July 2, 2015
Dr. Stephen Ostroff, M.D.
Acting Commissioner, Food and Drug Administration
Department of Health and Human Services
5630 Fishers Lane, Room 1061
Rockville, MD 20852
Dear Dr. Ostroff,
The undersigned submits this petition under the Federal Food, Drug, and Cosmetic Act 21 U.S.C. Section 355 (e) (3), and 21 C.F.R. 10.30 to request the Commissioner of Food and Drugs to designate all anticoagulant drugs (e.g., heparin, all low molecular weight heparins, fondaparinux, warfarin, dabigatran, ribaroxaban, apixaban, and edoxaban, etc.) contraindicated for patients with venous thromboembolism (VTE, i.e., deep venous thrombosis (DVT) and pulmonary embolism (PE)).
Specifics of the action requested
The exact wordings of the product labels for FDA approved anticoagulants are as follows:
1. Coumadin (warfarin)
Under indications for use:
Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE)
2. Heparin, sodium
Heparin Sodium Injection is indicated for:
- Anticoagulant therapy in prophylaxis and treatment of venous thrombosis and its extension…
- Prophylaxis and treatment of pulmonary embolism.
3. Enoxaparin (Lovenox):
Lovenox is a low molecular weight heparin [LMWH] indicated for:
- Inpatient treatment of acute DVT with or without pulmonary embolism (1.2)
- Outpatient treatment of acute DVT without pulmonary embolism. (1.2)
4. Tinzoparin (Innohep):
INNOHEP is indicated for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered in conjunction with warfarin sodium.
5. Dalteparin (Fragmin):
FRAGMIN® Injection is indicated for …
1.3 Extended treatment of symptomatic venous thromboembolism (VTE) to reduce the recurrence in patients with cancer. In these patients, the FRAGMIN therapy begins with the initial VTE treatment and continues for six months
6. Edoxaban (Savaysa):
SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.
7. Ribaroxaban (Xarelto):
- 1.2 XARELTO is indicated for the treatment of deep vein thrombosis (DVT).
- 1.3 XARELTO is indicated for the treatment of pulmonary embolism (PE).
- 1.4 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of Pulmonary Embolism XARELTO is indicated for the reduction in the risk of recurrence of deep vein thrombosis and of pulmonary embolism following initial 6 months treatment for DVT and/or PE.
8. Pradaxa (dabigatran):
Pradaxa® (dabigatran etexilate mesylate) capsules is indicated for the treatment of deep vein thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5-10 days
9. Apixaban (Elliquis):
- 1.3 Treatment of Deep Vein Thrombosis: ELIQUIS is indicated for the treatment of DVT.
- 1.4 Treatment of Pulmonary Embolism: ELIQUIS is indicated for the treatment of PE.
- 1.5 Reduction in the Risk of Recurrence of DVT and PE: ELIQUIS is indicated to reduce the risk of recurrent DVT and PE following initial therapy.
With these drugs and any other anticoagulants, this petition requests that FDA approval for the indications of treatment of DVT and PE be withdrawn and that, for each of these drugs, the contraindications section of the product labels should have added, “treatment of DVT and PE.”
Statement of grounds
Given the seriousness and frequency of major bleeding and other adverse events related to anticoagulants, they should have been thoroughly tested before receiving FDA approval for venous thromboembolism. However, rigorous randomized controlled trial evidence supporting anticoagulants for VTE is entirely absent. In 2001, I wrote to the FDA presenting evidence that anticoagulant drugs were neither effective nor safe in the treatment of VTE. The three page response from Robert Temple, MD, Associate Director of Medical Policy of CDER and Lilia Talarico, MD, Division of Gastrointestinal and Coagulation Drug Products(1) contained the following relevant passages:
…heparin sodium injection was first approved on June 22, 1939 for the prevention and treatment of postoperative thrombosis and embolism and re-review of the efficacy of the drug was conducted under the DES (“drug-efficacy study” and its implementation program following the Drug Amendments of 1962. The National Research Council of the National Academy of Sciences (NAN/NRS) concluded in 1970 that heparin was effective for the treatment and prevention of all venous and arterial thrombosis, thromboembolic disease, and the prevention and treatment of pulmonary embolism. The FDA evaluated and concurred with the NAS/NRS report…
Early clinical trials showed reduction in mortality in patients with DVT/PE treated with heparin compared to untreated placebo-treated patients (Barritt and Jordan, Lancet 1960).(2) Although the initial clinical trials of heparin were limited in size and not performed according to the current criteria and requirements of adequate and well-controlled design, they provided substantial evidence of efficacy. Over the years, numerous clinical trials have confirmed the efficacy and safety of heparin and other antithrombotic compounds for the treatment and prevention of thromboembolic events.
