I nclusion Criteria: P atient undergoing major gynecological operat ion e.g.: Hysterectomy (vaginal, abdominal), m yomectomy, o varian c ystectomy, v

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1 Journal of Basic Applied Sciences. Vol. 6 No. 4.. Pp Copyright by Journals. All Rights Reserved. F ull length Research P aper Oral Dabigatran v ersus Enoxaparin G ynecological P rocedure f or Thromboprophylaxis a fter Mahmoud Salah Mahmoud1 Sally Hosney Ali Sroor2 1. O bstetrics Gynecology Department, Al-A zhar Faculty of Medicine, Egypt 2. O bstetrics Gynecology Department-D amietta General Hospital, Egypt. A rticle history Received: Revised: Accepted: C orresponding Author: M ahmoud S. M ahmoud Obstetrics Gynecology D epartm ent, Al- Azhar Faculty o f Medicine, Egypt. A bstract Deep vein thrombosis (DVT) defined as formation of a thrombus in the deep veins of the leg, a lthough DVT may also occur in the veins of the upper limbs. Dabigatran was the first oral direct t hrombin inhibitor (DTI) marketed in the United States as well as the first of the group of drugs known as novel or non- v itamin K antagonist oral anticoagulants (NOACs). This is a cross section clinical observation study conducted in Al-A zhar University hospital ( New Damietta). This study includes 100 women with high risk factor for thromboembolism undergoing major gynecological operation started at the period from January 2016 to December p atients after gynecological operation with risk factor of DVT treated with oral dabigatran 50 patients after gynecological operation with risk factor of DVT treated with enoxaparin. Enoxaparine is better than dabigatran in Thromboprophylaxis after gynecological procedure. is an effective oral alternative to existing Thromboprophylaxis agents in patients undergoing major gynecological operation. In patients undergoing major operation should take dabigatran orally to avoid complication as venous thromboembolism dabigatran considered b etter than subcuta neous enoxaparin due to easily drug administration. I ntroduction C ommon signs symptoms of DVT include pain or tenderness, swelling, warmth, redness or discoloration distention of s urface veins, although about half of those with the condition have no symptoms. Signs symptoms alone are not sufficiently s ensitive or specific to make a diagnosis, but when considered in conjunction with k nown risk factors can help determine the l ikelihood of DVT ( Scarvelis Wells, 2006). S ymptoms are more often due to other causes such as c ellulitis, B aker's cyst, musculoskeletal injury or l ymphedema ( Hargett Tapson, 2008). Dabigatran (Pradaxa ) is an oral direct thrombin inhibitor that c an be used with fixed doses, without the need for routine anticoagulation laboratory monitoring the advantage of few drug or d iet interactions. Dabigatran is effective for stroke systemic thromboembolism in AF for the prophylaxis treatment of V TE. The drug has a good safety profile consistently shows a reduction in intracranial hemorrhage risk compared to warfarin ( A geno e t al., 2016). is a reversible, competitive inhibitor of thrombin, to which it binds in both freely circulating clot bound forms. L ike other NOACs, its mechanism of action does not interfere with the interaction of platelets platelet factor 4 (PF4) or that of a ntibodies with the heparin/pf4 complex ( B urness McKeage, 2012). In the active- control study, dabigatran was not inferior to warfarin for the prevention of VTE, once again with a lower risk of bleeding. In the placebo- control study, dabigatran s ignificantly reduced the rate of recurrent VTE but also showed a significantly higher risk of bleeding. The benefit of treatment with dabigatran was maintained during extended follow- up after the study drug was discontinued. The authors noted that the e fficacy of dabigatran its risk of clinically relevant bleeding versus placebo is similar to that of rivaroxaban compared to p lacebo ( Schulman et al., 2014). Low-molecular- weight heparins (LMWHs) as enoxaparin vitamin K antagonists are used routinely for a fter major orthopedic surgery ( Geerts et al., 2004). Although they effectively reduce the incidence of deep vein thrombosis ( DVT) pulmonary embolism (PE), a number of limitations restrict their use. Vitamin K antagonists, although orally a dministered have a slow onset of action, interpatient variability, need for frequent monitoring potential drug interactions, w hereas LMWHs a are administe red parenterally ( Eriksson et al., 2006). M aterials methods P atients methods This is a cross section clinical observation study conducted in Al- Azhar University hospital (New Damietta). This study i ncludes 100 women with high risk factor for thromboembolism undergoing major gynecological operation started at the period from J anuary 2016 to December 2016 participated after oral informed consent w ith the following criteria: Keywords: D VT, Dabigatran, Enoxaparin. 163

