Mar 24, 2013

New oral anticoagulants: other review articles

UPDATED FEB 17, 2014


(including systematic reviews and meta-analyses) on new oral anticoagulants, in reverse chronological order of appearance in PubMed.

NOACs not associated with with drug-induced liver injury
Evaluating 152,116 patients from 29 randomized controlled trials (mean follow-up: 16 months), the authors from Portugal reached the conclusion that new oral anticoagulants (NOACs) are not associated with an increased risk of serious drug-induced liver injury. Analyses of individual NOACs (dabigatran, rivaroxaban, apixaban, edoxaban, darexaban) and considering the different control groups (vitamin K antagonists, low molecular weight heparin placebo) could not identify NOAC-associated hepatotoxicity.

Caldeira D, Barra M, Santos AT, et al. Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis. Heart. 2014 Jan 29. [Epub ahead of print]. Abstract.

 VIP  Review: new oral anticoagulants in the cancer patient
Cancer increases the risk of venous thromboembolic events. The authors review “the basic pharmacology, current clinical indications, and approach to the use of NOACs in the cancer patient”.

Short NJ, Connors JM. New Oral Anticoagulants and the Cancer Patient. Oncologist. 2013 Dec 6. [Epub ahead of print]. Abstract.

 VIP  The Current and Future Role of the Novel Oral Anticoagulants-Indications Beyond Atrial Fibrillation.
Lee A, Rajaratnam R.
Heart Lung Circ. 2013 Oct 9. [Epub ahead of print]
“…Warfarin is still the predominant anticoagulant used for the treatment and prevention of venous thromboembolic events including deep vein thrombosis and pulmonary embolism as well as in patients with mechanical prosthetic heart valves. In this article, we review the current evidence for the use of dabigatran, rivaroxaban, apixaban and edoxaban in these settings. A summary of suggested regimens utilising these agents is provided. Importantly, in addition, attention is also drawn to clinical scenarios in which use of such agents is considered inappropriate.”

 VIP  Concerns About the Use of New Oral Anticoagulants for Stroke Prevention in Elderly Patients with Atrial Fibrillation.
Stöllberger C, Finsterer J.
Drugs Aging. 2013 Oct 30. [Epub ahead of print]
“… Frail elderly people were not represented in NOAC-investigating trials because of various exclusion criteria, and only one-third of patients were aged >75 years. A subgroup analysis from the dabigatran-investigating trial indicated that elderly patients might have a higher risk for extracranial bleeding complications with NOAC than with VKA. Further concerns about the use of NOAC in the elderly are the high prevalence of renal insufficiency in AF patients >75 years of age, the largely unknown risk of drug-drug and drug-food interactions, the lack of easily available laboratory monitoring tests of anticoagulant activity and the lack of an antidote. There is a need for independent studies comparing the efficacy and risk of side effects of NOAC with that of VKA in elderly AF patients.”

Tahir F, Riaz H, Riaz T, et al.
Thromb J. 2013 Sep 3;11(1):18. [Epub ahead of print]
“CONCLUSION: Considering their pharmacological properties, their efficacy and bleeding complications, the new oral agents offer a net favourable clinical profile in orthopedic surgery, atrial fibrillation, acute coronary syndrome and increase the risk of bleeding in critically ill patients. Further studies are necessary to determine the long term safety and to identify the specific reversal agents of these new drugs.”

Dabigatran, ROCKET atrial fibrillation, and beyond: basic science, mechanisms of agents, monitoring, and reversal.
Bauer KA.
Stroke. 2013 Jun;44(6 Suppl 1):S38-40. No abstract available.

 VIP  Treatment with novel oral anticoagulants: indications, efficacy and risks.
Ghanny S, Crowther M.
Curr Opin Hematol. 2013 Jul 11. [Epub ahead of print]
“SUMMARY: nOACs are an acceptable alternative to VKAs in certain situations - these are at least as effective as warfarin for secondary prevention of VTE and for prevention of stroke and systemic embolism in patients with atrial fibrillation. These compare favorably with warfarin with respect to their rate of fatal and major bleeding. However, special attention should be given when using these drugs in certain patient populations, in particular in patients with renal insufficiency, those receiving additional antithrombotic therapy, those with questionable compliance, patients of child bearing potential and those with a high risk of gastrointestinal bleeding.”

