Heparin Plus Aspirin Promotes Live Births in Women With Antiphospholipid Antibodies

Daniel M Keller, PhD

July 20, 2017

BERLIN, GERMANY — Aspirin in combination with heparin was superior to aspirin alone in promoting live births among women with antiphospholipid syndrome (APS) who had experienced repeated pregnancy loss, a systematic review and meta-analysis shows[1].

"This effect is driven by studies that investigated unfractionated heparin [UFH] and not low-molecular-weight heparin [LMWH]," medical student Mauritia Marijnen (Academic Medical Center, Amsterdam, the Netherlands) reported here at the International Society on Thrombosis and Haemostasis 2017 Congress.

She said her literature search of Embase and PubMed in March 2016 focused on publications of randomized controlled trials involving women with APS who had two or more pregnancy losses, which did not have to be consecutive. The women received low-dose aspirin (LDA) and/or LMWH or UHF vs LDA or placebo or no treatment. Live birth was the primary outcome.

The study was an update of a Cochrane Database Systematic Review by Empson and colleagues from 2005[2].

Marijnen identified 939 potential studies for inclusion. Screening out duplicates and eliminating inappropriate studies based on the title and abstract or study methodology left 10 studies that were included in the analysis. Studies were excluded if they did not meet the laboratory criteria of APS.

Eight of the studies lacked blinding of participants or personnel (potential performance bias), two studies each lacked random sequence generation or concealment of allocation (selection bias), and some studies may have been affected by attrition bias, reporting bias, or other sources of bias.

LDA alone had no significant effect on live birth compared with placebo.

Five studies compared either form of heparin plus LDA with LDA alone. When data from all five studies were combined, the likelihood of a live birth was 2.5-fold higher if heparin was used (odds ratio [OR] 2.51; 95% CI 1.48–4.25, P<0.001).

When UFH was added to LDA (three studies), the OR for live birth ranged from 3.37 to 5.09. When data from the studies were combined, the OR was 3.75 (95% CI 2.04–6.90, P<0.001, test for overall effect), showing a significant benefit on live birth by adding UFH. 

Conversely, combining LMWH with LDA (two studies) had no effect on the likelihood of live birth; that is, the ORs were not significantly different from 1 for the studies alone or when the data were combined.

Marijnen said her analysis was limited by size, no universal reporting of adverse effects in the original studies under consideration, different doses of aspirin and heparin used, and outdated studies. She advised that "there is an urgent need for a rigorous randomized controlled trial, in particular on the use of LMWH."

Dr Shannon Bates (McMaster University, Hamilton, ON) said that with this meta-analysis of both older and more recent studies, the question today remains whether to treat women who have antiphospholipid antibodies and recurrent pregnancy loss with aspirin and UFH or with aspirin and LMWH. UFH is an older drug with more side effects. "That's a debate that's raged back and forth," she told theheart.org | Medscape Cardiology.

"It looks like the benefit really lies with aspirin and unfractionated heparin, the older drugs. There's still a recommendation for the newer drug because there are other data that weren't captured in this analysis that suggest that LMWH and aspirin might be of just as much benefit," she said, "but it certainly doesn't take away from the take-home message that we definitely need more studies in this patient population to make sure that we're actually providing benefit to patients when prescribed certain interventions."

Bates pointed out that in the older studies using UFH, the women appeared at higher risk for miscarriage, so in the aspirin-only arm very few of them had successful pregnancies vs later studies comparing aspirin with LMWH, where the likelihood of a successful pregnancy was much higher in the aspirin-alone arms than in the earlier studies.

"So it suggests that when we're comparing the older and newer studies we're not actually comparing the same patient populations, and what we may actually find with the study, which would be really informative, is the way we currently define this population," Bates said. "Maybe neither combination is providing us with benefit, which is also what we need to consider and which makes it doubly important to do the study."

"People think it's not ethical to include pregnant women in studies, but what's not ethical is subjecting them to interventions that we're not really sure of the benefit, and we won't know until we do the right studies," she advised.

There was no outside funding of this study. Marijnen and Bates had no relevant financial relationships.

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