Four direct oral anticoagulants have been approved for use in many countries. These drugs are valuable alternatives to vitamin K antagonists, such as warfarin, for many patients requiring anticoagulation to prevent stroke due to nonvalvular atrial fibrillation and to treat and prevent venous thromboembolism. The mechanism of these agents is to selectively inhibit either thrombin or factor Xa, which are critical enzymes in the common pathway of blood coagulation. Dabigatran etexilate inhibits thrombin, whereas apixaban, edoxaban, and rivaroxaban inhibit factor Xa.
Direct oral anticoagulants have several pharmacologic advantages over vitamin K antagonists, including a wider therapeutic window, a rapid onset of action, and shorter half-lives that range between 7 hours and 14 hours in healthy persons. Direct oral anticoagulants are administered at fixed doses to adults without laboratory monitoring, which is more convenient than warfarin with its requirement for monitoring of the international normalized ratio and periodic dose adjustments. In randomized trials with good anticoagulation management (i.e., with international normalized ratios generally in the desired therapeutic range of 2 to 3 for >60% of the time), direct oral anticoagulants were noninferior, and in some cases superior, to dose-adjusted warfarin for the prevention and treatment of thrombosis. As compared with warfarin, direct oral anticoagulants reduced the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%.1
Despite the better bleeding profile of direct oral anticoagulants, as compared with warfarin, some physicians and patients have been unwilling to consider these drugs in the absence of an established way to reverse their anticoagulant activity. Although the anticoagulant activity of warfarin can be reversed with vitamin K, fresh-frozen plasma, and prothrombin complex concentrates, major bleeding events that occur in patients taking this drug often lead to poor outcomes; approximately 10% of patients who are hospitalized with warfarin-related bleeding die within 90 days,2,3 and the mortality among patients with intracranial hemorrhage can be as high as 50%.4,5 The high mortality is attributable in part to coexisting conditions in this patient population. Experimental data suggest that nonspecific reversal agents such as prothrombin complex concentrates, activated prothrombin complex concentrates, or recombinant factor VIIa can reduce the anticoagulant effect of direct oral anticoagulants in vitro, in animal models, and in human volunteers.6 However, these agents are of unproven benefit in improving hemostasis in patients with bleeding related to direct oral anticoagulant use, and they carry a risk of thrombosis; thus, they are currently reserved for patients with severe bleeding who cannot be treated with supportive measures.
With the growing use of direct oral anticoagulants, it would be advantageous to have reversal agents that can rapidly and completely neutralize the anticoagulant activity of the drug and restore normal hemostasis. Specific reversal agents in clinical development include andexanet alfa, a recombinant factor Xa variant that specifically binds all the oral factor Xa inhibitors but lacks coagulant activity.7 There is also a nonspecific reversal agent in clinical development, PER977, which binds to several of the direct oral anticoagulants by means of electrostatic interactions.8 Given that there are no established reversal strategies for the direct oral anticoagulants, it is appropriate to undertake clinical trials of these agents without a control group.
Idarucizumab is a humanized monoclonal antibody fragment with high affinity for the oral direct thrombin inhibitor dabigatran that selectively and immediately neutralizes its anticoagulant activity.9 Pollack et al.10 now report in the Journal the results of an interim analysis of data from 90 patients who were taking dabigatran and who presented with either serious bleeding or the need for urgent surgery or intervention and received intravenous idarucizumab. This multicenter observational study evaluated the effect of a single 5-g dose of antibody in eligible patients who were judged by the treating clinician to require a reversal agent. The major end points of the study were pharmacodynamic assessments of the ability of idarucizumab to neutralize the anticoagulant activity of dabigatran. The data are convincing that the antidote effectively and immediately neutralized the activity of dabigatran with a satisfactory safety profile. Normal hemostasis was reported in more than 90% of the patients who underwent procedures after the administration of idarucizumab.
Without a control group, it is difficult to assess the clinical benefit that is conferred by the administration of idarucizumab in patients with dabigatran-related bleeding. The mortality in the study population was high at 20%; half the deaths occurred more than 96 hours after the administration of the antidote and were attributable to coexisting illness. Given that the half-life of dabigatran is 12 to 14 hours if renal function is normal, how important is it to be able to neutralize the anticoagulant activity of dabigatran rapidly in addition to providing supportive care measures? Major bleeding events in patients taking anticoagulants originate from anatomical lesions, and anticoagulation can lead to a rapid loss of blood from these sites. Thus, the location and size of the lesion along with the coexisting conditions of the patient may have a greater effect on prognosis than the ability to rapidly neutralize an anticoagulant that the patient is taking.
Laboratory measurements of the concentration of dabigatran were performed centrally in this study and were not used to guide therapy. The results of one of these tests, the dilute thrombin time, were normal on study entry in nearly one quarter of the study population. This group of patients had little or no circulating anticoagulant in their blood and would not be expected to benefit from the administration of idarucizumab. Thus, it will be useful to have activity measurements available for the various direct oral anticoagulants in real time to help guide the treatment of such patients and to prevent overutilization of what will surely be a costly medication.