New-generation oral anticoagulants for the prevention of stroke: Implications for neurosurgery.
El Ahmadieh TY, Aoun SG, Daou MR, et l.
J Clin Neurosci. 2013 Jul 5. [Epub ahead of print]
“We discuss current evidence for the use of these novel agents, their limitations, existing methods of drug-level monitoring, and controversies related to anticoagulation reversal. We also discuss specific topics such as anticoagulation resumption after intracranial or intraspinal bleeding, perioperative anticoagulant administration, and the possibility of combination with tissue plasminogen activator in the setting of acute ischemic stroke. A special focus is given to the incidence of intracranial and intraspinal hemorrhage associated with each drug.”
Esmon CT.
Thromb Res. 2012 Oct;130 Suppl 1:S41-3.

 VIP  New oral anticoagulants: a review of the literature with particular emphasis on patients with impaired renal function.
Poulsen BK, Grove EL, Husted SE.
Drugs. 2012 Sep 10;72(13):1739-53.
“…These drugs may potentially cause bleeding complications in patients with reduced drug excretion due to impaired renal function. Dabigatran etexilate and rivaroxaban carry the highest risk due to a high degree of renal excretion, whereas the risk for apixaban, edoxaban and betrixaban seems lower…”

Arachchillage DJ, Cohen H.
Curr Rheumatol Rep. 2013 Jun;15(6):331.
“…These agents have been approved for several therapeutic indications based on phase III prospective randomised controlled clinical trials using warfarin at a target INR of 2.5 (i.e. range 2.0-3.0) as the comparator. However these trials may not be directly applicable to patients with antiphospholipid syndrome (APS) where prospective clinical studies of NOAC are the way forward.”

Stöllberger C, Finsterer J.
J Neurol Sci. 2013 Apr 26. [Epub ahead of print]
“…We advise caution in the use of NOAC in patients with stroke or cerebral hemorrhage because of the following reasons: 1) Patients with cerebral bleeding were excluded from the trials. 2) Stroke within 14days and severe stroke within 6months before screening were exclusion criteria in the trials investigating dabigatran and rivaroxaban. 3) There is no antidote for reversal and no reliable laboratory monitoring of the anticoagulant effect for emergency situations. 4) NOAC are either substrates of the P-glycoprotein (P-gp) or are metabolized by the cytochrome P450 (CYP) system, or both. Drug-drug interactions between NOAC and P-gp and CYP-affecting drugs are largely unknown. 5) Long-term effects of thrombin generation inhibition on the occurrence of infections, malignancies, dementia, and other diseases are unknown…”

Harder S, Graff J.
Eur J Clin Pharmacol. 2013 Apr 26. [Epub ahead of print]
“This review summarizes the pharmacology of rivaroxaban, apixaban, edoxaban, and dabigatran, and the indications for which they are approved. Issues regarding the optimization of the use of these anticoagulants for the management of thromboembolic disorders will also be discussed.”

 VIP  Novel oral anticoagulants for venous thromboembolism prophylaxis after total hip or knee replacement: an update on rivaroxaban (xarelto).
Stacy Z.
P T. 2013 Jan;38(1):45-50. No abstract available.

Pebanco GD, Kaiser SA, Haines ST.
Ann Pharmacother. 2013 Apr 19. [Epub ahead of print]
“CONCLUSIONS: When compared to enoxaparin, newer drugs exhibit slightly different safety and efficacy profiles when used for VTE prevention in older adults undergoing major orthopedic surgery. There are insufficient data for other indications. The benefits and risks of new pharmacologic methods of VTE prevention are unclear in the oldest old (age =85 years) and in those admitted to a hospital for an acute medical illness or to a skilled nursing facility.”

Ogbonna KC, Jeffery SM.
Drugs Aging. 2013 Apr 17. [Epub ahead of print]
“… This review will examine the newer anticoagulants safety and efficacy with particular attention to their role in treating older adults with AF …. Whether these agents represent advances in overall safety in older adults remains uncertain. More experience and research are needed before endorsing their widespread use as a replacement for warfarin in the geriatric population.”

