Low‐molecular‐weight‐heparin and pregnancy,when the dose does it: a nephrologist’s opinion: reply to a rebuttal

See also Roeters van Lennep JE, Meijer E, Klumper FJ, Middeldorp JM, Bloemenkamp KW, Middeldorp S. Prophylaxis with low‐dose low‐molecular‐weight‐heparin during pregnancy and postpartum: is it effective? J Thromb Haemost 2011; 9 : 473–80; Stratta P, Canavese C, Cena T, Quaglia M, Pergolini P, Bellomo G, Magnani C. Low‐molecular‐weight‐heparin and pregnancy, when the dose does it: a nephrologist’s opinion: a rebuttal. This issue, pp 2127–9.     

Women’s views on and adherence to low‐molecular‐weight heparin therapy during pregnancy and the puerperium

Summary. Background: Non‐adherence to prescribed medication represents a significant factor associated with treatment failure. Pregnant women identified at risk of venous thromboembolism are increasingly being prescribed low‐molecular‐weight heparin (LMWH) during pregnancy and the puerperium. It is important to understand women’s views on and adherence to LMWH during pregnancy and the puerperium, so that women gain maximum benefit from the treatment. Objectives: To monitor women’s adherence to enoxaparin, when prescribed during pregnancy and the puerperium, and explore their beliefs about the enoxaparin therapy prescribed. Patients/Methods: A prospective cohort study involving 95 nullparous and multiparous women prescribed enoxaparin for recognized antenatal indications. Adherence to enoxaparin was assessed through self‐completion of a diary, additionally verified through laboratory tests. An adapted beliefs about medication questionnaire was administered to women during their pregnancy. Results: Women were highly adherent to enoxaparin: antenatally, mean percentage adherence 97.92%; postnatally, mean percentage adherence 93.37% (paired t‐test, P = 0.000). In the cohort of women we followed, their perceived necessity for enoxaparin therapy outweighed any concerns they had regarding enoxaparin antenatally, necessity‐concerns differential 2.20. In some women, however, this perceived necessity does decrease postnatally. Conclusions: Our results suggest that most women prescribed enoxaparin are highly adherent to their therapy during the antenatal period and that women’s antenatal beliefs about enoxaparin are able to predict a decrease in postnatal adherence. Our results have important clinical implications, particularly when women are initiated on LMWH just during the postnatal period.     

Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT: a rebuttal

See also de Vries JIP, Hague WM and van Pampus MG; for the FRUIT‐Investigators. Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT: a reply to a rebuttal. This issue, pp 1196; de Vries JIP, van Pampus MG, Hague WM, Bezemer PD, Joosten JH, on behalf of FRUIT Investigators. Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset preeclampsia in women with inheritable thrombophilia: the FRUIT‐RCT. J Thromb Haemost 2012; 10 : 64–72.     

Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT: a reply to a rebuttal

See also Bujold E, Gouin K, Cote S.Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT: a rebuttal. This issue, pp 1195; de Vries JIP, van Pampus MG, Hague WM, Bezemer PD, Joosten JH, on behalf of FRUIT Investigators. Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT. J Thromb Haemost 2012; 10 : 64–72.     

Low‐molecular‐weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST‐elevation myocardial infarction: a meta‐analysis

Summary. Background: The aim of the current study was to perform two separate meta‐analyses of available studies comparing low‐molecular‐weight heparins (LMWHs) vs. unfractionated heparin (UFH) in ST‐elevation myocardial infarction (STEMI) patients treated (i) with primary percutaneous coronary intervention (pPCI) or (ii) with PCI after thrombolysis. Methods: All‐cause mortality was the pre‐specified primary endpoint and major bleeding complications were recorded as the secondary endpoints. Relative risk (RR) with a 95% confidence interval (CI) and absolute risk reduction (ARR) were chosen as the effect measure. Results: Ten studies comprising 16 286 patients were included. The median follow‐up was 2 months for the primary endpoint. Among LMWHs, enoxaparin was the compound most frequently used. In the pPCI group, LMWHs were associated with a reduction in mortality [RR (95% CI) = 0.51 (0.41–0.64), P < 0.001, ARR = 3%] and major bleeding [RR (95% CI) = 0.68 (0.49–0.94), P = 0.02, ARR = 2.0%] as compared with UFH. Conversely, no clear evidence of benefits with LWMHs was observed in the PCI group after thrombolysis. Meta‐regression showed that patients with a higher baseline risk had greater benefits from LMWHs (r = 0.72, P = 0.02). Conclusions: LMWHs were associated with greater efficacy and safety than UFH in STEMI patients treated with pPCI, with a significant relationship between risk profile and clinical benefits. Based on this meta‐analysis, LMWHs may be considered as a preferred anticoagulant among STEMI patients undergoing pPCI.     

Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT

Summary. Background: Early‐onset hypertensive disorders (HD) of pregnancy and small‐for‐gestational age infants (SGA) are associated with placental vascular thrombosis, these often recur and are also associated with inheritable thrombophilia. Aspirin reduces the recurrence risk. Objectives: Adding low‐molecular‐weight heparin (LMWH) to aspirin at < 12 weeks gestation reduces the recurrence of HD in women with previous early‐onset HD (pre‐eclampsia, hemolysis, elevated liver enzymes and low platelets [HELLP] syndrome and eclampsia) and/or SGA, in the context of inheritable thrombophilia without antiphospholipid antibodies. Patients/methods: In a multicenter randomized control trial (RCT), 139 women included were < 12 weeks gestation. Inclusion criteria: previous delivery < 34 weeks gestation with HD and/or SGA; inheritable thrombophilia (protein C deficiency, protein S deficiency, activated protein C resistance, factor V Leiden heterozygosity and prothrombin gene G20210A mutation heterozygosity); and no antiphospholipid antibodies detected. Intervention: either daily LMWH (dalteparin, 5000 IU weight‐adjusted dosage) with aspirin 80 mg or aspirin 80 mg alone. Main outcome measures: Primary outcomes: recurrent HD onset (i) < 34 weeks gestation and (ii) irrespective of gestational age. Secondary outcomes: recurrent SGA, preterm birth, maternal/neonatal hospitalization, spontaneous abortion and individual HD. Analysis by intention‐to‐treat. Results: Low‐molecular‐weight heparin with aspirin reduced recurrent HD onset < 34 weeks gestation (risk difference [RD] 8.7%: confidence interval [CI] of RD 1.9–15.5%; P = 0.012; number needed to treat [NNT] 12). Recurrent HD irrespective of gestational age was not different between the arms. No women withdrew as a result of adverse effects. Trial Registration: http://www.isrctn.org ) (isrctn87325378). Conclusions: Adding LMWH to aspirin at < 12 weeks gestation reduces recurrent HD onset < 34 weeks gestation in women with inheritable thrombophilia and prior delivery for HD/SGA <34 weeks. However, close monitoring of the mother and fetus remains important throughout pregnancy.     

Definition of major bleeding in surgery: an anesthesiologist’s point of view: a rebuttal

See also Schulman S, Angeras U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. Definition of major bleeding in clinical investigations of anti‐hemostatic medicinal products in surgical patients. J Thromb Haemost 2010; 8 : 202–4; Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. Definition of major bleeding in surgery: an anaesthesiologist's point of view: reply to a rebuttal. This issue, pp 1443–4.     

Definition of major bleeding in surgery: an anesthesiologist’s point of view: reply to a rebuttal

See also Schulman S, Angeras U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. Definition of major bleeding in clinical investigations of anti‐hemostatic medicinal products in surgical patients. J Thromb Haemost 2010; 8 : 202–4; Rosencher N, Zufferey P, Samama C‐M. Definition of major bleeding in surgery: an anesthesiologist's point of view: a rebuttal. This issue, pp 1442–3.     

