Warfarin And Renal Impairment Essay
Warfarin And Renal Impairment Essay
Author: Karishma Kak
H.BSc (2009)., BSc Pharm Candidate(2013)
Conflict of interest: Past work term working in a pharmacist-managed anticoagulation clinic with warfarin.
This manuscript is original, is not under consideration by another journal, has not been previously published, and has been approved by all authors.
Focus:
Focus will be placed on the specific risk associated with declining renal function and managing thromboembolic risk in the setting of atrial fibrillation with oral anticoagulation agents. Parenteral anticoagulants such as low molecular weight heparins although potentially an alternative for patients with moderate to severe CKD will not be discussed in this update because of lack of expert consensus on their use and their tendency to accumulate in renal dysfunction <1>. Stroke will be the primary clotting risk referred to in this update. Warfarin And Renal Impairment Essay.
Scope of this issue
Over 15 million people in the United States are currently suffering from chronic kidney disease <1,2>. Of this population, approx 530,000 have end-stage renal disease and approximately 370,000 receive maintenance dialysis <1>. Between 0.4-1 percent of the American population suffers from atrial fibrillation, with the rates climbing upto 8% in the elderly above 80 years of age <1,5>.
Atrial fibrillation and CKD are independent risk factors for thromboembolic events. To complicate matters further, AF is common in CKD patients, especially those with end-stage renal disease <1>. For example, in patients with hemodialysis between 8 -34% of patients have a diagnosis of AF <4,6>. Similarly, in patients with peritoneal dialysis, approximately 7% of the patients have a concurrent diagnosis of AF <1,4,6>. The rate of AF in this CKD population is 10-20 times higher than the rate of incidence of AF in the general population <1,8,9>
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Antithrombotic therapy typically used to reduce risk of stroke in AF increases risk of bleeding. This risk is further potentiated by chronic kidney disease. The efficacy and safety of antithombotic agents have not been adequately studied in CKD patients with AF, especially the chronic end-stage renal disease patients, with or without dialysis. In addition, the risk of stroke in patients with AF and CKD increases as their renal function declines <1>. Of note, CKD is not included as a risk factor in the CHADs or CHADs2 score, partly because patients with CKD are rarely included in randomized control trials for treatment and outcomes.Warfarin And Renal Impairment Essay. Similarly, most but not all studies also suggest an increase in the rates of both ischemic and hemorrhagic stroke in CKD patients because of AF. This increase in stroke risk is especially potentiated in dialysis patients with AF<1,5>.
The decision to anticoagulate
The need to carefully balance benefit of anticoagulation given high risk of stroke with the significantly increased risk of bleeding in CKD patients makes the decision to anticoagulate difficult.
Like risk of stroke, worsening renal function is associated with an increase in the risk of bleeding. In a report of 578 warfarin treated patients with CKD, the risk of major hemorrhage was significantly greater in those with severe renal impairment defined as eGFR <30 mls/min vs. those with lesser degrees of impairment<9>. In CKD patients receiving hemodialysis and on warfarin, bleeding rates increased significantly and the use of warfarin was associated with close to a doubling in the rate of bleeding. Of note, most of this bleeding occurred in the gastrointestinal tract <1,10,11>. A Danish registry study further investigated the impact of CKD on the risk of bleeding in patients with AF. Risk of bleeding was found to be higher for patients requiring renal-replacement therapy in this study and for those patients with some degree of CKD (not ESRD) <12>
This increased risk of bleeding is thought to be potentiated by several different mechanisms such as impairment of normal platelet function by uremic toxins, altered von Willebrand factor, abnormal platelet arachidonic acid metabolism, reduction in intracellular ADP and serotonin, as well as an increase in the frequency of the need for invasive procedures in this population<1>. In CKD patients of all stages but especially those on hemodialysis, prothrombotic changes can also occur, making them more likely to coagulatate<1>.
Literature on oral anticoagulants in CKD patients
This section will compare warfarin with the newer oral anticoagulants on the market, namely dabigatran, apixaban and rivaroxaban and outline recommendations for patients with varying degrees of renal impairment. Warfarin And Renal Impairment Essay.
Stage 3 CKD patients (eGFR 30-59 mls/min)
Older trials which compared warfarin to placebo, did not include patients with CKD, thus although this group is thought to receive similar anticoagulation benefit from warfarin, this benefit is only extrapolated <1>. Three trials have studied the safety and efficacy of oral antithrombotic agents in patients with Stage 3 CKD in subgroup analyses. Each of these large randomized trials, namely RE-LY, ARISTOTLE and ROCKET-AF studied the new anticoagulant agents dabigatran, abixaban and rivaroxaban respectively compared to treatment with adjusted dose warfarin to have INR’s between 2.0-3.0. The RE-LY trial found 150mg BID dose dabigatran superior to warfarin while the 110mg BID was noninferior to warfarin. The ARISTOTLE study found apixaban 5mg BID superior to warfarin and rivaroxaban at 15 mg daily was found to be non-inferior to warfarin. ARISTOTLE and ROCKET-AF both found an increased incidence of clotting events in patients with stage 3 CKD in all groups <13,14,15>.