 VIP  Prevention and treatment of venous thromboembolism with new oral anticoagulants: a practical update for clinicians.
Tun NM, Oo TH.
Thrombosis. 2013;2013:183616. Epub 2013 Feb 21.
Connolly G, Spyropoulos AC.
J Thromb Thrombolysis. 2013 Mar 27. [Epub ahead of print]

Thromboprophylaxis in the oldest old with atrial fibrillation: Between Scylla and Charybdis.
Mannucci PM.
Eur J Intern Med. 2013 Mar 14. [Epub ahead of print]

 VIP   META  New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis.
Oldgren J, Wallentin L, Alexander JH, et al.
Eur Heart J. 2013 Mar 6. [Epub ahead of print]
“Conclusion: In patients with a recent acute coronary syndrome, the addition of a new oral anticoagulant to antiplatelet therapy results in a modest reduction in cardiovascular events but a substantial increase in bleeding, most pronounced when new oral anticoagulants are combined with dual antiplatelet therapy.”

Prevention of VTE in patients having major orthopedic surgery.
Francis CW.
J Thromb Thrombolysis. 2013 Feb 10. [Epub ahead of print]

 VIP  Anticoagulant Therapy with the Oral Direct Factor Xa Inhibitors Rivaroxaban, Apixaban and Edoxaban and the Thrombin Inhibitor Dabigatran Etexilate in Patients with Hepatic Impairment.
Graff J, Harder S.
Clin Pharmacokinet. 2013 Feb 7. [Epub ahead of print]
“Hepatic impairment can affect the disposition of these anticoagulants considerably not only because of the hepatic metabolism of the direct FXa inhibitors but also because moderate to severely impaired hepatic function will affect coagulation. This review describes the key pharmacological properties of novel oral anticoagulants with special attention to patients with impaired hepatic function…Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients classified as Child-Pugh B and C. Apixaban can be used with caution in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment or in patients with alanine aminotransferase and aspartate aminotransferase levels >2× upper limit of normal (ULN). Apixaban is not recommended in patients with severe hepatic impairment and is contraindicated in those with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Dabigatran is not recommended in patients with elevated liver enzymes (>2× ULN). Dabigatran is contraindicated in patients with hepatic impairment or liver disease expected to have any impact on survival. Currently, edoxaban is not available in the US or European markets. However, the Japanese label did not restrict use in hepatic dysfunction but advises care in patients with severe hepatic impairment.”

 VIP  Systematic Review of Randomized Controlled Trials of New Anticoagulants for Venous Thromboembolism Prophylaxis in Major Orthopedic Surgeries, Compared With Enoxaparin.
Yoshida RD, Yoshida WB, Maffei FH, et al.
Ann Vasc Surg. 2013 Jan 23. [Epub ahead of print]
“CONCLUSIONS: New anticoagulants can be considered alternatives to conventional thromboprophylaxis regimens in patients undergoing elective major orthopedic surgery, depending on clinical characteristics and cost-effectiveness. The knowledge of some differences concerning efficacy or safety profile, pointed out in this systematic review, along with the respective limitations, may be useful in clinical practice.”

Novel oral anticoagulants for stroke prevention in atrial fibrillation: Key trial findings and clinical implications.
Goette A.
Trends Cardiovasc Med. 2013 Jan 10. [Epub ahead of print]

 VIP  New Oral Anticoagulants: Comparative Pharmacology with Vitamin K Antagonists.
Scaglione F.
Clin Pharmacokinet. 2013 Jan 5. [Epub ahead of print]

Greenspon AJ.
Postgrad Med. 2012 Nov;124(6):7-16.

Hollands JM, Gowan M, Riney JN, et al.
Ann Pharmacother. 2012 Dec;46(12):1656-70. Epub 2012 Dec 18.
“CONCLUSIONS: … Newer antithrombotic agents appear to be promising alternatives for the prevention of stroke in patients with AF; however, more data are needed to understand their role.”

Verheugt FW.
Am J Cardiol. 2012 Dec 6. [Epub ahead of print]

Shamoun FE, Martin EN, Money SR.
Surgery. 2012 Dec 4. [Epub ahead of print]

Mantha S, Cabral K, Ansell J.
Clin Pharmacol Ther. 2012 Dec 5. [Epub ahead of print]
“This review focuses on the available evidence and attempts to provide guidance to clinicians in the field.”

