Xarelto (varoxaban, a factor Xa inhibitor) is the first oral anti-coagulant approved for anti-coagulation in 60 years, since Warfarin (coumadin) was approved. A variety of parenteral options are available; however, the oral route is preferred by many physicains and patients. In November 2012, the U.S. Food and Drug Administration expanded the approved use of Xarelto (rivaroxaban) to include treating deep vein thrombosis (DVT) or pulmonary embolism (PE), and to reduce the risk of recurrent DVT and PE following initial treatment. Previously Xarelto was only approved for Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation.

The approval was approved based on three clinical studies. A total of 9,478 patients with DVT or PE were randomly assigned to receive Xarelto, a combination of enoxaparin and a vitamin K antagonist (VKA, Coumadin)), or a placebo. The studies ‘ end-point was the number of patients who experienced recurrent DVT, PE or death after receiving treatment.

Results showed Xarelto was as effective as the enoxaparin and VKA combination for treating DVT and PE. About 2.1 percent of patients treated with Xarelto compared with 1.8 percent to 3 percent of patients treated with the enoxaparin and VKA combination experienced a recurrent DVT or PE. Additionally, results from a third study showed extended Xarelto treatment reduced the risk of recurrent DVT and PE in patients. About 1.3 percent of patients treated with Xarelto compared with 7.1 percent of patients receiving placebo experienced a recurrent DVT or PE. With this results, when oral preparations are preferred for treatment of DVT or PE, Xarelto appears to have an advantage over par-enteral anticoagulants.

Eriksson BI, Borris LC, Friedman RJ, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775.

Kakkar AK, Brenner B, Dahl OE, et al; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31-39.

Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786.

For Lay version see here

Approval was based on a study involved 896 participants with an average age of 65 who were members of prescription benefit plans managed by Medco. Hospitalization rates for this group were matched against a historical control group of 2,688 individuals. Researchers collected DNA from either blood or buccal cells and determined patients’ genotypes for the CYP2C9 and VKORC genetic variants. Mutations in the CYP2C9 gene have been associated with decreased warfarin metabolism, while mutations in the VKORC1 gene are associated with warfarin sensitivity. Based on each individual’s genotype, clinicians used a dosing algorithm to determine that person’s initial dose. The study followed patients for 6 months after the start of their treatment. Compared with the control group, the genotyped patients had 31% fewer hospitalizations overall and 28% fewer hospitalizations for bleeding or thromboembolism during the follow-up period. The study results were first reported at theAmericanCollegeof Cardiology’s annual meeting in March of 2010 and are available online: J Am Coll Cardiol (doi:10.1016/j.jacc.2010.03.009).

This is the relevant information from the label for Warfarin: ”

The dose of COUMADIN must be individualized by monitoring the PT/INR. Not all factors causing warfarin dose variability are known. The maintenance dose needed to achieve a target PT/INR is influenced by:

• Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities and
• Genetic factors (CYP2C9 and VKORC1 genotypes).

Select the starting dose based on the expected maintenance dose, taking into account the above factors. Routine use of loading doses is not recommended as this may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation. If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg per day. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initiation doses for elderly and/or debilitated patients.

The patient’s CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose. Table 5 of the Prescribing Information describes the range of stable maintenance doses observed in multiple patients having different combinations of CYP2C9 and VKORC1 gene variants. Consider these ranges in choosing the initial dose.”

Some physians argue that this test should not routinely obtained and that only if it is “available” should it play a role in dose modification. I do not find this a credible interpretation of the Prescribing Information langauge.  Considering that the label of Warfarin includes CYP2c9 testing, this test should be considered medically necessary.

Food and Drug Administration. New labeling information for Coumadin. Approved 1/22/2010.

Anderson JL, Horne BD, Stevens SM et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007;116:2563-70.

The International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data.
N Engl J Med 2009;360:753-64.

Gage B, Eby C, Johnson J, Deych E et al. Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin.  Clinical Pharmacology & Therapeutics 2008: 84, 326–331

For teh Lay version see here

There some preliminary support that Ceptrotin may be useful in prupura fulminans adn sepsis. In these conditions, Protein C levels go down adn there may be a benefit to restoring them by inhusing Protein C concentrate. Only retrospective reviews and case series are currently available in the literatureadn there is a general agreement that prospective studies are warranted. A Surviving Sepsis Guideline does recommend a recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for postoperative patients). No such guideline si availalbe for purpura fulmonans, to my knowledge.

