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. 2009;302(22):2458-2464 (doi:10.1001/jama.2009.1800)
JAMA
Thomas T. Tsai; Thomas M. Maddox; Matthew T. Roe; et al.
Undergoing Percutaneous Coronary Intervention
Contraindicated Medication Use in Dialysis Patients
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Contraindicated Medication Use
in Dialysis Patients Undergoing
Percutaneous Coronary Intervention
Thomas T. Tsai, MD, MSc Thomas M. Maddox, MD, MSc Matthew T. Roe, MD, MHS David Dai, PhD Karen P. Alexander, MD P. Michael Ho, MD, PhD John C. Messenger, MD Brahmajee K. Nallamothu, MD, MPH Eric D. Peterson, MD, MPH John S. Rumsfeld, MD, PhDfor the National Cardiovascular Data Registry
I
N THE UNITEDSTATES, MEDICA -tion errors are implicated in more than 100 000 deaths annu-ally.1Medication errors includeadverse drug reactions related to inappropriately prescribed or admin-istered drugs.2To minimize
inappro-priate medication use, the US Food and Drug Administration (FDA) guides pharmaceutical manufacturers and clinicians through drug labeling of which medications are contraindi-cated or not recommended for use in specific patient groups. Few studies have evaluated the frequency of use and association between receipt of these medications and outcomes in clinical practice.
Patients receiving dialysis are an in-creasing population, projected to ex-ceed 2 million patients worldwide by 2010.3Since many medications are
eliminated through the kidneys,
dialy-sis patients are at elevated risk of medi-cation-related adverse events.4-7Thus,
many medications are contraindi-cated in dialysis patients.
A particularly challenging area of treatment of dialysis patients is percu-taneous coronary intervention (PCI) be-cause several antithrombotic medica-tions are not recommended for use in dialysis patients. Eptifibatide, a plate-let glycoprotein IIb/IIIa inhibitor, is
re-Author Affiliations: Denver VA Medical Center,
Denver, Colorado (Drs Tsai, Maddox, Ho, and Rumsfeld); University of Colorado Denver (Drs Tsai, Maddox, Ho, Messenger, and Rumsfeld); Colorado Cardiovascular Outcomes Research Group, Denver (Drs Tsai, Maddox, Ho, and Rumsfeld); Duke Uni-versity Medical Center, Duke Clinical Research Institute, Durham, North Carolina (Drs Roe, Dai, Alexander, and Peterson); and Ann Arbor VA Medi-cal Center, University of Michigan Hospital, Ann Arbor (Dr Nallamothu).
Corresponding Author: Thomas T. Tsai, MD, MSc,
Denver VA Medical Center, Cardiology Section 111B, 1055 Clermont St, Denver, CO 80220 (thomas.tsai @va.gov).
Context The US Food and Drug Administration guides clinicians through drug
la-beling of medications that are contraindicated or not recommended for use in specific patient groups. Little is known about the use of such medications and their effects on outcomes in clinical practice.
Objective To investigate the use of the contraindicated/not-recommended agents
enoxaparin and eptifibatide among dialysis patients undergoing percutaneous coro-nary intervention (PCI) and their association with outcomes.
Design, Setting, and Participants Data from 829 US hospitals on 22 778 dialysis
patients who underwent PCI between January 1, 2004, and August 31, 2008.
Main Outcome Measures In-hospital bleeding and death.
Results Five thousand eighty-four patients (22.3%) received a contraindicated
an-tithrombotic; of these patients, 2375 (46.7%) received enoxaparin, 3261 (64.1%) re-ceived eptifibatide, and 552 (10.9%) rere-ceived both. Compared with patients who did not receive a contraindicated antithrombotic, patients who did had higher rates of in-hospital bleeding (5.6% vs 2.9%; odds ratio [OR], 1.93; 95% confidence interval [CI],1.66-2.23) and death (6.5% vs 3.9%; OR, 1.68; 95% CI, 1.46-1.95). After mul-tivariable adjustment, patients receiving contraindicated antithrombotics had signifi-cantly higher risks of in-hospital bleeding (OR, 1.66; 95% CI, 1.43-1.92) and death (OR, 1.24; 95% CI, 1.04-1.48). In 10 158 patients matched by propensity scores, re-ceipt of contraindicated antithrombotics remained significantly associated with in-hospital bleeding (OR, 1.63; 95% CI, 1.35-1.98) but not in-in-hospital death (OR, 1.15; 95% CI, 0.97-1.36).