Alberts MJ, Eikelboom JW, Hankey GJ.
Lancet Neurol. 2012 Dec;11(12):1066-81.
“The direct thrombin inhibitor dabigatran etexilate and factor Xa inhibitors rivaroxaban and apixaban are new oral anticoagulants that are at least as efficacious and safe as warfarin. Their advantages are predictable anticoagulant effects, low propensity for drug interactions, and lower rates of intracranial haemorrhage than with warfarin. A disadvantage is the continuing need to develop and validate rapidly effective antidotes for major bleeding and standardised tests that accurately measure plasma concentrations and anticoagulant effects, together with the disadvantage of possible higher rates of gastrointestinal haemorrhage and greater expense than with warfarin.”

 VIP  Translational success stories: development of direct thrombin inhibitors.
Coppens M, Eikelboom JW, Gustafsson D, et al.
Circ Res. 2012 Sep 14;111(7):920-9.
“This Review highlights the development of DTIs as a translational success story; an example in which the combination of scientific ingenuity, structure-based design, and rigorous clinical trials has created a new class of anticoagulants that has improved patient care.”

 VIP  Oral anticoagulation in atrial fibrillation: balancing the risk of stroke with the risk of bleed.
Kosar L, Jin M, Kamrul R, Schuster B.
Can Fam Physician. 2012 Aug;58(8):850-8. No abstract available.

Dentali F, Riva N, Crowther M, et al.
Circulation. 2012 Oct 15. [Epub ahead of print]
“CONCLUSIONS: Novel oral anticoagulants are associated with an overall clinical benefit compared with vitamin K antagonists. Additional research is required to confirm these findings outside the context of randomized trials.”

Mak KH.
BMJ Open. 2012 Oct 6;2(5).
“CONCLUSIONS: The risk for coronary events was significantly higher for dabigatran but not significantly higher for ximelagatran. Conversely, this risk was lower among anti-Xa inhibitors. All-cause mortality was lower among those receiving novel antithrombotic agents. This information may be useful in selecting agents for specific subsets of patients requiring anticoagulation.”

Komócsi A, Vorobcsuk A, Kehl D, Aradi D.
Arch Intern Med. 2012 Sep 24:1-9. [Epub ahead of print]
“CONCLUSION: The use of anti-Xa or direct thrombin inhibitors is associated with a dramatic increase in major bleeding events, which might offset all ischemic benefits in patients receiving antiplatelet therapy after an ACS.”

Golwala H, Dib C, Tafur A, Abu-Fadel MS.
Am J Med Sci. 2012 Aug;344(2):128-35.
“This article will review 3 new antithrombotic medications that may potentially become the mainstay for treatment of patients with atrial fibrillation in the near future.”

Rajappan K.
Heart. 2012 Sep 28. [Epub ahead of print] No abstract available.

Martin LK, Bekaii-Saab T.
Thrombosis. 2012;2012:758385. Epub 2012 Sep 11.
“This paper reviews the existing efficacy and safety data for the use of novel oral anticoagulants (NOAs) dabigatran etexilate, rivaroxaban, and apixaban and discusses the potential role of these agents in the management of gastrointestinal cancer-related VTE.”
“In conclusion, although NOAs are promising for the treatment of VTE in the general population, they should not be used as first-line therapy for VTE in patients with advanced gastrointestinal cancers outside the setting of a clinical trial, as there is insufficient data to clearly define their efficacy and safety. LMWH should remain standard first-line therapy for cancer-related DVT. Prospective investigations of NOAs specific to the cancer population are necessary.”

Knesek D, Peterson TC, Markel DC.
Thrombosis. 2012;2012:837896. Epub 2012 Sep 16.
“The most recent American College of Chest Physicians (ACCP) and American Academy of Orthopedic Surgeons (AAOS) guidelines give clinicians a greater autonomy in choosing a prophylactic agent with greater emphasis placed on dialogue between the surgeon and patient as to the choice of prophylaxis.”

John M. Eisenberg Center for Clinical Decisions and Communications Science.
Comparative Effectiveness Review Summary Guides for Clinicians [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2007-.

Pisters R, Lane DA, Marin F, Camm AJ, Lip GY.
Circ J. 2012 Sep 25;76(10):2289-304. Epub 2012 Sep 19.
“Anticoagulation with vitamin K antagonists and dabigatran is cost-effective in patients at high risk of stroke, but not in patients without any other stroke risk factor beside AF.”

Ru San T, Chan MY, Wee Siong T, et al.
Thrombosis. 2012;2012:108983. Epub 2012 Sep 10.

