Dosing of warfarin is one of the most challenging problems in clinical practice today. This drug has a narrow therapeutic index, and achieving therapeutic objectives can be very cumbersome for both patient and physician. Various algorithms have been devised to solve this problem.It is well established that variations in two genes, one in the cytochrome P450 family (CYP2C9) and the other in the vitamin K epoxide reductase complex (VKORC1) play important roles in the variable dose requirements that different patients have for warfarin.A study recently published in the NEJM (http://content.nejm.org/cgi/content/abstract/360/8/753) demonstrated that a pharmacogenetic algorithm incorporating clinical information and information on these two genetic mutations performed better than an algorithm based solely on clinical factors or a fixed dose of 5 mg per day in predicting the correct dose requirement for warfarin.
I think the most interesting outcome of this retrospective study is the demonstration that significant percentages of patients had requirements well below and above the fixed dose of 5 mg per day. 33.9% of patients required 21 mg or less per week (<3>7 mg or more per day). It was in these outlier groups that the pharmacogenetic algorithm performed better than the clinical algorithm.
Does this mean that everyone should be tested for CYP2C9 or VKORC1?
No--not yet. As pointed out in the accompanying editorial (http://content.nejm.org/cgi/content/full/360/8/811), warfarin dosing is and always will be empiric, since "the pharmacodynamic end point is the entire basis of warfarin dosage." As yet, there is no randomized prospective trial demonstrating that pharmacogenetic testing and algorithmic dosing provides a clinical benefit. This study however could be the precursor to such a study.
From a clinical standpoint, it is important to remember that when a patient requires what seems like an unusually high or low dose of warfarin to obtain a therapeutic INR, it is most likely related to polymorphisms of either one of these genes, and one should not necessarily doubt the veracity of the INR test result.
Sunday, March 15, 2009
Sunday, March 1, 2009
The New England Journal of Medicine recently published two articles and an editorial on the impact of cytochrome P-450 polymorphisms and response to clopidogrel (Plavix) in its January 22, 2009 issue.
Clopidogrel is an inhibitor of the platelet P2Y12 receptor that requires activation by specific cytochrome P-450 (CYP) enzymes. Specifically, reduced responsiveness has been associated with specific alleles of the CYP2C19 and CYP3A4 genes.
In one study, from France, it was found that patients carrying any two CYP2C19 loss of function alleles had higher event rates after acute MI when treated with clopidogrel than those who did not carry such alleles. In the other study, from Boston, carriers of at least one CYP2C19 loss of function allele who were treated with clopidogrel had higher risk of stent thrombosis, death from MI and stroke as compared to non-carriers.
(Prasugrel, another P2Y12 inhibitor not yet on the U.S. market, appears to be unaffected by CYP2C19 variability. Recently, the FDA Cardiovascular and Renal Drugs Advisory Committee voted to approve prasugrel for the treatment of patients with acute coronary syndromes (ACS) managed with percutaneous coronary intervention (PCI). Prasugrel is accompanied by an increased risk of serious bleeding events compared to clopidogrel.)
As the accompanying NEJM editorial noted, it is not yet clear whether routine genetic testing should be performed when considering drug treatment with clopidogrel.
Here is a link to the editorial: http://content.nejm.org/cgi/content/full/360/4/411
Clopidogrel is an inhibitor of the platelet P2Y12 receptor that requires activation by specific cytochrome P-450 (CYP) enzymes. Specifically, reduced responsiveness has been associated with specific alleles of the CYP2C19 and CYP3A4 genes.
In one study, from France, it was found that patients carrying any two CYP2C19 loss of function alleles had higher event rates after acute MI when treated with clopidogrel than those who did not carry such alleles. In the other study, from Boston, carriers of at least one CYP2C19 loss of function allele who were treated with clopidogrel had higher risk of stent thrombosis, death from MI and stroke as compared to non-carriers.
(Prasugrel, another P2Y12 inhibitor not yet on the U.S. market, appears to be unaffected by CYP2C19 variability. Recently, the FDA Cardiovascular and Renal Drugs Advisory Committee voted to approve prasugrel for the treatment of patients with acute coronary syndromes (ACS) managed with percutaneous coronary intervention (PCI). Prasugrel is accompanied by an increased risk of serious bleeding events compared to clopidogrel.)
As the accompanying NEJM editorial noted, it is not yet clear whether routine genetic testing should be performed when considering drug treatment with clopidogrel.
Here is a link to the editorial: http://content.nejm.org/cgi/
Here are the links to the articles:
One more caveat: The CYP2C19 enzyme referred to above is not the same as the CYP2C9 enzyme involved in the metabolism of warfarin, single nucleotide polymorphisms of which have been implicated in the variability of dosing that some people require when being treated with warfarin.
