Accepted Manuscript The Medical Treatment of New Onset Peripartum Cardiomyopathy; a Systematic Review of prospective studies Olivier Desplantie, MDCM, Maxime Tremblay-Gravel, MD, MSc, Robert Avram, MD, Guillaume Marquis-Gravel, MD, MSc, Anique Ducharme, MD, MSc, E. Marc Jolicoeur, MD, MSc, MHS, FRCP-C, FACC, FSCAI PII:

S0828-282X(15)00354-2

DOI:

10.1016/j.cjca.2015.04.029

Reference:

CJCA 1674

To appear in:

Canadian Journal of Cardiology

Received Date: 17 November 2014 Revised Date:

8 April 2015

Accepted Date: 28 April 2015

Please cite this article as: Desplantie O, Tremblay-Gravel M, Avram R, Marquis-Gravel G, Ducharme A, Jolicoeur EM, For the BRO-HF initiative investigators, The Medical Treatment of New Onset Peripartum Cardiomyopathy; a Systematic Review of prospective studies, Canadian Journal of Cardiology (2015), doi: 10.1016/j.cjca.2015.04.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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The Medical Treatment of New Onset Peripartum Cardiomyopathy; a Systematic Review of prospective studies

Short title: The treatment of PPCM

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Olivier Desplantie MDCM1, Maxime Tremblay-Gravel MD, MSc1, Robert Avram MD1, Guillaume Marquis-Gravel MD, MSc1, Anique Ducharme MD, MSc2, E. Marc Jolicoeur MD, MSc, MHS, FRCP-C, FACC, FSCAI1,2, For the BRO-HF initiative investigators

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1 Adult Cardiology Training Program, Department of Medicine, Université de Montréal, Montréal, Québec, Canada

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2 Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada

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Keywords: Peripartum cardiomyopathy, systematic review

Address for correspondence Name: E. Marc Jolicoeur MD MSc MHS Address: 5000 Belanger street, Montreal, QC, Canada, H1T 1C8 Tel: 514-376-3330 Email: [email protected]

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ABSTRACT Background: Peripartum cardiomyopathy (PPCM) is a rare disorder with potentially fatal consequences, occurring mainly in previously healthy women. The etiology of PPCM

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remains unknown and various pathologic mechanisms have been proposed, including immune-mediated injuries and impaired response to oxidative stress and inflammatory cytokines. Several therapies have been studied, but few have been validated in a well-

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designed randomized controlled trial.

Methods: The present study sought to review the medical treatment intended for acute

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PPCM. To this end, we performed a systematic review of the literature of randomized and non-randomized prospective clinical studies.

Results: We identified two randomized controlled trials evaluating the dopamine agonist bromocriptine and the inotrope levosimendan, respectively, and one non-randomized study

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evaluating the non-selective phosphodiesterase inhibitor pentoxifylline. We reviewed the pathophysiological, pharmacological and clinical properties for each treatment option identified. Bromocriptine and pentoxifylline both improved left ventricular systolic function

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and patient-oriented clinical endpoints while levosimendan did not improve mortality or

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echocardiographic findings of PPCM. Conclusions: This review identified bromocriptine and pentoxifylline, but not levosimendan, as potentially useful agents to improve left ventricle function and outcomes in PPCM.

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SUMMARY Peripartum cardiomyopathy (PPCM) is a rare but highly morbid and potentially lethal disease in young otherwise healthy women. We performed a systematic review of the

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literature on the available medical therapy for PPCM. This review identified bromocriptine and pentoxifylline, but not levosimendan, as potentially useful agents to improve left

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ventricle function and outcomes.

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INTRODUCTION Peripartum cardiomyopathy (PPCM) is a rare disorder with potentially fatal consequences (1-3). It presents as a heart failure syndrome with a left ventricular ejection

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fraction 0.05); LV end-systolic diameter (cm) 4.7±1.4 vs.

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5.0±1.2 (p>0.05); LV end-diastolic diameter (cm) 6.1±0.9 vs. 6.3±0.7 (p>0.05); pulmonary artery systolic pressure (mmHg) 33.1±17.0 vs. 36.25±18.4 (p>0.05)). Given the small sample size, this trial might have been underpowered to detect significant benefits. No

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other trial has evaluated the role of levosimendan in the treatment of PPCM, and no study is

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currently ongoing on that topic.