Conclusions In a sample of dialysis patients undergoing PCI, 22.3% received a
contraindicated antithrombotic medication. In propensity-matched analysis, receipt of these medications was significantly associated with an increased risk of in-hospital major bleeding.
nally cleared and its use contraindi-cated in dialysis patients because of increased bleeding risk. Similarly, enoxaparin, a low-molecular-weight heparin, is an anticoagulant that is re-nally cleared and its use not recom-mended in dialysis patients because of the risk of bleeding complications.8-10
Non–renally cleared antithrombotic al-ternative medications are available, such as abciximab and unfractionated hep-arin.
The extent to which contraincated antithrombotics are used in di-alysis patients undergoing PCI and the association between use of these medi-cations and clinical outcomes is un-known. Using data from the National Cardiovascular Data Registry (NCDR), we evaluated the frequency with which enoxaparin, eptifibatide, or both were administered to dialysis patients un-dergoing PCI, and we examined the as-sociation between the receipt of these medications and in-hospital bleeding and death.
METHODS
Study Population
The NCDR CathPCI registry, cospon-sored by the American College of Car-diology (ACC) and the Society for Cardiovascular Angiography and Interventions, has been previously described.11,12The registry catalogs
data on patient and hospital charac-teristics, clinical presentation, treat-ments, and outcomes for PCI proce-dures from more than 800 sites across the United States. Data are entered into NCDR-certified software at par-ticipating institutions and exported in a standard format to the ACC. There is a comprehensive data quality pro-gram, including both data quality report specifications for data capture and transmission and an auditing pro-gram. The definitions variables were prospectively defined by a committee of the ACC and are available at http: //www.ncdr.com. Race/ethnicity data were recorded by chart abstractors as part of the standard case report form. The options were Caucasian, black, His-panic, Asian, Native American, and
other. In our analysis, patients were cat-egorized as white or nonwhite race (black, Hispanic, Asian, Native Ameri-can, and other).
This study included all dialysis patients undergoing PCI who were treated with 1 or more antithrombotic agents. Between January 1, 2004, and August 31, 2008, 1 357 758 PCI
patients from 829 hospitals were enrolled in the CathPCI registry, among whom 24 656 (1.8%) were receiving chronic dialysis. We then excluded those patients receiving war-farin (n = 1362; 5.5%) because of its unknown influence on antithrom-botic choices and other infrequently used antithrombotics, tirofiban
Table 1. Baseline Characteristics of the Study Cohort
Variable No. (%) P Value Overall (N = 22 778) Contraindicated Antithrombotics (n = 5084) Noncontraindicated Antithrombotics (n = 17 694) Demographics Age, mean (SD), y 63.9 (11.9) 64.1 (12.1) 63.8 (11.8) .03 Age, median (interquartile range), y 64.0 (56-73) 64.0 (56-74) 64.0 (56-73) .03 Female sex 9280 (40.7) 2147 (42.2) 7133 (40.3) .01 Nonwhite race 9118 (40.0) 1896 (37.2) 7222 (40.8) ⬍.001 Comorbidities Hypertension 21 221 (93.2) 4708 (92.6) 16 513 (93.3) .07 Dyslipidemia 16 481 (72.4) 3601 (70.8) 12 880 (72.8) .006 Diabetes 15 805 (69.4) 3451 (67.9) 12 354 (69.8) .008 Previous PCI 8957 (39.3) 1895 (37.3) 7062 (39.9) ⬍.001 Previous congestive heart failure 8385 (36.8) 1975 (38.9) 6410 (36.2) ⬍.001 Previous myocardial infarction 8208 (36.1) 1875 (36.9) 6333 (35.8) .16 Peripheral vascular disease 7471 (32.8) 1749 (34.4) 5722 (32.3) .006 Previous CABG 5606 (24.6) 1283 (25.2) 4323 (24.4) .24 Cerebrovascular disease 5224 (22.9) 1220 (24.0) 4004 (22.6) .04 Chronic lung disease 4849 (21.3) 1242 (24.4) 3607 (20.4) ⬍.001 Active tobacco use 3405 (15.0) 857 (16.9) 2548 (14.4) ⬍.001 Symptoms and conditions