New Drugs for ITP
The world of platelets and ITP has gone through some changes lately with the approval of two new drugs for ITP and the presentation of data on the use of established drug rituximab (Rituxan) for ITP at the recent American Society of Hematology (ASH) annual meeting earlier this month.
Approval of Nplate (romiplostim)(Amgen) came in August of this year, while approval of Promacta (eltrombopag) (GSK) came in in November. The main practical difference between these drugs is that Nplate is administered subcutaneously on a weekly schedule, while Promacta is given orally on a daily basis..
Both Nplate and Promacta have indications for patients with chronic immune thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Both drugs are thrombopoietin (TPO) receptor agonists that stimulate bone marrow megakaryocytes to produce platelets.
Areas of concern about these drugs have to do with increased reticulin formation and fibrosis in the bone marrow, thrombogenic potential from too high an increase in platelets, and possible malignant transformation to leukemia, especially in myelodysplastic disorders (MDS). Also, discontinuation of drug may cause rebound thrombocytopenia.
Although Nplate was the first to receive approval, it is my guess that Promacta will be more widely used given its oral availability. However, cost of both of these new drugs could limit their use. And, given that ITP is relatively uncommon, it is my guess that these drugs may try to find broader use in other situations, such as chemotherapy induced thrombocytopenias, MDS and chronic thrombocytopenia from hypersplenism due to chronic liver disease. The market potential in these situations is much larger.
In other news, the combination of Rituxan plus dexamethasone was reported by Italian investigators to be significantly better in inducing initial and sustained responses in patients with ITP than dexamethasone alone, in a plenary session abstract presented at the ASH annual meeting. It was concluded that the option of treatment with Rituxan plus dexamethasone could be offered as an option before splenectomy, particularly in patients who are at high risk of complications from surgery or who are reluctant to undergo splenectomy.
New oral anticoagulant drugs: report from ASH 2008
I had the privilege of attending last week's annual meeting of the American Society of Hematology, held in San Francisco. It was one of the most interesting meetings I have ever attended. I paid particularly close attention to the abstracts and educational symposia in the field of thrombosis and anticoagulant therapies.
What interested me the most is the emergence of new oral anticoagulants. These drugs fall into the category of direct thrombin inhibitors (DTIs) and factor Xa inhibitors.
The ideal anticoagulant drug would be one with a wide therapeutic index, oral administration, once a day administration, easy reversibility and availability of an effective antidote, short half life, lack of need for laboratory monitoring and reasonable cost.
While unfractionated heparin, low molecular weight heparins and warfarin in their own respects fulfill some of the above characteristics, none of them are by any means ideal and they all fall far short of fulfilling all of the above criteria.
The drugs to be on the watch for in my opinion are going to be rivaroxaban (Xarelto-Bayer), apixaban (Pfizer and BMS) and dabigatran (Pradaxa-Boehringer Ingelheim) which come much closer to being the "ideal" drug. The latter drug is a DTI that has been shown to be as effective and safe as enoxaparin (Lovenox) in reducing VTE after orthopedic surgery, while the first two are factor Xa inhibitors. Rivaroxaban has received approval in Canada and the EU for prevention of VTE in patients undergoing elective total hip or total knee replacement surgery. Apixaban failed to meet pre-specified criteria of non-inferiority in a study comparing it to enoxaparin in post-op patients but was numerically very similar in efficacy and statistically superior in terms of bleeding complications.
Also to watch for are potential antidote drugs, in particular one that is in development from Portola Pharmaceuticals (S. San Franciso), which is directed against the Xa inhibitors.
What interested me the most is the emergence of new oral anticoagulants. These drugs fall into the category of direct thrombin inhibitors (DTIs) and factor Xa inhibitors.
The ideal anticoagulant drug would be one with a wide therapeutic index, oral administration, once a day administration, easy reversibility and availability of an effective antidote, short half life, lack of need for laboratory monitoring and reasonable cost.
While unfractionated heparin, low molecular weight heparins and warfarin in their own respects fulfill some of the above characteristics, none of them are by any means ideal and they all fall far short of fulfilling all of the above criteria.
The drugs to be on the watch for in my opinion are going to be rivaroxaban (Xarelto-Bayer), apixaban (Pfizer and BMS) and dabigatran (Pradaxa-Boehringer Ingelheim) which come much closer to being the "ideal" drug. The latter drug is a DTI that has been shown to be as effective and safe as enoxaparin (Lovenox) in reducing VTE after orthopedic surgery, while the first two are factor Xa inhibitors. Rivaroxaban has received approval in Canada and the EU for prevention of VTE in patients undergoing elective total hip or total knee replacement surgery. Apixaban failed to meet pre-specified criteria of non-inferiority in a study comparing it to enoxaparin in post-op patients but was numerically very similar in efficacy and statistically superior in terms of bleeding complications.
Also to watch for are potential antidote drugs, in particular one that is in development from Portola Pharmaceuticals (S. San Franciso), which is directed against the Xa inhibitors.
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