Pentoxifylline

Pentoxifylline has pleiotropic effects that might improve hemodynamics in heart

failure. Inhibiting the production of TNF-α, a pro-apoptotic cytokine that has negative inotropic properties in vitro, is one mechanism through which pentoxifylline could stop disease progression in heart failure (44). However, two drugs that specifically inhibit TNF9

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α, etanercept and infliximab, failed to show any improvement in heart failure symptoms or mortality in randomized trials (45, 46). Other mechanisms include peripheral vasodilation, reduction of blood viscosity, improved erythrocyte flexibility and reduction of platelet

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aggregation (44, 47-49). Sliwa and colleagues evaluated pentoxifylline in PPCM in an openlabel non-randomized prospective study in 59 patients from South Africa (20). The first 29 patients received usual medical care whereas the following 30 patients received

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conventional therapy plus pentoxifylline 400 mg orally daily for six months. The composite primary endpoint including all-cause death, NYHA functional class III-IV/IV, or failure to

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improve LVEF by 10% in absolute value at last follow-up (mean follow-up not mentioned, echocardiography performed after six months of treatment) occurred in 52% of patients in the usual medical care group, and in 27% of patients in the pentoxifylline group (p=0.03). Pentoxifylline was independently associated with improved outcomes upon adjustment for

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baseline characteristics (p=0.04). These results have not been confirmed in appropriately designed clinical trials and no trial is currently ongoing.

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GUIDELINES FOR CLINICIANS

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Current Canadian practice guidelines do not support the use of any specific pharmacological agent for the treatment of PPCM, but these recommendations have not been updated since the publication of a favorable proof-of-concept trial with bromocriptine (18, 50). The European Society of Cardiology practice guidelines state that more trials are necessary before recommending the widespread use of bromocriptine, but that some physicians can consider it on an individual basis. While waiting for more studies, bromocriptine may be prescribed on a case-by-case basis. If used in PPCM, bromocriptine 10

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should be administered as 2.5 mg orally twice daily for two weeks, followed by 2.5 mg orally once daily for six weeks, which is the only posology tested in a clinical trial for this indication. It should be kept in mind that the only human trial that tested bromocriptine in

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PPCM was performed in a uniquely South African women population. Thus, its external generalizability to the North American population is unknown. Patients using triptans (e.g. for the treatment of migraines) should not use bromocriptine due to theoretical risks of

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serotoninergic syndrome or prolonged vasospastic reactions.

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CONCLUSION

Despite the high burden of mortality and morbidity attributed to PPCM in young otherwise healthy women, the evidence guiding clinicians in the treatment of this dramatic disease are scarce and of poor quality. To date, only 103 women with PPCM have been

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enrolled in prospective clinical studies reported in the literature. Only two randomized controlled trials have been performed, assessing the effects of bromocriptine and levosimendan, but they were all single-center and their results have never been replicated,

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thus preventing the translation of the use of these molecules in clinical practice. The results

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of these trials suggest that bromocriptine and pentoxifylline may improve clinical outcomes, while levosimendan failed to show a benefit. Future perspectives involve a randomized trial conducted in Germany that evaluates the effect of bromocriptine on LVEF in patients with PPCM. The BRO-HF initiative also aims at conducting a multi-center RCT in Canada to test the effect of bromocriptine on patient-oriented clinical outcomes in PPCM. This initiative will be the first North American study to assess the effect of bromocriptine in PPCM.