The benefit of anticoagulation in patients with CKD and CHADs score 0 is weak but given the superiority of warfarin over aspirin in RCT’s, oral anticoagulation is preferred over antiplatelets <1>.However, in some patients the increased risk of bleeding given renal dysfunction and anticoagulation may override the benefit and aspirin may be a suitable choice in these patients. In cases where anticoagulation is indicated (CHADs score >0), apixaban/rivaroxaban or dabigatran are preferred over warfain in patients with Stage 3 CKD <1>
Stage 4 CKD patients (eGFR 15-29 mls/min
Since risk of bleeding and clotting increases with declining renal function and most patients with Stage 4 CKD are excluded from big randomized trials, recommendation for the decision to anticoagulate and choice of anticoagulation therapy vary from management in patients with Stage 3 CKD <1>.
In these patients, risk of clotting is thought to exceed that of bleeding irrespective of CHADS2 score and although based on pharmacokinetics parameters, dabigatran 75 mg BID has been approved by the FDA for this population, its use in clinical practice is not recommended <1>. Warfarin is the agent recommended for anticoagulation in this agent because of its historical use and proven efficacy/safety. Warfarin And Renal Impairment Essay. Aspirin is not thought to provide sufficient protection in these patients. However patients with CKD stage 4 on warfarin will need to be educated about risk of bleeding and the need to hold anticoagulation in the event of a bleed <1>.
Stage 5 CKD: End stage renal disease (eGFR less than 15 mls/min) +AF
Stage 5 CKD patients are at an especially increased risk of both bleeding and clotting, rarely studied in clinical trials and have potentially difficulty in gaining access to veins for regular INR monitoring <1>. The results of the few studies looking at warfarin use in this population have yielded mixed results. The results of two retrospective studies of hemodialysis patients with AF demonstrated a potential for an increased risk of stroke in the warfarin group vs. placebo in one study, with the risk increased nearly two fold in the other <1,16,17>. Another report from the US Renal Data System comparing survival in two groups of ESRD patients, one receiving mechanical heart valves and oral anticoagulation and another receiving tissue valves and likely no oral anticoagulation found no difference in survival rates <1,18>.
Anticoagulation with warfarin is recommended in patients with a CHADS2 score of equal to or greater than 1. For patients with a CHADS2 score of 0, recommendations on anticoagulation are mixed. It may be beneficial for carefully selected patients based on clinical judgement <1>.
Warfarin and Renal impairment
Although warfarin is hepatically cleared, studies have found an association with increased bleeding and labile INR’s in patients with declining renal impairment. A study with 565 explored the relationship between renal impairment and warfarin dosing requirement. Patients in this study were stratified by baseline renal function (eGFR ≥60, 30 to 59, or less than 30 mL/min per 1.73 m2) <1,9,10>. Patients with severe CKD had significantly lower warfarin dosage requirements and lower INR’s in range compared to those with lesser degrees of renal impairment. Based on this study and several others, a lower starting dose of 2.5 mg x first two days of initiating warfarin is recommended for patients with CKD and eGFR of less than 30 mls/min <1>.
Clinical Bottom-line
CKD Stage 3: Anticoagulation with rivaroxaban or dabigatran over warfarin in patients with CHADS2 score equal to or greater than 1
CKD Stage 4: Chronic anticoagulation should be considered in patients with AF irrespective of their CHADS2 score. Warfarin And Renal Impairment Essay. Warfarin is the chosen agent in this population
CKD Stage 5: Warfarin is recommended in those with CHADS2 score of equal to or greater than 1 without a very high risk of bleeding, the decision to anticoagulate those with a CHADS2 score of 0 is unclear.
A starting dose of warfarin 2.5 mg daily x 2 days for patients with AF and CKD stage 3 or lower is recommended.
Warfarin, a drug primarily metabolized by the cytochrome P450 system, is initiated at similar doses and managed similarly in patients with kidney impairment as in the general medical population. Unfortunately, few data exist to guide dose adjustment in patients with reduced kidney function. Herein we determine the degree of warfarin dose reduction associated with kidney impairment and make recommendations for warfarin dosing.
Study Design
Cross-sectional analysis.
Setting & Participants
Chronic warfarin users followed at anticoagulation clinics (n=980); 708 participants from the University of Alabama (UAB) and 272 participants from the University of Chicago (UIC).