The National Research Council of the National Academy of Sciences review that Drs. Temple and Talarico referenced is not publicly available. I requested it from the FDA and have not yet received it.
While Drs. Temple and Talarico mentioned “initial clinical trials,” they only referenced one randomized controlled trial (RCT) to support the efficacy and safety of anticoagulants for VTE. Barritt and Jordan conducted this RCT, which was published in The Lancet in 1960.(2)
American College of Chest Physicians (ACCP) 2012 guidelines calling for anticoagulation treatment for VTE patients(3) said, “The first and only randomized trial that compared anticoagulant therapy with no anticoagulant therapy in patients with symptomatic DVT or PE was published in 1960 by Barritt and Jordan…”
So the scientific basis of anticoagulants for VTE as noted by Drs. Temple and Talarico and the ACCP anticoagulants for VTE guidelines depends entirely on the validity of the Barritt and Jordan trial. If the methods or results of this trial are invalid, we must completely reassess the evidence basis for anticoagulant drugs for VTE.
Barritt and Jordan, practicing in England (London and Bristol, respectively), enrolled 35 patients with the diagnoses of pulmonary embolism (PE) made by clinical history, physical exam, and chest x-ray alone into an RCT. The PE patients were to receive or not receive 3 days of intravenous heparin concurrently with oral nicoumalone (Sinthrome), a vitamin K antagonist, for a total of 14 days of anticoagulation. Anticoagulated patients had fewer deaths than placebo-treated patients (deaths with placebos: 5/19; deaths with anticoagulants: 0/16, P = 0.08).
By today’s standards of evidence-based medicine, this trial was highly flawed. Examples of the flaws are below.
- Doctors other than the investigators referred the patients into the trial, so the selection was not random.
- It was not double-blind.
- The investigators provided no information about the comparability of the anticoagulated and un-anticoagulated patients.
- The number of patients enrolled in the study (n = 35) was far too few to assess whether anticoagulants reduce the incidence of fatal PE, which is the primary purpose of anticoagulation. We know now that only about 0.5% of anticoagulated PE patients will die of recurrent PE (Table 2 below(4, 5). Most deaths will be from underlying diseases (e.g., cancer, heart failure, etc). To provide statistical evidence that anticoagulation prevents 75% of fatal PEs with such a rare primary endpoint (i.e., 2% fatal PEs with placebo versus 0.5% fatal PEs with anticoagulants), several thousand patients would need to be enrolled in a trial.
- Patients were kept at strict bed rest for 10 days. We have subsequently learned that early mobilization of patients is important for preventing VTE and the complications of VTE.
- Modern chest imaging tests (lung scans, angiograms, CT scans, etc.) were not available to investigators in the 1950s. Anticoagulation experts didn’t learn until 1990 that a clinical suspicion of PE is confirmed by modern imaging tests to actually diagnose PE only about 25% of the time.(6)
- Autopsy descriptions of the patients in this study show that in 4 of the 5 deaths, severe underlying diseases (e.g., cerebral infarction and cavitary pneumonia with sepsis) caused the deaths, with PE only appearing as a contributing factor.
In 2004, Medscape General Medicine published my systematic review of anticoagulants for VTE.(7) For that review and a subsequent review, based on the same data, published in the Cochrane Database of Systematic Reviews,(8) Cochrane archivists found 4 small RCTs comparing standard anticoagulation for VTE (full-dose heparin followed by warfarin or other vitamin K antagonist drugs) versus a placebo or a nonsteroidal anti-inflammatory drug (NSAID).
Our Cochrane review writing group excluded the randomized controlled trial by Barritt and Jordan that was published in The Lancet in 1960(2) because the authors, peer-reviewers, and editor of our review all deemed it too flawed by current standards to give valid data to inform the review.