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References

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1. Harper MA, Meyer RE, Berg CJ. Peripartum cardiomyopathy: population-based birth prevalence and 7-year mortality. Obstetrics and gynecology. 2012;120(5):1013-9. 2. Duran N, Gunes H, Duran I, Biteker M, Ozkan M. Predictors of prognosis in patients with peripartum cardiomyopathy. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2008;101(2):137-40. 3. Haghikia A, Podewski E, Libhaber E, Labidi S, Fischer D, Roentgen P, et al. Phenotyping and outcome on contemporary management in a German cohort of patients with peripartum cardiomyopathy. Basic research in cardiology.108(4):366. 4. Howlett JG, McKelvie RS, Costigan J, Ducharme A, Estrella-Holder E, Ezekowitz JA, et al. The 2010 Canadian Cardiovascular Society guidelines for the diagnosis and management of heart failure update: Heart failure in ethnic minority populations, heart failure and pregnancy, disease management, and quality improvement/assurance programs. Canadian Journal of Cardiology.26(4):185-202. 5. Hilfiker-Kleiner D, Sliwa K. Pathophysiology and epidemiology of peripartum cardiomyopathy. Nature reviews Cardiology. 2014. 6. Demakis JG, Rahimtoola SH, Sutton GC, Meadows WR, Szanto PB, Tobin JR, et al. Natural course of peripartum cardiomyopathy. Circulation. 1971;44(6):1053-61. 7. Sliwa K, Forster O, Libhaber E, Fett JD, Sundstrom JB, Hilfiker-Kleiner D, et al. Peripartum cardiomyopathy: inflammatory markers as predictors of outcome in 100 prospectively studied patients. European heart journal. 2006;27(4):441-6. 8. Sliwa K, Hilfiker-Kleiner D, Petrie MC, Mebazaa A, Pieske B, Buchmann E, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy. European journal of heart failure. 2010;12(8):767-78. 9. Gunderson EP, Croen LA, Chiang V, Yoshida CK, Walton D, Go AS. Epidemiology of peripartum cardiomyopathy: incidence, predictors, and outcomes. Obstetrics and gynecology. 2011;118(3):583-91. 10. Pearson GD, Veille JC, Rahimtoola S, Hsia J, Oakley CM, Hosenpud JD, et al. Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review. JAMA : the journal of the American Medical Association. 2000;283(9):1183-8. 11. MB L, J H, L W, J B, M L, RM L. Peripartum heart failure associated with prolonged tocolytic therapy. Am J Obstet Gynecol. 1993;168(2):493-5. 12. Horne B, Rasmusson K, Rami Alharethi R, Budge D, Brunisholz K, Carlquist J, et al. Peripartum Cardiomyopathy-Associated Sequence Variant at the PTHLH Locus is Not Predictive of Idiopathic or Ischemic Cardiomyopathy. Circulation. 2011;124:A16347(Abstract). 13. Diao M, Diop IB, Kane A, Camara S, Kane A, Sarr M, et al. [Electrocardiographic recording of long duration (Holter) of 24 hours during idiopathic cardiomyopathy of the peripartum]. Archives des maladies du coeur et des vaisseaux. 2004;97(1):25-30.

