However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see Drug Interactions 7 ].
Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information 17 ]. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.
Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Consider alternative drugs if continued anticoagulation therapy is necessary. COUMADIN can cause fatal and serious calciphylaxis or calcium uremic arteriolopathy, which has been reported in patients with and without end-stage renal disease.
Consider alternative anticoagulation therapy. In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur with COUMADIN, possibly in relation to episodes of excessive anticoagulation and hematuria [see Use in Specific Populations 8.
More frequent monitoring of anticoagulation is advised in patients with compromised renal function. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death.
Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations 8.
Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration.
Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with COUMADIN may minimize the incidence of tissue necrosis in these patients. As COUMADIN cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue COUMADIN before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits.
The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency. The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance. Pharmacodynamic mechanisms for drug interactions with COUMADIN are synergism impaired hemostasis, reduced clotting factor synthesis , competitive antagonism vitamin K , and alteration of the physiologic control loop for vitamin K metabolism hereditary resistance.
It is important to note that some drugs may interact by more than one mechanism. More frequent INR monitoring should be performed when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs, including drugs intended for short-term use e. Consult the labeling of all concurrently used drugs to obtain further information about interactions with COUMADIN or adverse reactions pertaining to bleeding.
Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive. Consult the labeling of all concurrently used drugs to obtain further information about CYP interaction potential. The CYP inhibition and induction potential should be considered when starting, stopping, or changing dose of concomitant medications.
Examples of drugs known to increase the risk of bleeding are presented in Table 3. Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin. There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin.
Closely monitor INR when starting or stopping any antibiotic or antifungal in patients taking warfarin. More frequent INR monitoring should be performed when starting or stopping botanicals.
Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation. Some botanicals may cause bleeding events when taken alone e. Because these data were not collected in adequate and well-controlled studies, this incidence of major birth defects is not an adequate basis for comparison to the estimated incidences in the control group or the U.
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U. In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses chondrodysplasia punctata and growth retardation including low birth weight. Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy.
Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy [see Contraindications 4 ].
Warfarin was not present in human milk from mothers treated with warfarin from a limited published study. Based on published data in 15 nursing mothers, warfarin was not detected in human milk.
Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Effects in premature infants have not been evaluated. Adequate and well-controlled studies with COUMADIN have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown.
Pediatric use of COUMADIN is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants.
Apixaban is an oral anticoagulant of the Factor Xa inhibitor class. Outcome Measures. Primary Outcome Measures : Stroke or death [ Time Frame: Up to 3 years ] Incidence of stroke of any type ischemic or hemorrhagic or death from any cause.
Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials. More Information. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Intracerebral Hemorrhage Atrial Fibrillation. Drug: Apixaban Drug: Aspirin. Phase 3. Study Type :. Interventional Clinical Trial. Estimated Enrollment :. Actual Study Start Date :.
Estimated Primary Completion Date :. Estimated Study Completion Date :. Active Comparator: Apixaban Apixaban dosing will be 5 mg tablet in morning and 5 mg tablet in evening. Other Name: Eliquis. Placebo Comparator: Aspirin Aspirin dose will be 81 mg tablet once daily. Contact: Angela Shapshak, MD. Contact: Rebecca Sugg. Contact: David Salvatore. Contact: Chelsea Kidwell, MD.
Contact: Krishna Nalleballe, MD. Contact: Lucian Maidan. Contact: Peter Adamczyk, MD. Contact: Dan Miulli, MD. Contact: Amy Towfighi, MD. Contact: Vaninder Chhabra. Contact: Nirav Patel, MD. Contact: Harsimran Brara, MD. Contact: Konrad Schlick, MD. Contact: Latisha Sharma, MD. Contact: David Brown.
Contact: Wengui Yu, MD. Contact: Kevin Attenhofer, MD. Contact: Arib Ohanian, MD. Disagreements, if any, were resolved by the mutual consensus of all 3 of us. After the data elements were verified for accuracy, they were subsequently entered into statistical software for further analysis. Pooled event rates expressed as percentage per year for the safety and efficacy outcomes in the warfarin arm were calculated using standard methods.
Fixed-effects modeling was primarily used to conduct outcomes meta-analysis from included studies. Random-effects modeling was used in the case of statistically significant heterogeneity. Assessment of heterogeneity was achieved by comparing the inclusion and exclusion criteria and the minor differences in the design and conduct of the clinical trials.