The results of the three remaining RCTs showed deaths with standard anticoagulation exceeded deaths with placebos or NSAIDs (anticoagulation: 6/66 versus no anticoagulation: 1/60, P = 0.12).(7, 9, 10, 11) the single death in the placebo or NSAID group was due to a myocardial infarction rather than pulmonary embolus.
Consequently, the limited RCT data strongly suggests that anticoagulants do not save lives in VTE patients and may well increase deaths.
Observational studies and non-inferiority trials regarding anticoagulants for VTE
According to the Center for Disease Control,(12) no more than 10% of patients presenting with DVT die within 1 month (i.e., die of pulmonary embolus or any other cause). Two studies of patients that died of pulmonary embolus confirmed by autopsy showed that between 95% and 96.5% of PE deaths were in people with underlying terminal illnesses (e.g., cancer, heart failure, etc.).(13,14) Consequently, the chance of an early death in a DVT patient being due to PE rather than to an underlying terminal illness is < 0.5% (0.10 (10% early death rate of DVT patients at most(12) x 0.05 (5% of deaths in VTE patients at most not due to underlying terminal disease(13,14)) = 0.005).
To provide a check on the above estimate of DVTs leading to fatal PE in < 0.5% of cases, consider recent large non-inferiority trials of various anticoagulants for DVT and PE (Tables 1 – 3).
Table 1. Non-inferiority trials with different anticoagulants for DVT
|Trial||Lead author||N||Fatal PE (%)||Cancer deaths (%)||Major bleeds (%)||Fatal bleeds (%)||Total deaths (%)|
|Fondaparinux versus enoxaparin + VKA 3 months(15)||Buller||2205||10||43||54||5||74|
|Idraparinux versus LMWH or unfractionated heparin/VKA 6 months(4)||van Gogh Investigators||2904||11+*||59+*||38+*||6+*||99+*|
|Unfractionated heparin versus LMWH (1 or 2 times/day) 3 months(16)||Breddin||1137||8||18||?||?||35|
|Ribaroxaban versus LMWH /VKA 3/6/12 months(17)||Einstein investigators||3449||10||45||34||7||87|
|Totals||9695||39+* (0.40)||165+* (1.70)||126+ (1.47)||19+ (0.22)||295+* (3.04)|
*For the 637 patients in the 3 months of anticoagulation stratum (22% of patients), data on deaths in the final 3 months of the trial were not reported.
Table 2. Non-inferiority trials with different anticoagulants for PE
|Trial||Lead author||N||Fatal PE (%)||Cancer deaths (%)||Major bleeds (%)||Fatal bleeds (%)||Total deaths|
|Idraparinux versus LMWH or unfractionated heparin + VKA 6 months(4)||van Gogh Investigators||2215||17+*||58+*||42+*||2+*||109+*|
|Rivaroxaban versus LMWH/VKA 3/6/12 months(5)||Einstein-PE investigators||4832||13||46||78||5||108|
|Totals||7047||30+* (0.43%)||104+* (1.50%)||120 (1.70)||7+ (0.10)||217+* (3.08%)|
*For the 105 patients in the 3 months of anticoagulation stratum (5% of patients), data on deaths in the final 3 months of the trial were not reported.
Table 3. Non-inferiority trials with different anticoagulants for VTE (DVT and PE)
|Trial||Lead author||N||Fatal PE||Cancer deaths||Major bleeds (%)||Fatal bleeds (%)||Total deaths|
|Dabigatran versus LMWH/warfarin 6 months(18)||Schulman||2539||4||?||44/2||44/2||42|
|Apixaban versus UFH/warfarin 6 months(19)||Agnetti||5395||28||28||64/3||64/3||93|
|Edoxaban versus LMWH/warfarin 3/6/12 months(20)||Hokusai-VTE Investigators||8240||52||108||122/12||122/12||258|
|Total||16174||84 (0.52%)||136 (1.00%)||230 (1.42)||17 (0.11)||393 (2.43%)|
These trials confirm the low rate of deaths by fatal pulmonary emboli (0.40% – 0.52% of patients) relative to deaths by cancer (1.00% – 1.70% of patients) and other causes. For most of the trials, patients with < 3 – 6 months expected survival from cancer or other advanced diseases were excluded. Yet underlying chronic diseases accounted for ≈ 80% of deaths.
