2/2 GLobal trial Of Bromocriptine for PeriPartum CardioMyopathy (GLOBal PPCM) - ABSTRACT Cardiomyopathy ranks as the primary cause of late postpartum pregnancy-related death in the US and globally. Whereas findings from animal and small human studies are promising about a role for the dopamine agonist bromocriptine in improving outcomes for postpartum patients with peripartum cardiomyopathy (PPCM) receiving standard medical therapy for heart failure, there is a critical need to fully assess the efficacy and safety of bromocriptine as add-on therapy for PPCM. In response to the call in a Cochrane Review for a large-scale trial to address this gap, we propose the GLobal trial Of Bromocriptine for PeriPartum CardioMyopathy (GLOBal PPCM). GLOBal PPCM, a 2-arm placebo-controlled trial, will randomize 650 postpartum patients with PPCM across at least 18 sites in 15 low- and middle-income countries (with some of the highest rates of PPCM incidence and severity in terms of maternal mortality and severe morbidity) to receive either bromocriptine or identical placebo. All patients will receive standard medical therapy. The primary outcome, assessed six months after randomization, will be a composite (one or more) of maternal death, persistent left ventricular ejection fraction ≤35%, or readmission for heart failure. Although tolerated by participants in preliminary trials, bromocriptine may reduce or arrest lactation in some patients and its safety for patients and their infants requires further evaluation. Therefore, a maternal secondary safety outcome (composite of outcomes highlighted in the FDA package insert including severe hypertension, symptomatic hypotension, syncope, stroke, seizure, thromboembolic events, myocardial infarction, psychiatric disorders, cardiac or pleural effusions, allergic reactions, headache or vomiting) will be assessed. Additionally, as a neonatal safety outcome, we will assess infant growth, by the mean difference in the weight-for-age Z- score, according to sex-specific growth reference standards, from enrollment to six months. We will also quantify infant deaths and a decrease in the sex-adjusted weight-for-age z score of ≥1 standard deviation. The GLOBal PPCM trial incorporates a robust community engagement plan inspired by its successful use in our affiliated NICHD Global and American Heart Association Networks. As agreed with the NHLBI team during extensive preapproval consultations and discussions with our GLOBal PPCM Consortium, we anticipate a future individual patient data meta-analysis with REBIRTH, a smaller US trial of bromocriptine for PPCM. If successful, data generated from GLOBal PPCM will transform both US and global healthcare policies leading to improvements in maternal and infant health and survival. Separate maternal and infant follow-up and mechanistic ancillary studies will further define the pathogenesis of PPCM and the role of bromocriptine therapy.