2 I nclusion Criteria: P atient undergoing major gynecological operat ion e.g.: Hysterectomy (vaginal, abdominal), m yomectomy, o varian c ystectomy, v aginal repair). R isk factor for DVT or Pulmonary Embolism e.g. : previous VTE, known high- risk t hrombophilia medical morbidities e.g. cancer, heart failure, active systemic lupus erythematosus, inflammatory p olyarthropathy or inflammatory bowel disease, nephrotic syndrome, type I diabetes mellitus with nephropathy, sickle cell disease, current intravenous drug user, family history of un provoked or estrogen-related VTE in first- degree relative, known l ow risk thrombophilia, Age > 35 years, obesity, parity >3, smoker, gross varicose veins. E xclusion Criteria: Hypersensitivity to dabigatran or e noxaparin., Elevated liver enzymes [ALT] greater than three times the upper limit of the normal range, Severe renal insufficiency [creatinine clearance <30 ml/minute], Concomitant treatment with s ystemic ketoconazole, cyclosporine, itraconazole dronedarone Prosthetic heart valves requiring anticoagulant t reatment. The following were taken: 1. C areful History taking to check for inclusion exclusion criteria according to stardized research protocol. 2. O bstetric history including Gravidity, parity, Multiple pregnancies, Pregnancy induced hypertension Gestational or p regestational diabetes 3. Past history including medical diseases (DM, Hypertension, Coagulopathies, cardiac pulmonary diseases.), p revious operations or others. S tatistical analysis: C omparison of maternal plasma concentrations of homocysteine with different Doppler scores was carried out u sing the Kruskal W allis test. The significance between the groups was evaluated by the Mann Whitney U- test with Bonferroni correction. Spearman correlation analysis was performed for correlations of non-p arametric va riables. R esults T able 1: D emographic data of studied groups P A ge (years) ± ±7. BMI (Kg/m ) 33.64± ± P arity 2.7± ± T his table shows that age, BMI parity were nearly comparable between group treated with Dabigatran group treated with 2 Enoxaparin (age: 42.6±6.6 Vs 43.4±7. years, BMI: 33.64±1. Vs 33.6± 3. 1 Kg/ m a nd parity: 2.7±1.5 Vs 2±1.6). T able 2: Surgical charact eristics of studied groups G eneral anesthesia N (%) 46 (2%) 7 (4%) S pinal anesthesia N (%) (6%) Duration of surgery (min) 6±16..5±21. 4 P value T his table shows that surgical characteristics between group treated with dabigatran group treated with Enoxaparin. They i nclude general anesthesia ( 2% Vs 4% ), spinal anesthesia (8% Vs 6%) duration of surgery ( 6±16. Vs 8.5±21.4 min). T able 3: Efficacy ou tcomes of studied groups M ajor VTE VTE related to mortality 5 (10%) T otal DVT P roximal D istal 10 (20%) 6 (12%) 7 (14%) 5 (10%) S ymptomatic DVT T his table shows that efficacy outcomes between group treated with Dabigatran group treated with Enoxaparin. They include major VTE VTE related to mortality (8% Vs 10%) total DVT (20% Vs 14%) which divided into proximal (8% Vs 10%) a nd distal (12% Vs 4%). 164

3 T able 4: S afety outcomes (bleeding) of studied groups M ajor bleeding events H emoglobin loss B lood transfusion Non-m ajor b leeding events T his table shows that safety outcomes between group treated with Dabigatran group treated with Enoxaparin. They include major bleeding events (2% Vs 0%), hemoglobin loss (2% Vs 0%), blood transfusion (2% Vs 0%) non- major bleeding events ( 4% Vs 2%). T able 5: Other safety outcomes of studied groups N o (%) of adverse events 2 (58%) 31 (62%) D rug related to adverse events P atient with wound hemorrhage T his table shows that other safety outcomes between group treated with Dabigatran group treated with Enoxaparin. They include percentage of adverse events (58% Vs 62%), drug related to adverse events (4% Vs 8%) patients with wound h emorrhage (0% Vs 2%). D iscussion G uidelines of the RCOG