Predictor
No/mild (eGFR≥60ml/min/1.73 m2), moderate (eGFR=30–59ml/min/1.73 m2) and severe (eGFR<30ml/min/1.73 m2) kidney impairment, CYP2C9 and VKORC1 genotype, age, race, gender, body mass, socio-demographic factors, smoking status, alcohol, vitamin K intake, comorbid conditions (e.g. CHF, etc.) and drug interactions (e.g. amiodarone, statins, etc.).
Outcome & Measurement
Warfarin dose (mg/day) was evaluated using linear regression after adjustment for clinical demographic and genetic factors.
Results
The prevalence of moderate kidney impairment (31.8% and 27.6%) and severe kidney impairment (8.9% and 6.6%) was similar in the UAB and UIC cohorts. Warfarin dose requirements were significantly lower in patients with moderate and severe kidney impairment compared to those with none/mild kidney impairment in the UAB (p<0.001) and UIC (p<0.001) cohorts. Compared to patients with no/mild kidney impairment, patients with moderate kidney impairment required 9.5% lower doses (p<0.001) and patients with severe kidney impairment required 19% lower doses (p<0.001). Warfarin And Renal Impairment Essay.
Limitations
No measurement of warfarin, serum albumin, vitamin K and clotting factor levels, no evaluation of other markers (e.g. cystatin).
Conclusion
Moderate and severe kidney impairment were associated with a reduction in warfarin dose requirements.
Chronic kidney disease (CKD) has emerged as a major public health concern, with about 26 million adults affected in the US.1, 2 These patients are at a substantially increased risk of cardiovascular disease, anemia, and bone disease, and require multiple drugs to treat these complications.3–7 Not surprisingly, drugs with primarily renal excretion require substantial dose reductions in patients with kidney impairment. Warfarin And Renal Impairment Essay. However, even among drugs eliminated primarily by metabolism or non-renal transport, 25% have a ~two-fold increase in area-under-the-curve in patients with severe kidney impairment, requiring significant dose reductions.8 Although the mechanisms of altered pharmacokinetics in kidney impairment are not well understood, animal studies suggest down-regulation of various cytochrome (CYP) enzymes and transporters, thereby influencing the response to drugs with primarily non-renal clearance. 9–11
Warfarin, the most commonly prescribed oral-anticoagulant, exhibits large inter-patient variability in dose requirements.12, 13 Initiation and maintenance of therapy is challenging due to the multitude of factors (diet, medications, genetics, etc.) that influence warfarin pharmacokinetics and pharmacodynamics.12 Although clinicians recognize that anticoagulation management is even more challenging among patients with kidney impairment, warfarin therapy is initiated at similar doses and managed similarly in patients with kidney impairment as in the general medical population.14–16Unfortunately, few published data exist to guide dose adjustments in patients with reduced kidney function. We recently reported that patients with reduced kidney function require lower warfarin doses, even after adjustment for clinical and genetic factors known to affect warfarin metabolism. These observations suggest that warfarin may need to be instituted at a lower dose in patients with moderate or severe kidney impairment, as compared to those with mild/no kidney impairment.17
This secondary cross-sectional analysis assesses the degree of warfarin dose reduction associated with moderate or severe kidney impairment in two independent cohorts and derives recommendations for warfarin dosing in patients with kidney impairment. Warfarin And Renal Impairment Essay.
Methods
Cohorts
University of Alabama at Birmingham (UAB) cohort
The Pharmacogenetic Optimization of Anticoagulation Therapy (POAT) and the Genetic and Environmental Determinants of Warfarin (GEDWR) are ongoing prospective cohort studies aimed at defining the influence of polymorphisms in CYP2C9 and other genes on warfarin response. Patients ≥20 years of age were considered eligible if the intended duration of anticoagulation therapy was ≥ 2 years, therapy was managed at the anticoagulation clinic and the INR was 2–3. The study was conducted under the approval of the Institutional Review Boards of the University of Alabama at Birmingham and Jefferson County Health System.
University of Illinois in Chicago (UIC) cohort
The UIC cohort comprised of participants ≥18 years of age who achieved stable warfarin dosing, defined as the dose that produced stable anticoagulation (INR within 0.2 units of the therapeutic range) for at least 3 consecutive clinic visits. The patients were recruited at the University of Illinois at Chicago (UIC) under the approval of the Institutional Review Board. Patients with a documented history of liver dysfunction or amiotransferase levels at least twice the upper limit of normal were excluded.
