred for surgery and the diagnosis was made histologically. The surgical management and postoperative course are described.