the National Institute for Health Clinical Excellence encourage the use of LMWH as in high- risk pregnancies during the postpartum period. However, these recommendations were largely based on expert opinion with little evidence from romized controlled trials meta-a nalyses (Wu e t al., 2013 ). With LMWH, extended i s significantly more effective in preventing VTE ( A rcelus et al., 2006). Extended w ith enoxaparin for four weeks has shown to significantly reduce the incidence of VTE significantly (0.5% vs. 3.27%) compared with short- term ( 7 to11 days) in Indian patients ( N air et al., 2013). H owever, subcutaneous administration of LMWHs such as enoxaparin for up to 35 days could cause discomfort also makes it difficult for patients to adhere to treatment post- discharge. Switch-t herapy modalities have been shown to provide clinicians an a dvantage of using enoxaparin safely during the hospitalization period then switch to dabigatran for ease of administration during the outpatient period ( O zler e t al., 2015). Dabigatran etexilate was as effective as enoxaparin for the primary prevention of V TE, with a similar safety profile ( E riksson et al., 2006). T he present work aimed to compare the efficacy safety of oral dabigatran, a direct thrombin inhibitor, versus subcutaneous enoxaparin for extended i n patients undergoing major gynecological operations e.g..: Hysterectomy (vaginal or abdominal or c a esarian), myomectomy, ovarian c ystectomy, vaginal repair caesarian section in high risk g roup. In the p resent study, age, BMI parity were nearly comparable between group treated with Dabigatran group treated with 2 Enoxaparin (age: 42.6±6.6 Vs 43.4±7. years, BMI: 33.64±1. Vs 33.6± 3. 1 Kg/ m a nd parity: 2.7±1.5 Vs 2±1.6 with no s tatistically significant differences) a nd these agree with M alhotra et al. (2015) who noticed that the mean age 47.7 years at 50. years at Enoxaparin treated group with insignificant statistical differences also BMI has no statistical s ignificant differences. In the present study, the surgical characteristics between group treated with Dabigatran group treated w ith Enoxaparin include general anesth esia ( 2% Vs 4% ), spinal anesthesia (8% Vs 6%) duration of surgery (6±16. Vs 8.5±21.4 min). E riksson et al. (2011) have published the results of the efficacy safety of oral dabigatran versus subcutaneous e noxaparin for a fter total hip arthroplasty. The surgical procedures mostly involved the use of regional anesthesia in both the Indian global patients. The first dose of enoxaparin was administered pre- surgery (median 12.6 hours) dabigatran was administered post-s urgery (median 2.8 hours) in all the Indian patients, whereas in the global counterpart, e noxaparin dabigatran were administered preoperatively as well as postoperatively depending on the local practice followed i n that particular country /or as per the i nvestigator s judgment. In the present study, t he efficacy outcomes between group treated with Dabigatran group treated with Enoxaparin include m ajor VTE VTE related to mortality (8% Vs 10%) total DVT (20% Vs 14%) which divided into proximal (8% Vs 10% ) a nd distal (12% Vs 4%). R osencher et al. (200) noticed that the composite of major VTE (proximal DVT /or PE) VTE- r elated mortality occurred in 3.3% (6 of 206) of the enoxaparin group, 3.0% (62 of 2033) of the dabigatran etexilate 220 mg group 3.8% (78 of 2071) of the 150-m g group. Major bleeding occurred in 1.4% of the enoxaparin group, 1.4% of the dabigatran etexilate 220 mg group 1.1% of the 150-m g group. Most of the major bleeding events (80-0%) occurred at the s urgical sit e. M alhotra et al. (2015) reported that major VTE VTE- related mortality were low in both the arms (7.% dabigatran.% enoxaparin) in Indian patients. Fewer patients were diagnosed with proximal DVT in the dabigatran group ( 7.% India 2.1% global population) compared with the enoxaparin group (.% India 3.% global population). However, in the Indian patients, distal DVTs were more often reported in the dabigatran group (10.7%) compared with the e noxaparin group (2.7%); whereas in the global population 5.4% 4.5% of the patients had distal DVTs in the dabigatran 165