Ceprotin, Prescribing information

Schellongowski, Peter; Bauer, Edith; Holzinger, Ulrike; Staudinger, Thomas; Frass, Michael; Laczika, Klaus; Locker, Gottfried J; Quehenberger, Peter; Rabitsch, Werner; Schenk, Peter; Knöbl, Paul; Treatment of adult patients with sepsis-induced coagulopathy and purpura fulminans using a plasma-derived protein C concentrate (Ceprotin).VOX SANGUINIS Vol. 90 Issue 4 May 2006

Veldman A, Fischer D, Wong FY, Kreuz W, Sasse M, Eberspächer B, Mansmann U, Schosser R.
Human protein C concentrate in the treatment of purpura fulminans: a retrospective analysis of safety and outcome in 94 pediatric patients.Crit Care. 2010;14(4):R156.

Bruley, Duane Frederick; Zymogen protein C concentrate for safer heterozygote surgery, “I am a guinea pig” ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Vol. 645 2009

Baratto, Fabio; Michielan, Flavio; Meroni, Muzio; Dal Palù, Antonella; Boscolo, Annalisa; Ori, Carlo; Protein C concentrate to restore physiological values in adult septic patients. INTENSIVE CARE MEDICINE Vol. 34 Issue 9 Sep 2008

A. Puxty et al, Recombinant activated protein C usage in Scotland: a comparison with published guidelines and a survey of attitudes†
Anaesthesia Volume 67, Issue 1, pages 43–50, January 2012

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008.Crit Care Med. 2008 Jan;36(1):296-327.

Lymphedema pumps (pneumatic compression devices) are generally considered medically necessary for home use for the treatment of lymphedema if the member has undergone a four-week trial of conservative therapy and the treating doctor determines that there has been no significant improvement or if significant symptoms remain after the trial. The trial of conservative therapy must include use of an appropriate compression bandage system or compression garment, exercise, and elevation of the limb.

In such cases, a non-segmented device or segmented device without manual control of the pressure in each chamber is generally considered medically necessary to meet the clinical needs of the member. A segmented device with manual control of the pressure in each chamber is considered medically necessary only if there is clear documentation of medical necessity in the individual case. A segmented device with manual control of the pressure in each chamber is considered medically necessary only when there is documentation that the individual has unique characteristics that prevent satisfactory pneumatic compression treatment using a non-segmented device with a segmented appliance/sleeve or a segmented device without manual control of the pressure in each chamber.

There is one randomized study. The results were published in the Canadian Medical Association Journal in 2001. It demonstrated a trend in favour of pneumatic compression pumps compared with no treatment. It concluded: “Further randomized trials are required to determine whether pneumatic compression provides additional benefit over compression garments alone”.

Flexitouch is a specific device. There is insufficient evidence in the peer-reviewed published medical literature that a 2-phase lymph preparation and drainage therapy device (Flexitouch Device, Tactile Systems Technology, Minneapolis, MN) provides superior outcomes to standard segmented pneumatic compression devices. According to the manufacturer, the 2-phase lymph preparation and drainage therapy device consists of an electronic controller unit and garments, worn on the trunk and upper and lower affected extremities and connected to the controller unit by tubing harnesses. The garment consists of 32 inflatable chambers that sequentially inflate and deflate and deflate at 1 to 3 second intervals, according to one of the 13 preprogrammed treatment patterns selected. Chamber pressure and treatment times can be adjusted. In essence it is an automated and more sophisticated version of the standard segmental compression pump. The manufacturer states that device’s sequential action evacuates lymph from the trunk and extremities and drains it into the venous system. The garments are made from stretch material and are fitted with Velcro enclosures, so custom fitting of garments is not required. There are no published studies comparing the effectiveness of this 2-phase lymph preparation and drainage therapy device to standard segmented pneumatic compression devices. It is also more expensive.

A 2009 review found that: “While numerous articles were reviewed noting that PCD has become standard of care in most countries, conclusive documentation of the benefits of this treatment modality are lacking. The opinion expressed by the Supportive Care Guidelines Group of Cancer CareOntario and the Ontario Ministry of Health and Long Term Care is illustrative of this dilemma when they state that “The lack of sufficient high quality evidence precludes definitive recommendations from being made.” While this statement was made in relation to treatment options for women with breast cancer and lymphedema, the document further states “There is some evidence which suggests that physical therapies such as compression therapy and manual lymphatic drainage may improve established lymphedema but further studies are needed.”