The development of antidotes that are able to neutralize the activity of the various direct oral anticoagulants rapidly and completely is an important advance. When they become available, guidelines and clinical pathways will need to be developed to care effectively for patients with, or at risk for, major bleeding related to direct oral anticoagulant use. Additional studies, however, will be required to determine in which situations the antidotes improve clinical outcomes.
This article was published on June 22, 2015, at NEJM.org.
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Hypothyroid patients who are taking levothyroxine (i.e., Synthroid), Cytomel, Thyrolar, or natural thyroid products like Armour and are in the normal thyroid range can give blood if they don’t have any other precluding conditions.
Graves’ disease or hyperthyroidism patients who are on antithyroid medicines, or who are not currently in normal thyroid range, cannot give blood.
Anyone with any other autoimmune disease should not give blood, unless they are asymptomatic and off all medications for one month.
In thyroid patients, and some of the more common autoimmune disease, you specifically should NOT give blood if you have:
Sinus or respiratory infections, colds or flu symptoms
Rheumatoid Arthritis, if you’re on steroids or immunosuppressive drugws
Lupus, unless asymptomatic, and off all medication for at least a month
Also, you can’t give blood if you:
Have ever used illegal intravenous drugs, even once
Are a man who has had sex with another man since 1977, even once
Are a hemophiliac
Have had a positive HIV test
Have had hepatitis any time after your eleventh birthday
Have had cancer (except localized skin cancer)
Have had a heart attack or stroke
Have taken Tegison for psoriasis
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A US Food and Drug Administration (FDA) advisory committee voted 8 to 3 to recommend marketing approval of soluble ferric pyrophosphate (SFP; Triferic, Rockland Medical) as a parenteral iron agent to treat iron loss or iron deficiency and to maintain hemoglobin in adults with hemodialysis-dependent chronic kidney disease.
However, members of the Oncologic Drugs Advisory Committee also recommended to FDA staff members that Rockland Medical, based in Wixom, Minnesota, conduct postapproval studies, should the FDA go along with the committee’s recommendation, into the safety and efficacy of the agent during prolonged use.
SFP is delivered during hemodialysis through a 5-mL ampule containing 27.2 mg elemental iron added to water for injection. Rockland Medical said that Triferic, delivered three to four times a week during hemodialysis, can compensate for an estimated 5 mg of iron loss from dialysis-related blood losses.
The company submitted evidence in its application for approval that included results from two identical phase 3 trials in which investigators tested SFP against placebo. In both studies, according to the company, patients in the SFP group experienced a statistically significant and clinically meaningful difference of 0.36 g/dL over the placebo group between baseline and end of treatment (P = .011 for both studies), with a safety similar to placebo.
FDA staff members called into question, however, the reliability of the company’s data. Staff members pointed out that although treatment duration was planned for up to 48 weeks, only 18% of patients went that long in the trial, and 44% completed only 24 weeks. The various time values make it difficult to draw inferences, they said.
FDA staff members also pointed out that twice the number of deaths occurred in the SFP treatment group than in the placebo group (12 vs 6).
However, after a long discussion involving minute details of the study results, most committee members chose to support the recommendation to approve marketing Triferic, with advice that the research continue.
Lakhmir Chawla, MD, chief of intensive care medicine at the Veterans Affairs Medical Center in Washington, DC, who voted yes, said, “I compliment the sponsor for putting together a very difficult-to-do study…and I do think that these initial results are interesting and the mechanism is interesting. But I am concerned about the ability to dose properly.”
“I’m excited about the possibility of maintaining the iron level,” said Michael Flessner, MD, PhD, director of inflammatory renal diseases at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, who voted yes. “I think that this study was well conducted, although complicated. I had to read it over about five times to understand it, but I do think in this case the applicants did show that this was an effective method of maintaining iron.”
Tito Fojo, MD, PhD, senior oncology investigator at the National Cancer Institute in Bethesda, said he voted no because he was not comfortable with the study and its results. “I thought the study was not all that well designed.”
Bernard F. Cole, PhD, a statistician and professor at the University of Vermont, Burlington, who voted no, said, “It was not a strong ‘no.’ I felt that the data show clearly that Triferic is active vs placebo….We have proof of principle, but in terms of clinical practice, I would have liked to see [the] study in a more realistic clinical setting.”
“I think the study as it was designed showed a benefit to the patients who received the treatment,” said panel Chair Deborah K. Armstrong, MD, professor of oncology at Johns Hopkins University School of Medicine, Baltimore, Maryland, who voted yes. “My concern is that the actual use of the drug will be quite different than it is from the data that was presented…. There needs to be some safety and potential efficacy studies looking into the prolonged use of the agent.”
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