Skin blood flow in adult human thermoregulation: how it works,when it does not,and why

The thermoregulatory control of human skin blood flow is vital to the maintenance of normal body temperatures during challenges to thermal homeostasis. Sympathetic neural control of skin blood flow includes the noradrenergic vasoconstrictor system and a sympathetic active vasodilator system, the latter of which is responsible for 80% to 90% of the substantial cutaneous vasodilation that occurs with whole body heat stress. With body heating, the magnitude of skin vasodilation is striking: skin blood flow can reach 6 to 8 L/min during hyperthermia. Cutaneous sympathetic vasoconstrictor and vasodilator systems also participate in baroreflex control of blood pressure; this is particularly important during heat stress, when such a large percentage of cardiac output is directed to the skin. Local thermal control of cutaneous blood vessels also contributes importantly--local warming of the skin can cause maximal vasodilation in healthy humans and includes roles for both local sensory nerves and nitric oxide. Local cooling of the skin can decrease skin blood flow to minimal levels. During menopause, changes in reproductive hormone levels substantially alter thermoregulatory control of skin blood flow. This altered control might contribute to the occurrence of hot flashes. In type 2 diabetes mellitus, the ability of skin blood vessels to dilate is impaired. This impaired vasodilation likely contributes to the increased risk of heat illness in this patient population during exposure to elevated ambient temperatures. Raynaud phenomenon and erythromelalgia represent cutaneous microvascular disorders whose pathophysiology appears to relate to disorders of local and/or reflex thermoregulatory control of the skin circulation.     

PRODIGE: a randomized placebo‐controlled trial of dalteparin low‐molecular‐weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma

Summary. Background and objectives: Venous thromboembolism (VTE) occurs in 20–30% of patients with malignant glioma per year of survival. We tested the efficacy of long‐term dalteparin low‐molecular‐weight heparin (LMWH) for prevention of VTE in these patients. Patients/methods: Adults with newly diagnosed malignant glioma were randomized to receive dalteparin 5000 anti‐Xa units or placebo, both subcutaneously once daily for 6 months starting within 4 weeks of surgery. Treatment continued for up to 12 months. The primary outcome was the cumulative risk of VTE over 6 months. The target sample size was 512 patients. Events were adjudicated by a committee unaware of treatment. Results: The trial began in 2002 and closed in May 2006 because of expiration of study medication. Ninety‐nine patients were randomized to LMWH and 87 to placebo. Twenty‐two patients developed VTE in the first 6 months: nine in the LMWH group and 13 in the placebo group [hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.19–1.4, P = 0.29]. At 6 months, there were three major bleeds on LMWH and none on placebo; at 12 months, 5 (5.1%) major bleeds on LMWH and 1 (1.2%) on placebo occurred (HR = 4.2, 95% CI: 0.48–36, P = 0.22). All major bleeds were intracranial and occurred while on study medication. The 12‐month mortality rates were 47.8% for LMWH and 45.4% for placebo (HR = 1.2, 95% CI: 0.73–2.0, P = 0.48). Conclusions: Trends suggesting reduced VTE and increased intracranial bleeding were seen in the LMWH thromboprophylaxis group. The role of long‐term anticoagulant thromboprophylaxis in patients with brain tumors remains uncertain.     

Low‐dose aspirin for in vitro fertilization or intracytoplasmic sperm injection: a systematic review and a meta‐analysis of the literature

Summary. Background: It was hypothesized that low‐dose aspirin could improve implantation rates in subsequent pregnancies in women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Previous studies have shown inconclusive results or focused on surrogate endpoints. We therefore conducted a systematic review and meta‐analysis of the literature investigating the effect of low‐dose aspirin on hard outcomes, including live birth rate, pregnancy rate and miscarriage. Methods: MEDLINE and EMBASE databases were searched up to November 2011. Randomized controlled trials comparing low‐dose aspirin with placebo/no treatment in IVF/ICSI women were included. Pooled odds ratios (ORs) and 95%confidence intervals (CIs) were calculated. Results: Seventeen studies with 6403 patients were included. The use of aspirin did not improve live birth pregnancy rate compared with placebo or no treatment (1.08; 95% CI, 0.90, 1.29). Pregnancy rates were significantly increased in patients randomized to low‐dose aspirin (OR, 1.19; 95% CI, 1.01, 1.39), but miscarriage rates were not (OR, 1.18; 95% CI, 0.82, 1.68). Results of sensitivity analyses including high‐quality studies did not show statistically significant differences in all considered endpoints. Conclusions: The results of this study do not show a substantial efficacy of aspirin inwomen undergoing IVF/ICSI and do not support the use of low‐dose aspirin to improve the success of IVF/ICSI in terms of pregnancy outcomes. Further high‐quality studies evaluating the possible efficacy of aspirin in selected groups of patients are warranted.