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• 0.61 for groups 1 and 2 vs . group 3 ( 95 % CI 0.50-0.75 ; p < 0.001 ; TABLE 1 )
“ The lower rate of bleeding in the two groups receiving rivaroxaban compared with the group receiving the VKA was consistent across multiple subgroups ,” the authors noted , which examined factors such as the type of stent used , type of P2Y 12 inhibitor used , and patients ’ HAS-BLED score ( a bleeding risk assessment tool ).
Rates of death related to cardiovascular events ( secondary endpoint ; defined as a composite of death from cardiovascular cases , myocardial infarction , or stroke ) also were similar among the three groups ( 6.5 %, 5.6 %, and 6 % for groups 1 , 2 , and 3 , respectively , TABLE 2 ).
“Treatment that included either low-dose or very – low-dose rivaroxaban was associated with a lower risk of clinically significant bleeding ... compared with standard triple therapy .”
— C . MICHAEL GIBSON , MD
“ The three groups had similar efficacy rates , although the observed broad confidence intervals diminish the surety of any conclusions regarding efficacy ,” the authors noted , adding that this study was not powered to establish either superiority or noninferiority of the rivaroxabanbased regimen .
Other potential limitations of the study include investigator ’ s choice of DAPT duration ( rather than random assignment ) and an imbalance in patient characteristics across these groups .
REFERENCE
Gibson CM , Mehran R , Bode C , et al . Prevention of bleeding in patients with atrial fibrillation undergoing PCI . N Engl J Med . 2016 ; 375:2423-34 .
Enoxaparin Does Not Prevent Placenta- Mediated Complications in Pregnant Women With Severe Preeclampsia
Pregnant women who have severe preeclampsia ( a disease characterized by impaired vascular response to placentation ) before 34 weeks of pregnancy are at an increased risk for severe maternal and perinatal complications , including a higher risk of developing eclampsia during subsequent pregnancies and a lower-than-average birthweight .
Though research has suggested that prophylactic doses of lowmolecular-weight heparin ( LMWH ) can decrease the risk of these placenta-mediated complications , results from a multicenter , randomized trial of women with a history of severe preeclampsia showed that treatment with the LMWH enoxaparin ( combined with lowdose aspirin ) did not reduce the risk of recurrent preeclampsia , perinatal death , or maternal death , compared with low-dose aspirin alone . The study was published in Obstetrics & Gynecology .
In the open-label , controlled HEPEPE ( Heparin-Preeclampsia ) trial , Bassam Haddad , MD , of the Department of Obstetrics – Gynecology and Reproductive Medicine at the University Paris Est Créteil in France , and investigators enrolled 257 women from 16 secondaryor tertiary-care centers in France between November 14 , 2009 , and February 21 , 2015 .
Women with a singleton pregnancy ( confirmed by ultrasound ) were eligible for inclusion . Patients were excluded if they :
• had a contraindication to receive heparin or aspirin
• had antiphospholipid antibody syndrome or acquired thrombophilia ( positive for lupus anticoagulants , anticardiolipin , or anti-ß2 glycoprotein antibodies )
Patients were randomized 1:1 before 14 weeks of pregnancy to receive either aspirin 100 mg ( n = 127 ) or aspirin with subcutaneous enoxaparin 4,000 IU daily ( n = 130 ). Aspirin was stopped at 35 weeks of pregnancy , while enoxaparin was continued until delivery . Thirteen patients were excluded after randomization or lost to follow-up , for a final patient population of :
• 122 patients in the aspirin-only group ( mean age = 31.5 ± 4.4 years )
• 122 patients in the enoxaparin – aspirin group ( mean age = 31.7 ± 4.9 years )
TABLE 3 . Outcomes Related to Composite Morbidity
Enoxaparin plus Aspirin ( n = 122 )
Preeclampsia * 22 ( 18 %)
Severe preeclampsia †
Small for gestational age ±
Placental abruption
16 ( 13.1 %)
26 ( 21.3 %)
3 ( 2.5 %)
Perinatal death 1 ( 0.8 %)
Aspirin alone ( n = 122 ) Relative risk
27 ( 22.1 %)
17 ( 13.9 %)
33 ( 27.3 %)
3 ( 2.5 %)
4 ( 3.3 %)
Patients were monitored every four weeks ( from 12 to 36 weeks of pregnancy ) for the composite morbidity outcome , adverse events , weight , blood pressure , and study drug compliance ( via a patient-recorded diary review ). The composite morbidity endpoint included : incidence of preeclampsia , small size for gestational age ( birthweight less than the 10th percentile ), placental abruption , perinatal death , and maternal death . Preeclampsia was defined as blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg in a woman who was normotensive before 20 weeks of pregnancy and had significant proteinuria .
The primary composite outcome did not differ between the two groups : 34.4 percent in the
0.81 ( 95 % CI 0.49-1.35 )
0.94 ( 95 % CI 0.50-1.78 )
0.78 ( 95 % CI 0.50-1.22 )
1 ( 95 % CI 0.21-4.86 )
0.25 ( 95 % CI 0.03-2.20 )
enoxaparin – aspirin group ( n = 42 ) and 41 percent in the aspirin-only group ( n = 50 ; relative risk [ RR ] = 0.84 ; 95 % CI 0.61-1.16 ; p = 0.29 ). See TABLE 3 for outcomes of each element of the composite morbidity endpoint .
Enoxaparin was well tolerated , Dr . Haddad and authors noted . In the enoxaparin – aspirin group , 13 patients ( 10.7 %) experienced anygrade bleeding , compared with seven patients ( 5.7 %) in the aspirin-only group ( RR = 1.86 ; 95 % CI 0.77-4.50 ; absolute RR = – 24.9 %; p = 0.16 ). There were no significant differences in major or minor bleeding .
Absolute risk reduction
4.1 ( 95 % CI −5.9-14.1 )
0.8 ( 95 % CI −0.8-0.9 )
6 ( 95 % CI −4.8-16.7 )
0 ( 95 % CI −3.9-3.9 )
2.5 ( 95 % CI −1.1-6 )
Maternal death 0 0 − − −
p value 0.42
* Defined as systolic blood pressure ( BP ) ≥140 mm Hg or diastolic BP ≥90 mm Hg in a woman who was normotensive before 20 weeks of pregnancy and significant proteinuria † Defined as ≥1 of the following criteria : systolic BP ≥160 mm Hg or diastolic BP ≥110 mm Hg on two occasions at least 6 hours apart while the patient was on bed rest ; proteinuria ≥5 g in a 24-hour urine specimen or ≥3 g on two random urine samples collected at least 4 hours apart . ± Excludes one early loss in the aspirin alone group .
0.85
0.28
1.00
0.37
“ Systemic inflammation is hypothesized to contribute to endothelial dysfunction in preeclampsia , and LMWH has emerged as a novel therapeutic option to prevent impaired placentation-related complications because it has been shown to be antiinflammatory and improve vascular functions ,” the authors stated . However , these results “ highlight the importance of multicenter studies before [ instituting the routine use of drugs such as prophylactic enoxaparin ].”
The study is limited by its openlabel design and the lack of a placebo cohort . ●
REFERENCE
Haddad B , Winer N , Chitrit Y , et al . Enoxaparin and aspirin compared with aspirin alone to prevent placenta-mediated pregnancy complications : a randomized controlled trial . Obstet Gynecol . 2016 ; 128:1053-63 .
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