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      Fondaparinux vs warfarin for the treatment of unsuspected pulmonary embolism in cancer patients

      1 , 2

      Drug Design, Development and Therapy

      Dove Medical Press

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          Abstract

          Dear editor We read with great interest the study published on June 23, 2016 by Amato et al entitled “Fondaparinux vs warfarin for the treatment of unsuspected pulmonary embolism in cancer patients.”1 While we value the importance of this study in highlighting this important topic, we have several issues to be addressed. Venous thromboembolisms (VTEs), especially pulmonary embolism (PE), in asymptomatic patients are well-described clinical entities that are usually underrecognized. It is believed that most fatal PEs are not suspected clinically and are not treated.2,3 This issue is even more important in cancer patients where respiratory symptoms can often be attributed to the cancer itself or its treatment. We fully agree with the authors that incidental, or unsuspected PE, is not a benign diagnosis especially in cancer patients. We previously reported our experience in 34 incidental PEs in such patients.4 Except for five (15%), all other patients were anticoagulated; all with low-molecular-weight heparin (LMWH). With follow-up, two patients developed recurrent PE, two others had clinical and echocardiographic evidence of pulmonary hypertension, and nine (26%) died suddenly within 30 days of the diagnosis of PE; two of these were among the five patients who were not anticoagulated. In their introduction, the authors stated that “Warfarin is commonly used prophylactically in patients with a high risk of thromboembolic events.” This statement is not accurate as warfarin is not used for VTE prophylaxis. We assume that the authors meant active treatment (not prophylaxis) of VTE. Also, the authors stated that “Fondaparinux, is the newest agent with venous thromboembolism (VTE) prophylaxis activity” and this statement is not accurate, either. Fondaparinux, which was introduced and approved initially for VTE prophylaxis then for active treatment of both deep vein thrombosis and PE for over 15 years now, is not new anymore.5,6 The “relatively new” oral anticoagulants, the direct thrombin inhibitors (dabigatran) and the direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), are the most recently introduced anticoagulants in clinical practice.7,8 The authors clearly stated that asymptomatic PE should be treated the same way symptomatic PE is treated; a statement that is fully supported by many published guidelines, including the American College of Chest Physicians.9 The authors also stated, based at least on the CLOT trial,10 that LMWH (dalteparin) is superior to warfarin. Yet, the authors used warfarin, not LMWH, to compare fondaparinux with. Though we agree with the authors that the recently published CATCH trial failed to show superiority of LMWH (tinzaparin) over warfarin in this setting,11 however, due to many factors addressed by the authors in their paper, LMWHs are still the preferred agents for active VTE treatment in cancer patients. Additionally, the CATCH study showed that tinzaparin significantly reduced the risk of clinically relevant nonmajor bleeding compared with warfarin. Together with the adverse events data, CATCH demonstrated that tinzaparin, even when given at a full therapeutic dose for up to 6 months, is a safe and convenient drug in cancer patients. It should also be noted that the CATCH study results were published after enrolling all patients in the current study under discussion. More recently, our group participated in a pooled analysis of 926 cancer patients from eleven cohorts, all with incidental PE. While VTE recurrence risk was comparable under LMWH and warfarin (6.2% vs 6.4%; hazard ratio 0.9; 95% confidence interval 0.3–3.1), the risk of major hemorrhage was higher under warfarin than under LMWH (13% vs 3.9%; hazard ratio 3.9; 95% confidence interval 1.6–10).12 We believe that the era of having warfarin as a drug to compare new anticoagulants within clinical trials, in cancer patients, is not attractive anymore. Researchers are moving forward, comparing the new oral anticoagulants, such as rivaroxaban versus LMWH, in a huge research program called the “CALLISTO”. This program is evaluating cancer patient populations being treated for VTEs or at high risk for developing them. Such a program will encompass the field of cancer-associated thrombosis through nine studies, including seven clinical trials and two registries across various cancer types, in >4,000 patients globally.13 Fondaparinux, on the other hand, has a major advantage over all other heparins, including LMWH. Being a small molecule with just five sugars (pentasaccharide), it is rarely associated with thrombocytopenia, thus allowing its clinical use in the treatment of heparin-induced thrombocytopenia.14 In conclusion, we want to congratulate the authors for addressing such an important topic, but we believe that such a study would have a better impact if the authors chose one of the LMWHs to compare fondaparinux with. The real excitement in antithrombotic therapy in cancer patients will be the introduction of oral direct thrombin and anti-Xa inhibitors.

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          Most cited references 14

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          Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.