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14. Desai D, Moodley J, Naidoo D. Peripartum cardiomyopathy: experiences at King Edward VIII Hospital, Durban, South Africa and a review of the literature. Tropical doctor. 1995;25(3):118-23. 15. Barasa A, Rosengren A, Ladfors L, Swedberg K, Schaufelberger M. Longterm Mortality in 272 Women with Peripartum Cardiomyopathy. Circulation. 2012;126:A18643 (Abstract). 16. Elkayam U. Clinical characteristics of peripartum cardiomyopathy in the United States: diagnosis, prognosis, and management. Journal of the American College of Cardiology. 2011;58(7):659-70. 17. Goland S, Modi K, Bitar F, Janmohamed M, Mirocha JM, Czer LS, et al. Clinical profile and predictors of complications in peripartum cardiomyopathy. J Card Fail. 2009;15(8):645-50. 18. Sliwa K, Blauwet L, Tibazarwa K, Libhaber E, Smedema JP, Becker A, et al. Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof-ofconcept pilot study. Circulation. 2010;121(13):1465-73. 19. Biteker M, Duran NE, Kaya H, Gunduz S, Tanboga HI, Gokdeniz T, et al. Effect of levosimendan and predictors of recovery in patients with peripartum cardiomyopathy, a randomized clinical trial. Clinical Research in Cardiology.100(7):571-7. 20. Sliwa K, Skudicky D, Candy G, Bergemann A, Hopley M, Sareli P. The addition of pentoxifylline to conventional therapy improves outcome in patients with peripartum cardiomyopathy. Eur J Heart Fail. 2002;4:305-9. 21. Negoro S, Kunisada K, Fujio Y, Funamoto M, Darville MI, Eizirik DL, et al. Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase. Circulation. 2001;104(9):979-81. 22. Patten IS, Rana S, Shahul S, Rowe GC, Jang C, Liu L, et al. Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature. 2012;485(7398):333-8. 23. Lkhider M, Castino R, Bouguyon E, Isidoro C, Ollivier-Bousquet M. Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions. Journal of cell science. 2004;117(Pt 21):5155-64. 24. Ferrara N, Clapp C, Weiner R. The 16K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells. Endocrinology. 1991;129(2):896-900. 25. Singh N, Dhalla AK, Seneviratne C, Singal PK. Oxidative stress and heart failure. Molecular and cellular biochemistry. 1995;147(1-2):77-81. 26. Hilfiker-Kleiner D, Kaminski K, Podewski E, Bonda T, Schaefer A, Sliwa K, et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell. 2007;128(3):589-600. 27. Iffy L, Lindenthal J, Mcardle J, Ganesh V. Severe cerebral accidents postpartum in patients taking bromocriptine for milk suppression. Isr J Med Sci. 1996;32(5):309-12. 28. Cheryl L, Dragovic L. Acute Coronary Artery Thrombosis in a Postpartum Woman Receiving Bromocriptine. Am J Forensic Med Pathol. 1998;19(3):258-60. 29. Hopp L, Weisse A, Iffy L. Acute myocardial infarction in a healthy mother using bromocriptine for milk suppression. Can J Cardiol. 1996;12(4):415-8. 30. Larrazet F, Spaulding C, Lobreau H, Weber S, Guerin F. Possible BromocriptineInduced Myocardial Infarction. Ann Intern Med. 1993;118(3):199-200. 13

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31. Eickman F. Recurrent myocardial infarction in a postpartum patient receiving bromocriptine. Clin Cardiol. 1992;15(10):781-3. 32. de Jong-van den Berg L, Mintzes B. Bromocriptine and lactation suppression: are the risks acceptable? Pharmacy world & science : PWS. 1995;17(4):93-5. 33. Krupp P, Monka C. Bromocriptine in pregnancy: safety aspects. Klin Wochenschr. 1987;65(17):823-7. 34. Serratrice J, Disdier P, Habib G, Viallet F, Weiller PJ. Fibrotic valvular heart disease subsequent to bromocriptine treatment. Cardiology in review. 2002;10(6):334-6. 35. Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E. Dopamine agonists and the risk of cardiac-valve regurgitation. The New England journal of medicine. 2007;356(1):2938. 36. Hilfiker-Kleiner D, Meyer G, Schieffer E, Goldmann B, Podewski E, Struman I, et al. Recovery From Postpartum Cardiomyopathy in 2 Patients by Blocking Prolactin Release With Bromocriptine. J Am Coll Cardiol. 2007;50(24):2354-5. 37. Jahns B, Stein W, Hilfiker-Kleiner D, Pieske B, Emons G. Peripartum cardiomyopathy—a new treatment option by inhibition of prolactin secretion. Am J Obstet Gynecol. 2008;199(4):e5-e6. 38. Dutt S, Wong F, Spurway JH. Fatal myocardial infarction associated with bromocriptine for postpartum lactation suppression. The Australian & New Zealand journal of obstetrics & gynaecology. 1998;38(1):116-7. 39. Papp Z, Csapo K, Pollesello P, Haikala H, Edes I. Pharmacological mechanisms contributing to the clinical efficacy of levosimendan. Cardiovasc Drug Rev. 2005;23(1):7198. 40. Haikala H, Kaheinen P, Levijoki J, Lindén I. The role of cAMP- and cGMP-dependent protein kinases in the cardiac actions of the new calcium sensitizer, levosimendan. Cardiovascular research. 1997;34(3):536-46. 41. Sorsa T, Pollesello P, Rosevear P, Drakenberg T, Kilpeläinen I. Stereoselective binding of levosimendan to cardiac troponin C causes Ca2+-sensitization. Eur J Pharmacol. 2004;486(1):1-8. 42. De Luca L, Colucci W, MS. N, Massie B, Gheorghiade M. Evidence-based use of levosimendan in different clinical settings. European heart journal. 2006;27:1908-20. 43. McMurray J, Adamopoulos S, Anker S, Auricchio A, Böhm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. European heart journal. 2012;33:1787-847. 44. Finkel M, Oddis C, Jacob T, Watkins S, Hattler B, Simmons R. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science. 1992;257(5068):387-9. 45. Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004;109(13):1594-602. 46. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT, Anti TNFTACHFI. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107(25):3133-40. 14