Since autopsies were not performed in most patients who died in these trials, deaths from PE (0.40% – 0.52%) included cases in which fatal PE “could not be ruled out.” So, PE as the primary cause of death without advanced underlying disease likely occurs in much less than 0.5% of cases.
Major bleeding due to anticoagulants for VTE treatment
In these trials, anticoagulant related bleeding caused deaths in 0.10% – 0.22% of patients. It also led to cases of permanently disabling, non-fatal, intracranial bleeding.
Averaging the rates of major and fatal bleeding in these anticoagulants for VTE non-inferiority trials (Tables 1 – 3) gives a mean incidence of major bleeding = 1.50% and fatal bleeding = 0.135%. With at least 600,000 people anticoagulated for venous thromboembolism in the USA each year,(21, 22, 23) this translates into at least 9000 major bleeds and 800 fatal bleeds per year. The bleeding morbidity and mortality is likely higher because VTE patients not participating in a RCT are likely have higher rates of anticoagulant caused major and fatal bleeding.(3) I estimated 1000 – 3500 per year of bleeding deaths from anticoagulants for VTE based on observational studies.(7)
Rebound hypercoagulation related thromboses in anticoagulated VTE patients
Rebound hypercoagulability (i.e., elevated levels of fibrinogen, fibrinopeptide A, thrombin, thrombin-antithrombin III complexes, coagulation factors VII and IX levels, and activated thromboplastin) occurs in vitro in the first few weeks after discontinuation of warfarin and other vitamin K antagonists (VKAs). By 2 months after discontinuation of anticoagulants, these tests are no longer abnormal.(24, 25, 26, 27) In 2008, Medscape General Medicine published my systematic review entitled, “Clinical evidence for rebound hypercoagulability after discontinuing oral anticoagulants for venous thromboembolism.”(28) This review demonstrated that the rate of recurrent VTE in the 2 months after discontinuing oral anticoagulants is about 3 times the subsequent VTE recurrence rate (i.e., 1.57%/month versus 0.56%/month). Withdrawing warfarin has also been associated with increased rates of ischemic stroke(29) and myocardial infarction.(30)
Goldhaber and colleagues reported on 384 patients who developed in-hospital DVT or PE or who developed VTE within 30 days of prior hospital discharge over a 2 year period at the Brigham and Women’s Hospital in Boston. He wanted to demonstrate that in-hospital VTE results most often from the lack of anticoagulant drug prophylaxis. However, of patients in this group that died with PE as the primary cause of death, 12/13 had received anticoagulant prophylaxis.(31) An additional 20 of these patients died of underlying diseases with PE contributing to their deaths.
An autopsy study by Lindblad and colleagues from Malmo, Sweden showed a strong association of prophylactic anticoagulation with fatal PE. From a population of 31,238 post-operative patients from the 1980s, they found that 27/30 patients with autopsy-proven fatal PE had received post-op prophylactic anticoagulants.(32)
These studies all show the association of discontinuation of anticoagulation, whether anticoagulation as treatment or as prophylaxis, with a subsequent increase in clinically devastating thromboses. This includes both medical and surgical patients. Given this association of withdrawal of anticoagulation with increased thromboses, including fatal PE, it is likely that a significant portion of deaths of patient in the non-inferiority trials of anticoagulation for VTE (Tables 1 – 3) could have been due to rebound hypercoagulation related vascular thromboses (e.g., fatal PE, myocardial infarctions and strokes) in patients with underlying diseases. Although the methods of these trials designated that patients with less than an expected prognosis of 3 – 6 months were ineligible for these RCTs, over 2% of patients in all these trials died within 3 months of their underlying diseases. Autopsies were rarely done in these patients to see if PE was the primary or contributing cause of death. Consequently, rebound hypercoagulation related thromboses may have shortened the lives of a significant number of these patients.