In cases of significant heterogeneity, the heterogeneity was first explored in the studies, and subsequently a random-effects meta-analysis was performed to statistically account for the heterogeneity. Publication bias was assessed using the funnel plot method and Begg and Mazumdar rank correlation testing. Subgroup analyses were performed to determine event rates in different strata of the study population.
All the subgroup analyses were prespecified. Eight RCTs including 32 patients were included in the meta-analysis. The pooled analysis yielded 55 patient-years of follow-up. The characteristics of the included trials are given in Table 1.
There were minor differences in the inclusion criteria, primary safety end point, and efficacy outcomes across the trials. The flow diagram for study selection is depicted in Figure 1. The characteristics of included patients in the warfarin arm of each trial are given in Table 2. We observed significant heterogeneity in the baseline characteristics of included individuals across various trials. Table 3 demonstrates the event rates of efficacy outcomes in the warfarin arm across the included trials.
Similarly, the rates of MI, all-cause mortality, and composite outcomes varied from 0. The pooled analysis of safety outcomes is demonstrated in Figure 3. Analysis of publication bias using the funnel plot method and the Begg and Mazumdar rank correlation method did not reveal any significant publication bias in the reporting of efficacy outcomes examined in the meta-analysis. The definition of major and minor bleeding varied considerably across the included studies; hence, a valid pooled estimate for these outcomes could not be calculated.
Quiz Ref ID The incidence of major bleeding episodes ranged from 1. The safety outcomes in the warfarin arm across the included trials are summarized in Table 3. The annual rate of intracranial hemorrhage in patients with AF taking warfarin ranged from 0. Meta-analysis of intracranial hemorrhage yielded a pooled event rate of 0. The cumulative adverse event rate, defined as major vascular events reported or death or major bleeding episodes, was observed to range from 3.
Table 4 demonstrates the event rates for stroke and non-CNS embolism in patients treated with warfarin across the included trials, stratified by prespecified subgroups. Table 5 provides the summary statistics obtained from the studies included in the previous meta-analysis examining trials from to that evaluated the efficacy and safety of warfarin compared with placebo.
This was a considerably higher estimate compared with the incidence rate of stroke observed in the present meta-analysis. There was significant variation in the target INR range observed in the earlier clinical trials. The lower limit of the target INR range was less than 2.
In addition, there was significant variation in the proportion of time in the target INR range. In comparison, the clinical trials included in the present meta-analysis have a uniform target INR range 2. The present meta-analysis takes advantage of a large body of contemporary evidence to evaluate the efficacy and safety of warfarin therapy in patients with nonvalvular AF treated with warfarin.
Quiz Ref ID Using a database of more than 30 patients, the pooled annual incidence rate of stroke or non-CNS embolism was estimated to be 1. Due to nonstandardized definitions, rates of major bleeding events ranged from 1. Quiz Ref ID Subgroup analyses demonstrated a significantly increased risk of thromboembolic complications in females, in patients 75 years and older, in patients with previous stroke or TIA, and in patients with no previous exposure to vitamin K antagonists.
We observed a significantly higher risk of thromboembolic events in warfarin-treated patients with intermediate risk 1. Warfarin has been a pharmacotherapeutic standard for stroke prevention in AF; its efficacy for stroke prevention has been demonstrated in patients with AF, particularly those with a high baseline risk of stroke eg, older age groups. Several model-based studies have shown warfarin to be an extremely cost-effective strategy for stroke prevention, especially in patients older than 75 years.
Even after consideration of the costs associated with regular INR testing, in most settings, the overall cost of therapeutic strategies using these newer agents will exceed the costs of comparative strategies incorporating generic warfarin. Thus, despite the development of newer antithrombotic agents with increased ease of administration that are superior or noninferior to warfarin, 6 , 8 , 9 most patients with nonvalvular AF will probably continue to be treated with warfarin in the near future owing to cost considerations.
Indeed, warfarin will likely continue to be widely used as the drug of choice in several countries around the world. The clinical and cost-related outcomes associated with warfarin therapy depend on the duration of therapeutic anticoagulation indicating the quality of anticoagulation and rates of warfarin discontinuation.
This decline in event rate is likely due to the increased rates of therapeutic anticoagulation observed in recent studies. In addition, the reduction in the stroke rates may be partially attributable to a significant improvement in the management of atherosclerotic risk factors, such as hypertension and dyslipidemia. Atrial Fibrillation Cardiology Rhythm Disorders. Full Text pdf link PDF open access. Full Text pdf link PDF free. Full Text pdf link PDF free has multimedia.
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