4 e noxaparin groups respectively. Distal DVTs (associated with calf veins) are less serious than the proximal DVTs as thrombi in c alf veins are generally small have little chance of embolization. Distal DVTs are therefore not usually associated with clinical disability or other complications. Distal DVTs may be at risk of embolization if they extend proximally ( K earon, 2003). T he incidence of proximal DVT observed with enoxaparin (2.8%) was lower than that observed in previous studies that used 40 m g enoxaparin (5.2%) ( E riksson et al., 2005) which was similar to that observed in the rivaroxaban (active factor X) twice- daily dosing study (4.7%). The incidence of symptomatic VTE events was low during treatment follow-up after short- term r ivaroxaban (6 to 10 days) ( E riksson et al., 2005). In a prospective study conducted in New Delhi, the overall incidence of VTE w as reported to be 6.12% among patients undergoing major surge ries ( Bagaria et al., 2006). The incidence of proximal DVT observed with enoxaparin (2.8%) was lower than that observed in previous studies that used 40 m g enoxaparin (5.2%) ( E riksson et al., 2005). I n the present study, the safety outcomes between group treated with Dabigatran group treated with Enoxaparin include major bleeding events (2% Vs 0%), hemoglobin loss (2% Vs 0%), blood transfusion ( 2% Vs 0%), non- major bleeding events (4% Vs 2%), p ercentage of adverse events (58% Vs 62%), drug related to adverse events ( 4% Vs 8%) patients with wound hemorrhage (0% Vs 2%). L assen e t al. (2002) reported that there was a significant dose trend for major postoperative bleeding across the rivaroxaban treatment groups. The observed incidences were similar in the 5-10-m g rivaroxaban groups the enoxaparin g roup (2.3% 0.7% versus 1.%, respectively). The observed incidences in the 20-, 30-, 40-m g rivaroxaban dose groups were higher than with enoxaparin, but no dose g roup was discontinued because of e xcessive bleeding. Importantly, t here were no fatal bleeding events or bleeding into a critical o rgan; all major bleeding events w ere confined to t he surgical site. H uisman et al. (2010) reported that there was a 7- f old proportional difference in the rate of m ajor bleeding for patients receiving enoxaparin in trials versus dabigatran than versus rivaroxaban (mean, 1.4% versus 0.2%). T his is almost certainly related to recognized differences in the definition of major bleeding. O nly one patient had a major bleeding event prior to the administration of dabigatran as evidenced by a fall in hemoglobin level ( >20 g/l) leading to blood transfusion ( Malhotra et al., 2015). T he observed incidence of clinically relevant, non m ajor bleeding was lower in all activ e factor X (rivaroxaban) dose groups than that o bserved with enoxaparin, minor bleeding followed the s ame pattern as major bleeding, with a similar incidence c ompared with enoxaparin in the lower rivaroxaban dose groups. The proportion of patients requ iring transfusion was s imilar in all rivaroxaban dose groups the enoxaparin group, similar to t hat reported in other clinical trials i nvestigating anticoagulants in patients undergoing hip replacement s urgery ( E riksson et al., 2003). A nticoagulants prevent VTE, but the risk of bleeding associated with their use can be fatal. The risk of gastrointestinal b leeding related to dabigatran is similar to warfarin ( A braham et al., 2015). Also, dabigatran enoxaparin pose a similar risk of c linically significant bleeding, major bleeding clinically relevant nonmajor bleeding ( Gomez- O utes et al., 2012). The o ccurrence of all adverse events (AEs) in the Indian population was slightly lower (58.2% dabigatran group 61.4% enoxaparin g roup) than the global population (67% dabigatran group 6% enoxaparin group). Occurrence of safety adverse events was more frequent in the enoxaparin (.1%) group compared with the dabigatran (4.4%) group in the Indian patients. As per the i nvestigator s evaluation, a higher number of drug related AEs were reported in the enoxaparin group (6.8%) than the dabigatran g roup (3.3%) in the Indian patients ( Malhotra et al., 2015). Till now according to our knowledge there is now study published to c ompare the efficacy safety of oral dabigatran versus subcutaneous enoxaparin for extended in patients u ndergoing major gynecological operations. R eferences A braham NS, Singh S, Alexer GC, et al. (2015): C omparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, a nd warfarin: population based cohort study. BMJ., 350: h1857. 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