Data Collection
A detailed history documented clinical information including self-reported race, age, height and weight, serum urea nitrogen (SUN), serum creatinine (SCr), warfarin dose, INR, indication for therapy, co-morbid conditions, medications, smoking, alcohol use as detailed in recent publications.18, 19 Concurrent therapy with medications such as non-steroidal anti-inflammatory drugs (NSAIDs) or antiplatelet agents or drugs that alter warfarin pharmacokinetics including CYP2C9 inhibitors (e.g. amiodarone), CYP2C9inducers (e.g. rifampin), or CYP2C9 substrates (e.g. losartan) 20, 21 were documented. Both cohorts documented information on clinical, demographic and genetic factors in a similar fashion. Warfarin And Renal Impairment Essay.
Kidney function
The glomerular filtration rate (eGFR) was estimated by using the 4-variable MDRD Study equation.22 Patients were categorized into 3 groups based on eGFR as recommended by the National Kidney Foundation. Patients with eGFR ≥60 ml/min/1.73 m2 were categorized as having no/mild kidney impairment, those with eGFR =30–59 ml/min/1.73 m2 were categorized as having moderate kidney impairment and those with eGFR <30 ml/min/1.73 m2 were categorized as having severe kidney impairment. Patients receiving maintenance dialysis were categorized as having severe kidney impairment.23, 24
CYP2C9 and VKORC1 Genotypes
Genotypes were determined using PCR-RFLP (polymerase chain reaction– restriction fragment length polymorphism) analysis, pyrosequencing, and iPLEX technology (a single-base extension multiplex PCR assay with mass spectrometric readout from Sequenom Inc [www.sequenom.com], and performed at the Broad Institute [Cambridge, MA]) from DNA extracted from whole blood or buccal cells as detailed in recent manuscripts.19, 25, 26 Specifically, in the CYP2CP gene, we assessed the single-nucleotide polymorphisms (SNPs) with reference SNP (rs) identification numbers rs1799853, rs1057910, rs28371686, rs9332131, and rs28371685. These correspond to CYP2C9 alleles *2, *3, *5, *6, and *11, respectively, which are polymorphisms 430C/T, 1075A/C, 1080C/G, 818delA, and 1003C/T in the CYP2C9 cDNA. In the VKORC1gene (which encodes vitamin K epoxide reductase complex, subunit 1), we assessed SNPs −1639G>A (rs9923231) and 1173C/T(rs9934438).
Outcome Definitions and Statistical Methods
Analysis of variance was used to assess group differences for continuous variables and χ2 test of independence for categorical variables. The assumption of Hardy-Weinberg equilibrium was tested using the χ2 test of independence.
Warfarin dosewas defined as the average mainte nance dose required to maintain therapeutic anticoagulation for the duration of therapy (UAB cohort) or the dose that produced stable anticoagulation for at least 3 consecutive clinic visits (UIC cohort). Warfarin And Renal Impairment Essay.To improve model fit and limit heteroscedascity, we used a logarithmic transformation of warfarin dose. Evaluation of the effects of individual predictor variables on warfarin dose employed both univariate and multivariable linear regression.
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Linear-regression analysis was conducted to assess the influence of CKD, CYP2C9 and VKORC1 genotype, age, race, gender, body mass, socio-demographic factors, smoking status, alcohol, vitamin K intake, comorbid conditions (e.g. CHF, etc.) and drug interactions (amiodarone and statins). Backward elimination technique was used to select influential predictors (p<0.2). CYP2C9 and VKORC1 genotypes were assessed in both additive and dominant models. To assess model fit, we examined residuals, and median prediction error (mg/day). The influence of predictor variables was determined in the UAB cohort and UIC cohorts separately and then combined the two data sets to perform analysis (as described above) to provide robust estimates of the influence of genetic and clinical predictors. All analyses were performed using SAS version 9.1 (SAS Institute, www.sas.com) at a non-directional alpha level of 0.05.
Results
Of the 797 eligible participants at the University of Alabama at Birmingham (UAB cohort), 76 participants (9.5%) declined participation in the study, and thirteen were excluded due to missing serum creatinine values. The remaining 708 participants (mean age 61±15 years, 50.0% men) comprised the UAB cohort (327 African Americans, 377 European Americans, 3 Hispanic and 1 Asian). Of the 303 eligible participants at UIC, 31 (10.2%) declined participation. The UIC cohort (n=272) was comprised of 207 African Americans, 23 European Americans, 42 Hispanic participants (mean age 56±16 years, 25.7% men).
Clinical, demographic and genetic characteristics for participants are presented in Table 1. Genotype distributions for CYP2C9 and VKORC1 were in within each race group (all p-values >0.2). As reported previously, European Americans had a higher frequency of variant CYP2C9 (35.4%) and VKORC1 1173 (59.7%)genotypes as compared to African Americans (11.2% and 18.4%, respectively <0.001). Genotype frequencies did not differ across GFR categories (Table 1). Warfarin And Renal Impairment Essay.