at presentation
No symptoms 5178 (22.7) 783 (15.4) 4395 (24.8) Atypical chest pain 1672 (7.3) 311 (6.1) 1361 (7.7) Stable angina 2688 (11.8) 381 (7.5) 2307 (13.0)
⬍.001 ACS: unstable angina 6717 (29.5) 1509 (29.7) 5208 (29.4)
ACS: non-STEMI 5038 (22.1) 1578 (31.0) 3460 (19.6) ACS: STEMI 1482 (6.5) 522 (10.3) 960 (5.4)
Congestive heart failure 6317 (27.7) 1702 (33.5) 4615 (26.1) ⬍.001 Cardiogenic shock 821 (3.6) 254 (5.0) 567 (3.2) ⬍.001 Treatment variables
Intra-aortic balloon pump 672 (3.0) 235 (4.6) 437 (2.5) ⬍.001 Multivessel PCI 3955 (17.4) 946 (18.6) 3009 (17.0) .008 Drug-eluting stent use 14 593 (64.1) 3240 (63.7) 11 353 (64.2) .85 Preprocedure TIMI flow
Complete 13 317 (58.5) 2619 (51.5) 10 698 (60.5) Partial 4700 (20.6) 1134 (22.3) 3566 (20.2)
⬍.001 Slow 2463 (10.8) 653 (12.8) 1810 (10.2)
None 2130 (9.4) 633 (12.5) 1497 (8.5) Postprocedure TIMI flow
Complete 21 706 (95.3) 4819 (94.8) 16 887 (95.4) Partial 434 (1.9) 118 (2.3) 316 (1.8) .08 Slow 159 (0.7) 39 (0.8) 120 (0.7) None 398 (1.8) 84 (1.7) 314 (1.8) (continued)
(n = 126; 0.51%), argatroban (n = 70; 0.28%), lepirudin (n = 23; 0.09%), thrombolytics (n = 189; 0.77%), dalteparin (n=67; 0.27%), and nadro-parin (n = 41; 0.17%), to decrease heterogeneity in the comparison groups. The final analytic cohort was 22 778 dialysis patients undergoing PCI.
Variables
The independent variables of interest were receipt of eptifibatide, enoxapa-rin, or both. Eptifibatide is contraindi-cated in dialysis patients because it is predominantly renally cleared and is associated with an increased risk of bleeding. The manufacturer’s package insert states treatment with eptifi-batide is contraindicated in patients with dependency on renal dialysis; dosing information for dialysis patients is excluded. Pharmacologic references such as Lexi-Comp also state that dialysis is a contraindication to its use.1 3 Enoxaparin similarly
has predominantly renal clearance
and an associated increased risk o f b l e e d i n g a m o n g p a t i e n t s o n dialysis.8-10The warnings and
precau-tions section of the package insert states that its use in patients with renal impairment has been associated with hyperkalemia and increased bleeding; dosing information for dialysis patients is excluded. Pharmacologic references such as Lexi-Comp do not recommend its use, noting that enoxa-parin has not been FDA approved for use in dialysis patients and that seri-ous bleeding complications have been reported with use in patients who are dialysis dependent.13
The study outcomes were in-hospital major bleeding and all-cause in-hospital death. In-hospital major bleeding is defined in NCDR as bleed-ing requirbleed-ing a transfusion, prolong-ing the hospital stay, or causprolong-ing a de-crease in hemoglobin of more than 3 g/dL at 1 or more of the following sites: percutaneous entry site, retroperito-neum, gastrointestinal, genital-urinary, or other/unknown.
Statistical Analysis
P a t i e n t s w e r e c l a s s i f i e d i n t o 2 groups: receipt of enoxaparin and/or eptifibatide or receipt of noncontra-indicated antithrombotics (unfrac-tionated heparin, bivalirudin, or abciximab). Differences between groups were compared using2tests
for categorical variables and the Wil-coxon rank sum or Kruskal-Wallis test for continuous variables.
To assess the association between contraindicated antithrombotics and in-hospital major bleeding and death, we used multivariable analysis with gen-eralized estimating equations to ad-just for potential confounders and within-hospital correlations. Vari-ables from the NCDR PCI mortality model1 4 and NCDR PCI bleeding
model15were used for in-hospital
mor-tality risk adjustment and in-hospital major bleeding risk adjustment, respec-tively. Patients transferred to another hospital were excluded from the death analysis; patients who died the same day as the procedure were excluded from the bleeding analysis.