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47. Skudicky D, Bergemann A, Sliwa K, Candy G, Sareli P. Beneficial effects of pentoxifylline in patients with idiopathic dilated cardiomyopathy treated with angiotensinconverting enzyme inhibitors and carvedilol: results of a randomized study. Circulation. 2001;103:1083-8. 48. Sliwa K, Skudicky D, Candy G, Wisenbaugh T, Sareli P. Randomised investigation of effects of pentoxifylline on left-ventricular performance in idiopathic dilated cardiomyopathy. Lancet. 1998;351(9109):1091-3. 49. Stevens J, Simpson E, Harnan S, Squires H, Meng Y, Thomas S, et al. Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication. Br J Surg. 2012;99:1630-8. 50. Howlett JG, McKelvie RS, Costigan J, Ducharme A, Estrella-Holder E, Ezekowitz JA, et al. The 2010 Canadian Cardiovascular Society guidelines for the diagnosis and management of heart failure update: Heart failure in ethnic minority populations, heart failure and pregnancy, disease management, and quality improvement/assurance programs. The Canadian journal of cardiology. 2010;26(4):185-202. 51. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. Bmj. 2011;343:d5928. 52. Sliwa K, Skudecky D, Candy G, Bergemann A, Hopley M, Sareli P. The addition of pentoxifylline to conventional therapy improves outcome in patients with peripartum cardiomyopathy. Eur J Heart Fail. 2002;4:305-9.

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FIGURE LEGEND

Results of Reports Search and Selection Process

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Figure 1.

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Results of Reports Search and Selection Process

Reports were screened for retrieval

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518

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Figure 1.

Reports excluded (non-related topics)

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Reports excluded (Retrospective clinical studies)

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510

Report after manual search of reference lists and abstracts from major conferences

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Reports underwent full text reading

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3

Reports were included in this review

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TABLE LEGEND

Overview of Systematic Review Results Abbreviations:

RCT: Randomized Control Trial; PCS: Prospective

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Table I.

Cohort Study; LVEF: Left Ventricular Ejection Fraction; NYHA: New York Heart Association; ATP: Adenosine Triphosphate; TNF: Tumour

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Necrosis Factor

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Table I. Overview of Systematic Review Results

Agent used

Sample size

Purported mode of action

n = 20

Dopaminergic inhibition of prolactin secretion, preventing cleavage of 16kDa prolactin

Quality of evidence

Principal findings

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Author

Limitations

Improved LVEF

Biteker et al. (19)

n = 59

Inhibiting the production of TNFα, which has negative inotropic effects on the heart

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Single center experience in African women

RCT

No improvement in clinical recovery, defined as resolution of symptoms and clinical findings of HF and LVEF recovery to ≥50%, persistent LV damage or death at 12 months

Improved composite of death, failure to improve PCS

LVEF by ≥10 absolute points, or functional class III/IV at last followup

Small sample size Single center experience Open-label design

Small sample size Single center experience Open-label design

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Pentoxifylline

n = 24

Inodilator agent with positive inotrope activity and vasodilator

Small sample size

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Sliwa et al. (52)

Levosimendan

RCT

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Bromocriptine

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Sliwa et al. (18)

Improved composite end point of death, NYHA class III/IV, or LVEF < 35% at 6 months

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TABLE LEGEND

Search Strategies for Randomized Studies and Non-Randomized Prospective Studies Abbreviations: mp: multi-purpose

Supp Table II.

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Supp Table I.