Gurdal SO, Kostanoglu A, Cavdar I, et al. Comparison of intermittent pneumatic compression with manual lymphatic drainage for treatment of breast cancer-related lymphedema. Lymphat Res Biol. 2012; 10(3):129-135.Hammond T. Reduction of complications and costs associated with Flexitouch therapy for lymphedema. Open Rehabil J. 2009; 2:54-57.

Flexitouch can handle trunkal edema, which is an advantage. However, there are also dedicated devices specifically for trunkal edema, such as LymphoJacket and others.

Kligman L, Wong RK, Johnston M, Laetsch NS. The treatment of lymphedema related to breast cancer: A systematic review and evidence summary. Support Care Cancer. 2004;12(6):421-431.

Swedish Council on Technology Assessment in Health Care (SBU). Manual lymph drainage combined with compression therapy for arm lymphedema following breast cancer treatment (Alert). Stockholm, Sweden: SBU; 2005.

Tactile Systems Technology. Flexitouch Device. Physician Information [website]. Minneapolis, MN: Tactile Systems; 2005. Available at: http://www.tactilesystems.com/html/professionals.html.

Kligman L, Wong RK, Johnston M, Laetsch NS. The treatment of lymphedema relatedto breast cancer: a systematic review and evidence summary. Support Care Cancer.2004;12(6):421-31.

Szuba A, Achalu R, Rockson S. Decongestive lympatic therapy for patients with breastcarcinoma-associated lymphedema. Cancer 2002;95(11):2260-2267.Winifred S. Hayes (Hayes, Inc.). Pneumatic Compression Devices for Treatment ofPeripheral Lymphedema. Hayes Brief. June 6, 2005 and January 7, 2008.

Harris SR, Hugi MR, Olivotto I, Levine M for the Steering Committee for ClinicalPractice Guidelines for the Care and Treatment of Breast Cancer. Clinical PracticeGuidelines for the care and treatment of breast cancer: 11. Lymphedema. CanadianMedical Association Journal 2001;164(2):191-199.21

Harvey N. Mayrovitz, PhD, Dawn Brown-Cross, PT, EdD, CLT Nova Southeastern University Barbara L. Mayrovitz, RN, BA Home Health Service Alison H. Golla, MA, OTR/L, CLT Tactile Systems Technology, Inc.”Lymphedema: Role of Truncal Clearance as a Therapy Component”
Home Health Care Management Practice OnlineFirst. Feb 27, 2009

Tina Hammond,Can Truncal Edema Be Treated With Pneumatic Compression”
National Lymphedema Network’s  LymphLink,  Volume 21

Poage E, Singer M, Armer J, Poundall M, Shellabarger MJ. Demystifying lymphedema: development of the lymphedema putting evidence into practice card. Clin J Oncol Nurs. 2008 Dec;12(6):951-64. [61 references]

Manual lymphatic drainage for lymphedema following breast cancer treatment.Cochrane Database Syst Rev. 2015 May 21;(5):CD003475. doi: 10.1002/14651858.CD003475.pub2.

Stuiver MM, ten Tusscher MR, Agasi-Idenburg CS, Lucas C, Aaronson NK, Bossuyt PM.Conservative interventions for preventing clinically detectable upper-limb lymphoedema in patients who are at risk of developing lymphoedema after breast cancer therapy.
Cochrane Database Syst Rev. 2015 Feb 13;(2):CD009765.

Inherited severe hyperhomocysteinemia (plasma level higher than 100 mmol/L), as seen in classic homocystinuria, may result from homozygous MTHFR or CBS deficiencies and, more rarely, from inherited errors of cobalamin (vitamin β12) metabolism. Inherited mild to moderate hyperhomocysteinemia (plasma level between 15 and 100 mmol/L) may result from heterozygous MTHFR and CBS deficiencies, but most commonly results from the C677T gene polymorphism, which is the most common mutation in the gene that codes for the MTHFR enzyme. Individuals who are heterozygous for the tlMTHFR variant have normal plasma homocysteine levels, whereas homozygous carriers may have mild to moderate fasting hyperhomocysteinemia in the setting of concomitant folate deficiency.  However, homozygosity for the tlMTHFR in the absence of hyperhomocysteinemia does not appear to be associated with an increased risk of VTEs, and most patients with hyperhomocysteinemia do not have the tlMTHFR polymorphism. Excess homocysteine in the plasma is the risk factor and is the target of therapeutic intervention, not the C677T mutation. The pathophysiology of thrombosis in hyperhomocysteinemia is also unclear. Acquired homocyteneiamia may present in the absence of MTHFR mutation.