RCT data of VTE patients treated without anticoagulants are limited (DVT patients: fatal PE with placebo or NSAID: 0/60) but suggest a very low rate of fatal PE. No valid RCT data is available to assess anticoagulation versus placebo for PE patients. Non-inferiority trials of anticoagulants for VTE also show low rates of fatal PE (0.40% – 0.52%). Based on non-inferiority RCTs in VTE patients treated with anticoagulants, bleeding deaths of VTE patients in the USA total 800 – 3500 per year. Rebound hypercoagulation related thromboses in VTE patients treated with anticoagulants likely account for earlier deaths in some VTE patients who have other underlying diseases (e.g., cancer and heart failure).
There is no scientific evidence supporting the use of anticoagulant drugs to treat patients with VTE. Anticoagulants cause major harm from bleeding and rebound hypercoagulation related thromboses.
To be in compliance with the FDA’s mission of protecting the public health, the FDA leadership should withdraw the indications for all anticoagulant drugs for treatment of venous thromboembolism and label anticoagulants as contraindicated for treatment of VTE.
Environmental Impact Statement
On request of the FDA.
David K. Cundiff, MD
333 Orizaba Ave
Long Beach, CA 90814
- Lilia Talarico M, Division of Gastrointestinal and Coagulation Drug Products,, Robert Temple, MD, , Medical Director of the FDA Letter regarding anticoagulants for venous thromboembolism to David K. Cundiff, MD. Department of Health and Human Services Food and Drug Administration, 2001. http://whistleblowerdoctor.org/wp-content/uploads/2015/04/Robert-Temple-re-AC-for-VTE.pdf Accessed June 26, 2015
- Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism — A controlled trial. Lancet. 1960; 1:1309-1312. Available at: http://whistleblowerdoctor.org/wp-content/uploads/2015/04/Barritt-and-Jordan1960Lancet.pdf
- Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic Therapy for VTE Disease. Chest. 2012; 141(2 suppl):e419S-e494S. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278049/pdf/112301.pdf
- The van Gogh Investigators. Idraparinux versus Standard Therapy for Venous Thromboembolic Disease. N Engl J Med. September 13, 2007; 357(11):1094-1104. Available at: http://content.nejm.org/cgi/content/abstract/357/11/1094
- The EINSTEIN–PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. New England Journal of Medicine. 2012; 366(14):1287-1297. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1113572
- Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators. JAMA. 1990; 263(20):2753-2759. Available at: http://jama.jamanetwork.com/article.aspx?articleid=381954
- Cundiff DK. Anticoagulation Therapy for Venous Thromboembolism. MedGenMed. 2004; 6(3). Available at: http://www.medscape.com/viewarticle/487577
- Cundiff DK, Manyemba J, Pezzullo JC. Anticoagulants versus non-steroidal anti-inflammatories or placebo for treatment of venous thromboembolism. The Cochrane Database of Systematic Reviews. 2006; (Issue 1). Available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003746.pub2/abstract
- Nielsen HK, Husted SE, Krusell LR, et al. Anticoagulant therapy in deep venous thrombosis. A randomized controlled study. Thrombosis Research. 1994; 73(3-4):215-226. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8191414
- Ott P, Eldrup E, Oxholm P. The value of anticoagulant therapy in deep venous thrombosis in the lower limbs in elderly, mobilized patients. A double-blind, placebo-controlled investigation with open therapeutic guidance. Ugeskr Laeger. 1988; 150:218-221. Available at: http://www.ncbi.nlm.nih.gov/pubmed/?term=3287734
- Kakkar VV, Flanc C, Howe CT, O’Shea M, Flute PT. Treatment of deep vein thrombosis. A trial of heparin, streptokinase, and arvin. British Medical Journal. 1969; 1(647):806-810. Available at: http://www.ncbi.nlm.nih.gov/pubmed/4879792
- Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous Thromboembolism. American Journal of Preventive Medicine. 2010; 38(4):S495-S501. Available at: http://www.ajpmonline.org/article/S0749-3797(09)00946-5/pdf
- Nielsen H, Bechgaard P, Nielsen P, Husted S, Geday E. 178 fatal cases of pulmonary embolism in a medical department. Acta Med Scand. 1981; 209(5):351-355. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7246271