 VIP  New oral anticoagulants for atrial fibrillation.
Spinler SA, Shafir V.
Circulation. 2012 Jul 3;126(1):133-7. No abstract available.
Klein L.
Ann Intern Med. 2012 Sep 18;157(6):JC3-2.
“CONCLUSION: In patients with atrial fibrillation, new oral anticoagulants (apixaban, dabigatran, and rivaroxaban) reduced a composite of stroke and systemic embolism, ischemic or unspecified stroke, hemorrhagic stroke, all-cause mortality, vascular mortality, and intracranial bleeding compared with warfarin.”

Costopoulos C, Niespialowska-Steuden M, Kukreja N, Gorog DA.
Int J Cardiol. 2012 Sep 15. [Epub ahead of print]

Bona R.
Ann Intern Med. 2012 Aug 21;157(4):JC2-5.
“CONCLUSION: In patients having total knee or hip replacement, oral direct factor Xa inhibitors reduced symptomatic deep venous thrombosis compared with low-molecular-weight heparin but did not differ for mortality, pulmonary embolism, or bleeding.”

Circulation. 2012 Mar 27;125(12):1577-83.

Hart RG, Eikelboom JW, Ingram AJ, Herzog CA.
Nat Rev Nephrol. 2012 Jul 24. [Epub ahead of print]

Pengo V, Crippa L, Falanga A, et al.
J Thromb Haemost. 2012 Jul 24. [Epub ahead of print]

Pollack CV Jr.
Am J Emerg Med. 2012 Jul 12. [Epub ahead of print]

Tripodi A, Palareti G.
J Intern Med. 2012 Jun;271(6):554-65.

Kar S, Bhatt DL.
Coron Artery Dis. 2012 Jun 21. [Epub ahead of print]

Gallego P, Roldan V, Lip GY.
Am J Respir Crit Care Med. 2013 May 14. [Epub ahead of print]
“Whilst awaiting long-term safety data, the choice between all these available therapies should be based on patient preferences, compliance and ease of administration, as well as on local factors affecting cost-effectiveness.”

Oral IIa- and Xa-Inhibitors for Prevention of Stroke in Atrial Fibrillation: Clinical Studies and Regulatory Considerations.
Deftereos S, Tsounis D, Giannopoulos G, et al.
Curr Clin Pharmacol. 2012 May 7. [Epub ahead of print]

Deftereos S, Bouras G, Giannopoulos G, et al.
Curr Clin Pharmacol. 2012 May 7. [Epub ahead of print]

Deftereos S, Hatzis G, Kossyvakis C, et al.
Curr Clin Pharmacol. 2012 May 7. [Epub ahead of print]

Hankey GJ.
Nat Rev Neurol. 2012 May 8. doi: 10.1038/nrneurol.2012.77. [Epub ahead of print]

Liew A, Eikelboom JW, O'Donnell M.
Curr Opin Cardiol. 2012 May 8. [Epub ahead of print]

Miller CS, Grandi SM, Shimony A, et al.
Am J Cardiol. 2012 Apr 24. [Epub ahead of print]
“In conclusion, the new oral anticoagulants are more efficacious than warfarin for the prevention of stroke and systemic embolism in patients with AF. With a decreased risk for intracranial bleeding, they appear to have a favorable safety profile, making them promising alternatives to warfarin.”

Katsnelson M, Sacco RL, Moscucci M.
Circulation. 2012 Mar 27;125(12):1577-83.

Bassand JP.
Europace. 2012 Mar;14(3):312-24.

Soff GA.
Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):569-74.

Cabral KP, Ansell J.
Nat Rev Cardiol. 2012 Feb 28. doi: 10.1038/nrcardio.2012.19. [Epub ahead of print]

Morales-Vidal S, Schneck MJ, Flaster M, Biller J.
Expert Rev Neurother. 2012 Feb;12(2):179-89; quiz 190.

 VIP  Controversies in Cardiovascular MedicineShould Newer Oral Anticoagulants Be Used as First-Line Agents to Prevent Thromboembolism in Patients With Atrial Fibrillation and Risk Factors for Stroke or Thromboembolism?
Granger CB, Armaganijan LV.
Circulation. 2012 Jan 3;125(1):159-64; discussion 164.
Ansell J.
Circulation. 2012 Jan 3;125(1):165-70; discussion 170.

 VIP  means very important / interesting paper
 META  means meta-analysis