A recent review (Abrahams and Cho et al) concludes: “Although evidence suggests that the homocysteine hypothesis is still relevant as a predictor of cardiovascular risk, we cannot conclude that measuring the homocysteine level is useful in guiding treatment. Furthermore, studies of primary and secondary prevention show no evidence that taking folic acid or other B vitamins lowers the risk of cardiovascular events.”

ACMG Recommendations:

• MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia or recurrent pregnancy loss.
•  MTHFR polymorphism genotyping should not be ordered for at risk family members.
• A clinical geneticist who serves as a consultant for a patient in who an MTHFR polymorphism(s) is found should ensure that the patient has received a thorough and appropriate evaluation for his or her symptoms.
• If the patient is homozygous for the “thermolabile” variant c.665CT, the geneticist may order a fasting total plasma homocysteine, if not previously ordered, to provider more accurate counseling.
•  MTHFR status does not change the recommendation that women of childbearing age should take the standard dose of folic acid supplementation to reduce the risk of neural tube defects as per the general population guidelines.

American College of Medical Genetics Practice Guidelines: Lack of Evidence for MTHFR Polymorphism Testing. Scott E. Hickey, M.D., FACMG, Cynthia J. Curry, M.D., FACMG and Helga V. Toriello, PhD, FACMG, Genetics in Medicine 2013:15(2):153-156

Colleen M. Johnson, MD Hypercoagulable States: A Review Vascular and Endovascular Surgery, Vol. 39, No. 2, 123-133 (2005)

U.S. Preventive Services Task Force (USPSTF). Using Nontraditional Risk Factors in Coronary Heart Disease Risk Assessment: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med
October 6, 2009 vol. 151 no. 7 474-482.

TJOELLYN M. ABRAHAM, MD, LESLIE CHO, MD The homocysteine hypothesis: Still relevant to the prevention and treatment of cardiovascular disease? Cleveland Clinic Journal of Medicine December 2010 vol. 77 12 911-918

Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344:1222-1231.

De Stefano V, Casorelli I, Rossi E, et al: Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism. Semin Thromb Hemost 2000;26:305-311

Near-patient testing (NPT) is becoming increasingly common in some countries. In the United Kingdom, for example, near-patient testing is used both by patients at home, and by some anticoagulation clinics (often hospital-based) as a fast and convenient alternative to the lab method. After a period of doubt about the accuracy of NPT results, a new generation of machines and reagents seems to gaining acceptance for its ability to deliver results close in accuracy to those of the lab.
In a typical NPT setup a small table-top device is used; for example the Roche Coagucheck® S, or the more recently (2005) introduced HemoSense INRatio®. A drop of capillary blood is obtained with an automated finger-#####, which is almost painless. This drop is placed on a disposable test strip with which the machine has been prepared. The resulting INR comes up on the display a few seconds later. Similar testing methods are used by diabetics on insulin, and are easily taught and practiced.

Local policy determines whether the patient or a coagulation specialist (nurse, general practitioner or hospital doctor) interprets the result and determines the dose of medication. In Germany, patients may adjust the medication dose themselves, while in the UK and the USA this remains in the hands of a health care professional.

The advantages of the NPT approach are obvious: it is fast and convenient, usually less painful, and offers, in home use, the ability for patients to measure their own INRs when required. Among its problems are that quite a steady hand is needed to deliver the blood to the exact spot, that some patients find the finger-######## difficult, and that the cost of the test strips must also be taken into account. In the UK these are available on prescription so that elderly and unwaged people will not pay for them and others will pay only a standard prescription charge, which at the moment represents only about 20% of the retail price of the strips. In the USA, NPT in the home is currently reimbursed by Medicare for patients with mechanical heart valves, while private insurers may cover for other indications.

Patients on Warfarin usually require monitoring at least once a week.INR is measured daily or every second day during the first week of treatment, with the dose of warfarin (taken in the evening) titrated against the morning’s INR. It is then measured at increasing intervals depending on response. Many patients, once the dose is stable, can be well controlled with 4-6-weekly testing and dose adjustment, but others need more frequent assessment. The guideline with Ansell as first author says: “The most frequent testing frequency is weekly but lower frequency of testing can be justified based on institutional or patient conditions.”