          Patients with cancer have a substantial risk of recurrent thrombosis despite the use of oral anticoagulant therapy. We compared the efficacy of a low-molecular-weight heparin with that of an oral anticoagulant agent in preventing recurrent thrombosis in patients with cancer. Patients with cancer who had acute, symptomatic proximal deep-vein thrombosis, pulmonary embolism, or both were randomly assigned to receive low-molecular-weight heparin (dalteparin) at a dose of 200 IU per kilogram of body weight subcutaneously once daily for five to seven days and a coumarin derivative for six months (target international normalized ratio, 2.5) or dalteparin alone for six months (200 IU per kilogram once daily for one month, followed by a daily dose of approximately 150 IU per kilogram for five months). During the six-month study period, 27 of 336 patients in the dalteparin group had recurrent venous thromboembolism, as compared with 53 of 336 patients in the oral-anticoagulant group (hazard ratio, 0.48; P=0.002). The probability of recurrent thromboembolism at six months was 17 percent in the oral-anticoagulant group and 9 percent in the dalteparin group. No significant difference between the dalteparin group and the oral-anticoagulant group was detected in the rate of major bleeding (6 percent and 4 percent, respectively) or any bleeding (14 percent and 19 percent, respectively). The mortality rate at six months was 39 percent in the dalteparin group and 41 percent in the oral-anticoagulant group. In patients with cancer and acute venous thromboembolism, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding. Copyright 2003 Massachusetts Medical Society
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            • Article: not found

            Tinzaparin vs Warfarin for Treatment of Acute Venous Thromboembolism in Patients With Active Cancer: A Randomized Clinical Trial.

            Low-molecular-weight heparin is recommended over warfarin for the treatment of acute venous thromboembolism (VTE) in patients with active cancer largely based on results of a single, large trial.
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              • Article: not found

              Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism.

              The standard initial treatment of hemodynamically stable patients with pulmonary embolism is intravenous unfractionated heparin, requiring laboratory monitoring and hospitalization. We conducted a randomized, open-label trial involving 2213 patients with acute symptomatic pulmonary embolism to compare the efficacy and safety of the synthetic antithrombotic agent fondaparinux with those of unfractionated heparin and to document noninferiority in terms of efficacy. Patients received either fondaparinux (5.0, 7.5, or 10.0 mg in patients weighing less than 50, 50 to 100, or more than 100 kg, respectively) subcutaneously once daily or a continuous intravenous infusion of unfractionated heparin (ratio of the activated partial-thromboplastin time to a control value, 1.5 to 2.5), both given for at least five days and until the use of vitamin K antagonists resulted in an international normalized ratio above 2.0. The primary efficacy outcome was the three-month incidence of the composite end point of symptomatic, recurrent pulmonary embolism (nonfatal or fatal) and new or recurrent deep-vein thrombosis. Forty-two of the 1103 patients randomly assigned to receive fondaparinux (3.8 percent) had recurrent thromboembolic events, as compared with 56 of the 1110 patients randomly assigned to receive unfractionated heparin (5.0 percent), for an absolute difference of -1.2 percent in favor of fondaparinux (95 percent confidence interval, -3.0 to 0.5). Major bleeding occurred in 1.3 percent of the patients treated with fondaparinux and 1.1 percent of those treated with unfractionated heparin. Mortality rates at three months were similar in the two groups. Of the patients in the fondaparinux group, 14.5 percent received the drug in part on an outpatient basis. Once-daily, subcutaneous administration of fondaparinux without monitoring is at least as effective and is as safe as adjusted-dose, intravenous administration of unfractionated heparin in the initial treatment of hemodynamically stable patients with pulmonary embolism. Copyright 2003 Massachusetts Medical Society
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                24 August 2016
                : 10
                : 2677-2679
                Affiliations
                [1 ]Department of Internal Medicine
                [2 ]Department of Radiology, King Hussein Cancer Center, Amman, Jordan
                [1 ]Interuniversity Center of Phlebolymphology (CIFL), International Research and Educational Program in Clinical and Experimental Biotechnology, University Magna Graecia of Catanzaro, Viale Europa, Catanzaro
                [2 ]Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples
                [3 ]Department of Health Sciences
                [4 ]Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro, Italy
                Author notes
                Correspondence: Hikmat Abdel-Razeq, Department of Internal Medicine, King Hussein Cancer Center, 202 Queen Rania Al Abdullah Street, Amman, 11941 Jordan, Tel +962 6 530 0460 ext 1000, Email habdelrazeq@ 123456khcc.jo
                Correspondence: Raffaele Serra, Department of Medical and Surgical Sciences, University of Catanzaro, Viale Europa, Catanzaro 88100, Italy, Tel +39 961 364 7380, Email rserra@ 123456unicz.it
                Article
                dddt-10-2677
                10.2147/DDDT.S115852
                5003511
                27601884
                © 2016 Abdel-Razeq and Mansour. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Pharmacology & Pharmaceutical medicine

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