Quality of Reporting for the Studies Selected in the Systematic

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Review Footnotes:

†Quality

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*Quality assessment inspired from the Cochrane Handbook (51) assessment according to the Newcastle-Ottawa Quality

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Assessment Scale (42)

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Supplemental Table I. Search Strategies for Randomized Studies and Non-

Cochrane 1. randomized controlled trial.mp. or Randomized Controlled Trial/ 2. controlled clinical trial.mp. or Controlled Clinical Trial/ 3. randomized.mp. 4. trial.mp. 5. 1 or 2 or 3 or 4 6. Pregnancy Complications, Cardiovascular/ or peripartum cardiomyopathy.mp. 7. bromocriptine.mp. or Bromocriptine/ 8. heart failure.mp. or Heart Failure/ 9. pregnancy.mp. or Pregnancy/ 10. 8 and 9 11. 5 and 7 12. 6 or 10 13. 11 and 12

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Ia. Search Strategies for Randomized Studies Medline EMBASE 1. randomized controlled trial/ 1. controlled clinical trial.mp. or Controlled Clinical Trial/ 2. controlled clinical trial.mp. or 2. randomized controlled trial.mp. or controlled clinical trial/ 3. randomized.mp. Randomized Controlled Trial/ 4. trial.mp. 3. randomized.mp. 4. Placebos/ or placebo.mp. 5. 1 or 2 or 3 or 4 6. peripartum cardiomyopathy.mp. 5. drug therapy.mp. or Drug or peripartum cardiomyopathy/ Therapy/ 7. bromocriptine/ or 6. Clinical Trial/ or trial.mp. 7. groups.mp. bromocriptine.mp. 8. 1 or 2 or 3 or 4 or 5 or 6 or 7 8. pregnancy.mp. or pregnancy/ 9. heart failure.mp. or heart failure/ 9. limit 8 to humans 10. 8 and 9 10. Pregnancy Complications, Cardiovascular/ or peripartum 11. 6 or 10 12. 5 and 7 cardiomyopathy.mp. 13. 11 and 12 11. bromocriptine.mp. or Bromocriptine/ 12. Pregnancy/ or pregnancy.mp. 13. heart failure.mp. or Heart Failure/ 14. 12 and 13 15. 9 and 11 16. 10 or 14 17. 15 and 16

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Randomized Prospective Studies

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Ib. Search Strategies for Non-Randomized Prospective Studies Medline EMBASE 1. Pregnancy Complications, 1. peripartum cardiomyopathy.mp. or peripartum cardiomyopathy/ Cardiovascular/ or peripartum cardiomyopathy.mp. 2. bromocriptine/ or bromocriptine.mp. 2. Pregnancy/ or pregnancy.mp. 3. heart failure.mp. or Heart Failure/ 3. heart failure.mp. or heart failure/ 4. 2 and 3 4. pregnancy.mp. or pregnancy/ 5. bromocriptine.mp. or 5. 3 and 4 6. 1 or 5 Bromocriptine/ 6. limit 5 to humans 7. 2 and 6 7. 1 or 4 8. 6 and 7

Cochrane 1. Pregnancy Complications, Cardiovascular/ or peripartum cardiomyopathy.mp. 2. bromocriptine.mp. or Bromocriptine/ 3. heart failure.mp. or Heart Failure/ 4. pregnancy.mp. or Pregnancy/ 5. 3 and 4 6. 1 or 5 7. 2 and 6

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Supplemental Table II. Quality of Reporting for the Studies Selected in the Systematic Review

Random sequence

Blinding of participants and

Allocation concealment generation

personnel

Sliwa et al. (18)

Yes

No

No

Yes

No

No

Exposed and non-exposed

Main outcome not

Comparability of cohorts

cohorts are representative

present at start of study

(Bromocriptine) Biteker et al. (19)

Blinding of outcome

Incomplete outcome

assessment

data

Yes

No

No

No

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(Levosimendan)

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Randomized Controlled Studies*

Non-Randomized Studies†

Sliwa et al. (20)

Yes

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Assessment of outcomes

No

Yes

for outcomes to occur exposure

Yes

No

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(Pentoxifylline)

Follow-up long enough

and ascertainment of

based on design/analysis

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