There is some evidence to suggest that NPT may be less accurate for certain patients, for example those who have the lupus anticoagulant.

In addition, in a recent study, the researchers compared weekly patient self-testing (PST), using an interactive voice-response reporting system and Web-based local monitoring, and currently recommended practice: high-quality anticoagulation management (HQACM), with testing carried out monthly at a clinic. The primary end point was an aggregate of stroke, major bleeds, and death. Over an average of 54 months and 8370 patient-years of follow-up, there were 544 primary end-point events—237 deaths, 263 major bleeds, and 44 strokes—but there was no statistical difference in the number of events between the intervention groups. When they looked at total events, not just first events, between the two groups, there was a consistent trend toward benefit for PST on all three components of the primary end point, but none of the trends reached statistical significance. These results of The Home INR Study (THINRS) were presented at the American Heart Association 2008 Scientific Sessions.

Gardiner C, Williams K, Mackie IJ, et al. Patient self-testing is a reliable and acceptable alternative to laboratory INR monitoring. Br J Haematol. 2005;128(2):242-247.

Ansell J, Jacobson A, Levy J, Völler H, Hasenkam JM (March 2005). “Guidelines for implementation of patient self-testing and patient self-management of oral anticoagulation. International consensus guidelines prepared by International Self-Monitoring Association for Oral Anticoagulation”. Int. J. Cardiol. 99 (1): 37–45

1. Fitzmaurice DA. Oral anticoagulation control: The European perspective. J Thromb Thrombolysis. 2006;21(1):95-100.
2. Brown A, Wells P, Jaffey J, et al. Point-of-care monitoring devices for long-term oral anticoagulation therapy: Clinical and cost effectiveness. Technology Report No. 72. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); February 2007. Available at: http://www.cadth.ca/index.php/en/hta/reports-publications/search/publication/679

Low Molecular Weight Heparins are used for the prophylaxis or treatment of deep vein thrombosis. The decision to use LMWH instead of standard heparin or warfarin will depend upon the clinical scenario and individual patient factors such as risk of bleeding or availability of venous access.

Several studies have shown that patients with malignancy and thrombosis do not respond well to warfarin and many of them have recurrent DVT on warfarin. The National Comprehensive Cancer Network has issued its first guidelines for how to prevent deep vein thrombosis (DVT) in cancer patients and how to treat a DVT. The guidelines listed the following agents for anticoagulation:

Unfractionated heparin: 5,000 units subcutaneously three times a day.
Low molecular weight heparin, dosed according to standard operating procedures of individual institutions, with either dalteparin, enoxaparin or tinzaparin.
Pentasaccharide, fondaparinux, 2.5 mg subcutaneous daily.

The guidelines were revealed at the 11th annual conference of the NCCN — a consortium of 19 of the leading cancer centers in the country. They included recommendations for prophylaxis of venous thromboembolism in cases of patients with cancer or who are suspected of cancer. If they do not have contraindication for anticoagulation, then therapy was suggested with or without sequential compression devices. If there is a contraindication for anticoagulant therapy then use of compression devices, including graduated compression stocking, were considered.

For initial treatment of DVT or PE, either UFH or LMWH should be administered. For postoperative patients, an agent such as UFH, which has a short half life and is readily reversible, may be preferable. For more stable patients who are not at high risk for bleeding, LMWH is probably the treatment of choice.

Chronic VTE therapy with anticoagulants in cancer patients is a challenge. Many anticancer medications interact with oral anticoagulants (eg, warfarin), he added, and make it difficult to control the level of anticoagulation, particularly in cancer patients with more extensive disease. In a study of patients with and without cancer receiving oral anticoagulants, the VTE recurrence rate and risk of bleeding were substantially higher in patients with advanced cancer, particularly in the first 2 months of therapy. Recent results from the CLOT trial showed that the incidence of VTE recurrence was significantly lower in patients with advanced cancer receiving dalteparin (Fragmin) versus those receiving oral anticoagulation therapy over a 6-month period. The bottom line is that LMWH should be strongly considered in patients who have advanced metastatic cancer (Lee AY et al. N Engl J Med 2003;349:146–153).New guideline recommendations have been released for the use of anticoagulation in the prevention and treatment of venous thromboembolism (VTE) in patients with cancer. The guidelines, which were prepared by an international panel of researchers and are published in the October 29 Early Release Articles issue and were published in the December 1, 2007 issue of the Journal of Clinical Oncology.
The ASCO panel was a mix of world-famous experts in thrombosis and methodology, he added, and the resulting guidelines underwent extensive internal and external review by other leading experts before further review by the ASCO board of directors and their own reviewers.

