Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal failure.
Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.
The administration of warfarin sodium via the intravenous (I.V.) route should provide the patient with the same concentration of an equal oral dose, but maximum plasma concentration will be reached earlier. However, the full anticoagulant effect of a dose of warfarin may not be achieved until 72 to 96 hours after dosing, indicating that the administration of I.V. warfarin sodium should not provide any increased biological effect or earlier onset of action.
ATRIAL FIBRILLATION (AF)
In five prospective randomized controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (See Table 1). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%) which stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6 to 2.7% (see Table 1). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0 to 4.5) or low INR (1.4 to 3.0). There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients are not available.
|CLINICAL STUDIES OF WARFARIN IN NON-RHEUMATIC AF PATIENTS*|
|Study||N||PT Ratio||INR||Thromboembolism||% Major Bleeding|
|Warfarin-||Control||% Risk||p- value||Warfarin-||Control|
*All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhage and transient ischemic attacks.
WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks postinfarction treated with warfarin to a target INR of 2.8 to 4.8. [But note that a lower INR was achieved and increased bleeding was associated with INR's above 4.0; (see DOSAGE AND ADMINISTRATION)]. The primary endpoint was a combination of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in the following table:
|Total Patient Years of Follow-up||2018||1944|
|Total Mortality||94 (4.7/100 py)||123 (6.3/100 py)||0.76 (0.60, 0.97)||24 (p=0.030)|
|Vascular Death||82 (4.1/100 py)||105 (5.4/100 py)||0.78 (0.60, 1.02)||22 (p=0.068)|
|Recurrent MI||82 (4.1/100 py)||124 (6.4/100 py)||0.66 (0.51, 0.85)||34 (p=0.001)|
|Cerebrovascular Event||20 (1.0/100 py)||44 (2.3/100 py)||0.46 (0.28, 0.75)||54 (p=0.002)|
RR=Relative risk; Risk reduction=(I-RR); CI=Confidence interval; MI=Myocardial infarction; py=patient years
WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin target INR 2.8 to 4.2, aspirin 160 mg/day, or warfarin target INR 2.0 to 2.5 plus aspirin 75 mg/day prior to hospital discharge. There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in the following table1:
|Table 3: WARIS II — Distribution of Separate Events According to Treatment Group*|
|Event||Aspirin||Warfarin||Aspirin Plus Warfarin||Rate Ratio||p-value|
|Thromboembolic stroke||32||17||17||0.52 (0.28-0.98)a||0.03|
|Major Bleeding c||8||33||28||3.35a (ND)||ND|
|Minor Bleeding d||39||103||133||3.21a (ND)||ND|
* CI denotes confidence interval.
a The rate ratio is for aspirin plus warfarin as compared with aspirin.
b The rate ratio is for warfarin as compared with aspirin.
c Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating
d Minor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention of blood transfusion.
ND =not determined.
MECHANICAL AND BIOPROSTHETIC HEART VALVES
In a prospective, randomized, open label, positive-controlled study2 in 254 patients, the thromboembolic-free interval was found to be significantly greater in patients with mechanical prosthetic heart valves treated with warfarin alone compared with dipyridamole-aspirin (p<0.005) and pentoxifylline-aspirin (p<0.05) treated patients. Rates of hromboembolic events in these groups were 2.2, 8.6, and 7.9/100 patient years, respectively. Major bleeding rates were 2.5, 0.0, and 0.9/100 patient years, respectively.
In a prospective, open label, clinical trial comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events/100 patient years, respectively). Major bleeding was more common in the high intensity group (2.1 events/100 patient years) vs. 0.95 events/100 patient years in the moderate intensity group3.
In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0 to 2.25 vs. INR 2.5 to 4.0) for a three month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively and minor embolic events 10.8% vs. 10.2%, respectively). Major bleeding complications were more frequent with the higher intensity (major hemorrhages 4.6%) vs. none in the lower intensity4.
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.