Bromocriptine for the treatment of peripartum cardiomyopathy: a multicentre randomized study

Abstract

Aims: An anti-angiogenic cleaved prolactin fragment is considered causal for peripartum cardiomyopathy (PPCM). Experimental and first clinical observations suggested beneficial effects of the prolactin release inhibitor bromocriptine in PPCM.

Methods and results: In this multicentre trial, 63 PPCM patients with left ventricular ejection fraction (LVEF) ≤35% were randomly assigned to short-term (1W: bromocriptine, 2.5 mg, 7 days) or long-term bromocriptine treatment (8W: 5 mg for 2 weeks followed by 2.5 mg for 6 weeks) in addition to standard heart failure therapy. Primary end point was LVEF change (delta) from baseline to 6 months assessed by magnetic resonance imaging. Bromocriptine was well tolerated. Left ventricular ejection fraction increased from 28 ± 10% to 49 ± 12% with a delta-LVEF of + 21 ± 11% in the 1W-group, and from 27 ± 10% to 51 ± 10% with a delta-LVEF of + 24 ± 11% in the 8W-group (delta-LVEF: P = 0.381). Full-recovery (LVEF ≥ 50%) was present in 52% of the 1W- and in 68% of the 8W-group with no differences in secondary end points between both groups (hospitalizations for heart failure: 1W: 9.7% vs. 8W: 6.5%, P = 0.651). The risk within the 8W-group to fail full-recovery after 6 months tended to be lower. No patient in the study needed heart transplantation, LV assist device or died.

Conclusion: Bromocriptine treatment was associated with high rate of full LV-recovery and low morbidity and mortality in PPCM patients compared with other PPCM cohorts not treated with bromocriptine. No significant differences were observed between 1W and 8W treatment suggesting that 1-week addition of bromocriptine to standard heart failure treatment is already beneficial with a trend for better full-recovery in the 8W group.

Clinical trial registration: ClinicalTrials.gov, study number: NCT00998556.

Keywords: Bromocriptine; Peripartum cardiomyopathy; Prolactin; heart failure.

Figure 1

Randomization, treatment, and follow-up of the patients. Left ventricular ejection fraction (LVEF), §patient was excluded from all between-groups comparisons for efficacy; *23 with adequate imaging quality for primary end point. # 28 with adequate imaging quality for primary end point. §One patient was not treated according to protocol and excluded from efficacy analyses.

Figure 2

Analyses of global left ventricular ejection fraction (LVEF) change from baseline to 6 months follow-up determined by CMR. (A) Individual courses of LVEF change from baseline to 6-months follow-up in the 1W group (n = 23) and 8W group (n = 28) with a between-groups difference at 6-months follow-up of 2.0% in favour of the 8W groups (P = 0.38). (B) Individual courses of LVEF change from baseline to 6-months follow-up for the subgroup of patients with LVEF <30% at study entry in the 1 W group (n = 14) and the 8W group (n = 18) with between-groups differences at 6-months follow-up of 4.3% and for LVEF change of 4.7% in favour of the 8W groups (P = 0.22).

Figure 3

Outcome of patients at 6-months follow-up. (A) Left ventricular ejection fraction (LVEF) at 6-months follow-up according to predefined categories in all patients of the present study (treated 1W, n = 32 or 8W, n = 31 with bromocriptine, baseline LVEF <35%). Red columns illustrate the percentage of patients with no recovery (event or final LVEF <35%, prematurely terminated the trial or had missing LVEF data), yellow columns illustrate the percentage of patients with partial recovery (final LVEF 35% to < 50%) and green columns depict percentage of women with complete recovery (final LVEF ≥50%). (B) Step-wise change in LVEF measured by echocardiography during follow-up period in the 1 W (n = 21) and the 8W group (n = 24). The number 1–5 marks time course of the five patients who did not recover LVEF >35% after 6-months. However, after ≥12 months Number 1 displayed a LVEF = 62%, 2 a LVEF = 47%, 3 and 4 a LVEF = 50%, and 5 a LVEF = 15%.

Figure 4

Disease specific therapy with bromocritine. Scheme depicting inducers of increased oxidative stress in the peripartum maternal heart that mediate the generation of antiangiogenic 16kDa prolactin from the nursing hormone prolactin which drives PPCM as well as the hypothetic mechanisms how the prolactin release blocker bromocriptine together with standard heart failure medication interferes with it.