Their guideline recommendations included the following:

Patients with cancer who are hospitalized should be considered candidates for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications to anticoagulation.

Routine prophylaxis with an antithrombotic agent is not recommended for ambulatory patients during systemic chemotherapy, but patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis.

All patients undergoing major surgical intervention for malignant disease should be considered for thromboprophylaxis.

Low molecular weight heparin (LMWH) represents the preferred agent for both the initial and continuing treatment of patients with cancer who have established VTE.

The impact of anticoagulants on survival of patients with cancer requires additional study and cannot be recommended at present.

Patients with cancer should be encouraged to participate in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapies.

INNOHEP is indicated for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered in conjunction with warfarin sodium. The safety and effectiveness of INNOHEP were established in hospitalized patients. It is an FDA approved indication.

Lyman GH, Khorana AK, Falanga A, et al: American Society of Clinical Oncology guideline: Recommendations for
 venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007;25:

Agnes Y.Y. Lee Thrombosis in Cancer: An Update on Prevention, Treatment, and Survival Benefits of Anticoagulants
Highlights of the NCCN 11th Annual Conference: Clinical Practice Guidelines & Quality Cancer Care™, published as a supplement to The Oncology Report by Elsevier Oncology. © 2006 NCCN. ASH Education Book December 4, 2010 vol. 2010 no. 1 144-149

nccn, Anticoagulation 2012

Bevacizumab (Avastin) has shown a small benefit in sarcoma patients, when given with doxorubicin and other drugs. One such combination is now in a clinical trial: Phase II Study of Doxorubicin, Ifosfamide, and Bevacizumab in Sarcoma,  NCT00755261. A recent (2006) TEC assessment concluded that Avastin is not supported by evidence for off-label treatment of soft -tissue sarcoma. It is not NCCN recommended.

D’Adamo D, Anderson S, Albritton K, et al. Phase II Study of Doxorubicin and Bevacizumab for Patients With Metastatic Soft-Tissue Sarcomas. Journal of Clinical Oncology. 2005; 23:  7135-7142.

http://www.bcbs.com/blueresources/tec/vols/21/21_09.html

NCCN.ORG, Sarcoma

In May 2012, the Institute for Safe Medication Practices released its “Quarterwatch” report reviewing data from the third and fourth quarters of 2011. They concluded that Pradaxa had the most reports of serious, disabling, and fatal events, accounting for 3,781 domestic reports overall in 2011, including 542 patient deaths. It surpassed all other regularly monitored drugs in reports of hemorrhage, acute renal failure, and stroke.

Warfarin, on the other hand, accounted for 1,106 cases overall in 2011, including 72 deaths.

It is far from clear that it is better alternative than older anti-coagulants in the settings of chemotherapy of stem cell transplantation.

Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M, ES; Kamphuisen, PW; Sijpkens, MK; Meijers, JC; Buller, HR; Levi, M (2011-10-04). “Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects”. Circulation 124 (14): 1573–9.

^ van Ryn J, Stangier J, Haertter S, et al. (2010 Jun). “Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity”. Thrombosis and Haemostasis 103 (6): 1116–27.

R. Romanelli et al, Dabigatran Versus Warfarin for Atrial Fibrillation in Real-World Clinical Practice
A Systematic Review and Meta-Analysis. Circulation 2020 2016;9:126134

Read the Layperson version here.

Halkin H, Shapiro J, Kurnik D, Loebstein R, Shalev V, Kokia E. Increased warfarin doses and decreased international normalized ratio response after nationwide generic switching. Clin Pharmacol Ther. 2003;74:215-221.

Witt DM, Tillman DJ, Evans CM. Evaluation of the clinical and economic impact of a brand name-to-generic warfarin sodium conversion program. Pharmacotherapy. 2003;23:360-368.

Jennifer A Pereira et al, Are Brand-Name and Generic Warfarin Interchangeable? Multiple N-of-1 Randomized, Crossover Trials The Annals of Pharmacotherapy: Vol. 39, No. 7, pp. 1188-1193.