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Bromocriptine shows efficacy, safety for peripartum cardiomyopathy

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Results demand we weigh bromocriptine as standard of care

This is a very important trial that was extremely difficult to conduct, and the results are exciting. It represents an effective bedside to bench to bedside sequence of research. The problem of peripartum cardiomyopathy was recognized in clinical practice, understood through basic research that led to a potential treatment, and the treatment is now confirmed through clinical testing. The results provide a reason for hope for the women who develop this disease.

Dr. Mariell Jessup

Dr. Mariell Jessup

In 2016, a panel assembled by the Heart Failure Association of the European Society of Cardiology (and which included Dr. Hilfilker-Kleiner and Dr. Sliwa) spelled out a comprehensive plan to guide the management of women with severe peripartum cardiomyopathy (Eur J Heart Failure. 2016 Sept;18[9]:1096-105). That document said that treatment with bromocriptine for severe cases “should be considered.” With these new findings we need to reconsider this guidance, and the heart failure community needs to determine whether bromocriptine should now be declared standard treatment. A real issue is finding out how much more information we need before we start using bromocriptine routinely on women who develop severe peripartum cardiomyopathy.

These trial results are important for all mothers, for all women, and for anyone born from a woman.

Mariell Jessup, MD, is a heart failure specialist and chief scientific officer of the Leducq organization in Boston. She had no disclosures. She made these comments as designated discussant for the report by Dr. Hilfiker-Kleiner.



– Two regimens of bromocriptine treatment administered with anticoagulation and standard heart failure management were safe, and often effective, for normalizing ejection fraction levels in women diagnosed with peripartum cardiomyopathy in a study with 63 women and designed to be the pivotal trial for this management strategy.

“Bromocriptine therapy applied for 1 week seems sufficient to promote healing from PPCM [peripartum cardiomyopathy] in most patients, although critically ill patients may profit from prolonged [8 week] treatment,” Denise Hilfiker-Kleiner, PhD, said at a meeting of the Heart Failure Association of the ESC.

Dr. Denise Hilfiker-Kleiner Mitchel L. Zoler/Frontline Medical News

Dr. Denise Hilfiker-Kleiner

“I would recommend bromocriptine for every woman” with clearly diagnosed PPCM, based on a postpartum left ventricular ejection fraction of 39% or less, Dr. Hilfiker-Kleiner said in an interview. “The 7-day protocol has now been used in many, many women, and it’s safe and effective. There is no reason not to use it. In our study, we only enrolled the most severely affected women, with an ejection fraction of less than 35%,” added Dr. Hilfiker-Kleiner, professor of molecular cardiology at the Hannover (Germany) Medical School.

Women who are suspected of having PPCM but with less compromised ventricular output, with an ejection fraction of 40%-45%, should be closely followed with repeated clinical examinations for 6 months and echocardiography examinations at 3 and 6 months to see if their cardiac output worsens enough to justify initiating a bromocriptine regimen, she advised. “We don’t recommend that every woman with an postpartum ejection fraction of 45% needs to immediately stop lactation [with bromocriptine treatment], but she should be frequently seen by a cardiologist to see whether she recovers or deteriorates further.”

Dr. Karen Sliwa

Dr. Karen Sliwa

Dr. Hilfiker-Kleiner and her primary clinical collaborator, Karen Sliwa, MD, developed and evaluated bromocriptine as a treatment for PPCM over several years after work by Dr. Hilfiker-Kleiner identified bromocriptine as a rational therapeutic strategy. The drug works by blocking release of prolactin from the pituitary gland. A cleaved subunit of prolactin that is produced during periods of oxidative stress causes endothelial inflammation, impaired cardiomyocyte metabolism, and the reduced cardiomyocyte contraction that is the proximate cause of PPCM. Dr. Hilfiker-Kleiner and Dr. Sliwa first tested the clinical validity of this mechanism and the efficacy of bromocriptine in a pilot, controlled clinical study with 20 women (Circulation. 2010 Apr 5;121[13]:1465-73). Their success using bromocriptine in that study led to the current trial.

The PPCM (Effect of Bromocriptine on Left Ventricular Function in Women With Peripartum Cardiomyopathy) trial enrolled 63 women with PPCM and severely depressed left ventricular ejection fraction at 12 German centers. Randomization placed 32 women into a group assigned to received 1 week of bromocriptine treatment, with 26 completing the study, and 31 in a group treated with bromocriptine for 8 weeks, with all 31 completing the study. The patients averaged 34 years of age. All patients also received standard heart failure treatment.

The study’s primary endpoint, the change in left ventricular ejection fraction from baseline to 6-month follow-up, was similar in the two treatment groups, with the 1-week regimen leading to an average 21% improvement in ejection fraction and the 8-week regimen averaging a 24% gain in pump function. Among a subgroup of 37 women who entered the study with a left ventricular ejection fraction of less than 30%, slightly more than 60% achieved full heart function by 6-month follow-up with an ejection fraction of 50% or greater, and an additional 35% had partial recovery, with a follow-up ejection fraction of 35%-49%, Dr. Hilfiker-Kleiner reported.

No women in the study developed a thrombotic complication, a potential danger of the bromocriptine intervention. All participants received antithrombotic prophylaxis with either warfarin or subcutaneous heparin. Although the bromocriptine strategy has already been adopted for routine treatment of PPCM in Germany and in many other parts of the world, its uptake in the United States has lagged, largely because of concerns about thrombotic complications, noted Dr. Sliwa, professor of medicine and director of the Hatter Institute for Cardiovascular Research in Africa at the University of Cape Town, South Africa.

Among all 57 women available for a follow-up echocardiography assessment 6 months after the start of treatment, roughly 60% had a left ventricular ejection fraction of 50% or greater, and more than 20% achieved an ejection fraction of 35%-49%. The remaining roughly 18% of women either did not have a 6-month follow-up or failed to reach at least a 35% ejection fraction at 6 months.

PPCM can be a diagnostic challenge, said Dr. Hilfiker-Kleiner, but it is relatively common, with an average worldwide incidence of about 1 case for every 1,000 deliveries. The incidence may be even higher with many cases going undetected, often because the clinical signs of PPCM, including fatigue, difficulty sleeping, edema, and dyspnea, can be dismissed as the results of recent pregnancy or caring for a newborn baby. Certain racial or ethnic groups appear to have an increased incidence of the disease, including African and Hispanic women, likely because of genetic factors, said Dr. Sliwa. Clinical factors that boost risk include pre-eclampsia, smoking, obesity, older age, and multiparity, but not diabetes.

Testing for N-terminal-pro B-type natriuretic peptide levels appears to be a good screen for women who have developed PPCM, with a level of at least 500 pg/mL high enough to warrant further assessment, Dr. Sliwa said. She recommended running an NT-proBNP test on any recent postpartum women with a clinical or demographic risk factor or suggestive clinical presentation, but she also stressed that PPCM can occur in younger, totally healthy, and athletic women who appear to have a normal delivery.

A significant concern about bromocriptine treatment is that it precludes breastfeeding, a reason not to use the drug in women with an ejection fraction of 40% or greater, especially in settings where access to safe baby formula is a challenge.

The PPCM trial enrolled 63 women at 12 German centers.

The trial received no commercial funding. Dr. Hilfiker-Kleiner and Dr. Sliwa had no disclosures.

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