- Karwinski B, Svendsen E. Comparison of clinical and post-mortem diagnosis of pulmonary embolism. J Clin Pathol. 1989; 42:135-139. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1141815/
- Buller HR, Davidson BL, Decousus H, et al. Fondaparinux or Enoxaparin for the Initial Treatment of Symptomatic Deep Venous Thrombosis: A Randomized Trial. Ann Intern Med. 2004; 140(11):867-873 Available at: http://www.annals.org/cgi/reprint/140/11/867.pdf
- Breddin HK, Hach-Wunderle V, Nakov R, Kakkar VV. Effects of a Low-Molecular-Weight Heparin on Thrombus Regression of Recurrent Thromboembolism in Patients with Deep-Vein Thrombosis. The CORTES Investigators. New England Journal of Medicine. 2001; 344(9):626-631. Available at: http://www.nejm.org/doi/full/10.1056/NEJM200103013440902
- Oral Rivaroxaban for Symptomatic Venous Thromboembolism. New England Journal of Medicine. 2010; 363(26):2499-2510. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1007903
- Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. New England Journal of Medicine. 2009; 361(24):2342-2352. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa0906598
- Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, . Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369:799–808. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1302507
- The Hokusai-VTE Investigators. Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism. New England Journal of Medicine. 2013; 369(15):1406-1415. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1306638
- Heit JA, Silverstein MD, Mohr DN, et al. The Epidemiology of Venous Thromboembolism in the Community. Thrombosis and Haemostasis. 2001; 86(1):452-463. Available at: http://th.schattauer.de/en/contents/archive/issue/872/manuscript/2847.html
- White RH. The Epidemiology of Venous Thromboembolism. Circulation. 2003; 107(23 suppl 1):I-4-I-8. Available at: http://circ.ahajournals.org/content/107/23_suppl_1/I-4.abstract
- Goldhaber SZ, Bounameaux H. Pulmonary embolism and deep vein thrombosis. The Lancet. 379(9828):1835-1846. Available at: http://dx.doi.org/10.1016/S0140-6736(11)61904-1
- Palareti G, Legnani C, Guazzaloca G, et al. Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants–a prospective study. Thromb Haemost. 1994; 72(2):222-226. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7831656
- Grip L, Blomback M, Schulman S. Hypercoagulable state and thromboembolism following warfarin withdrawal in post-myocardial-infarction patients. Eur Heart J. 1991; 12(11):1225-1233. Available at: http://eurheartj.oxfordjournals.org/cgi/content/abstract/12/11/1225
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- Tardy B, Tardy-Poncet B, Laporte-Simitsidis S, Mismetti P, Decousus H, Guyotat D BJ. Evolution of blood coagulation and fibrinolysis parameters after abrupt versus gradual withdrawal of acenocoumarol in patients with venous thromboembolism: a double-blind randomized study. Br J Haematol. 1997; 96:174-178. Available at: http://www.medscape.com/medline/abstract/9012705
- Cundiff DK. Clinical evidence for rebound hypercoagulability after discontinuing oral anticoagulants for venous thromboembolism. Medscape J Med. 2008; 10(11):258. Available at: http://www.medscape.com/viewarticle/582408
- Broderick JP, Bonomo JB, Kissela BM, et al. Withdrawal of Antithrombotic Agents and Its Impact on Ischemic Stroke Occurrence. Stroke. 2011; 42(9):2509-2514. Available at: http://stroke.ahajournals.org/content/42/9/2509.long
- Grip L, Blomback M, Schulman S. Hypercoagulable state and thromboembolism following warfarin withdrawal in post-myocardial-infarction patients. Eur Heart J. January 1, 1991; 12(11):1225-1233. Available at: http://eurheartj.oxfordjournals.org/cgi/content/abstract/12/11/1225
- Goldhaber S, Dunn K, MacDougall R. New onset of venous thromboembolism among hospitalized patients at Brigham and Women’s Hospital is caused more often by prophylaxis failure than by withholding treatment. Chest. 2000; 118:1680-1684. Available at: http://journal.publications.chestnet.org/data/Journals/CHEST/21955/1680.pdf
- Lindblad B, Eriksson A, Bergqvist D. Autopsy-verified pulmonary embolism in a surgical department: analysis of the period from 1951 to 1988. Br J Surg. 1991; 78(7):849-852. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1873716