We also developed a propensity score for the receipt of contraindicated anti-thrombotics using variables from the NCDR PCI mortality model.13Based on
the estimated logits, we selected matched pairs, conducted a McNemar test to determine whether in-hospital major bleeding or death was different between patient groups, and com-puted an odds ratio (OR) to test the as-sociation between contraindicated an-tithrombotics and in-hospital major bleeding or death.
In secondary analyses, multivariable regression analyses were repeated within the anticoagulant and anti-platelet medication classes. To evalu-ate the association of enoxaparin with outcomes, we restricted the cohort to patients who received the anticoagulants bivalirudin, enoxapa-rin, or unfractionated hepaenoxapa-rin, adjusting for receipt of antiplatelet agents. To evaluate the association of eptifibatide with outcomes, we restricted the cohort to patients who received eptifibatide or abciximab,
Table 1. Baseline Characteristics of the Study Cohort (continued)
Variable No. (%) P Value Overall (N = 22 778) Contraindicated Antithrombotics (n = 5084) Noncontraindicated Antithrombotics (n = 17 694) Hospital variables No. of beds ⬍200 1660 (7.3) 437 (8.6) 1223 (6.9) ⱖ200-⬍400 7271 (31.9) 1773 (34.9) 5498 (31.1) ⬍.001 ⱖ400-⬍600 7754 (34.0) 1735 (34.1) 6019 (34.0) ⱖ600 6093 (26.8) 1139 (22.4) 4954 (28.0) Location/community type Rural 2258 (9.9) 673 (13.2) 1585 (9.0) Suburban 5622 (24.7) 1286 (25.3) 4336 (24.5) ⬍.001 Urban 14 898 (65.4) 3125 (61.5) 11 773 (66.5) Profit type Government 297 (1.3) 60 (1.2) 237 (1.3) Private/community 19 548 (85.8) 4647 (91.4) 14 901 (84.2) ⬍.001 University 2933 (12.9) 377 (7.4) 2556 (14.5) Training program 12 556 (55.1) 2599 (51.1) 9957 (56.3) Average annual PCI volume
⬍500 5099 (22.4) 1344 (26.4) 3755 (21.2) ⱖ500-⬍1000 8157 (35.8) 1922 (37.8) 6235 (35.2)
ⱖ1000-⬍1500 4156 (18.3) 796 (15.7) 3360 (19.0) ⬍.001 ⱖ1500-⬍2000 3039 (13.3) 608 (12.0) 2431 (13.7)
ⱖ2000 2327 (10.2) 414 (8.1) 1913 (10.8)
Abbreviations: ACS, acute coronary syndrome; CABG, coronary artery bypass graft: PCI, percutaneous coronary inter-vention; STEMI, ST-segment elevation myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction.
adjusting for receipt of anticoagu-lants. Then, the association between receipt of contraindicated antithrom-botics and outcomes was assessed in strata of patients who underwent PCI in the setting of an acute coronary syndrome (ACS) vs non-ACS PCI. A first-order interaction was assessed for ACS status and outcome. Analy-ses were performed using SAS soft-ware version 9.0 (SAS Institute, Cary, North Carolina).
This study was reviewed by the Duke University Health System insti-tutional review board and was deter-mined to meet the definition of research not involving human sub-jects.
RESULTS
Baseline characteristics of the study population are shown in TABLE 1.
Patients receiving a contraindicated antithrombotic were more likely to have heart failure, lung disease, or active tobacco use; to present with ACS; and to be cared for at private or community centers with lower pro-cedural volume. Patients who did not receive a contraindicated antithrom-botic were more likely to have non-white race, diabetes, and history of prior PCI and to be treated at centers that were urban, had training pro-grams, and had higher procedural volume.
Overall, 5084 patients (22.3%) re-ceived a contraindicated antithrom-botic medication; 2375 (46.7%) re-ceived enoxaparin, 3261 (64.1%) received eptifibatide, and 552 (10.9%) received both. In the overall cohort, in-hospital major bleeding occurred in 3.6% (805/22 778) and in-hospital death occurred in 4.5% (963/22 778).
TABLE2 shows the frequency of major
bleeding sites stratified by the receipt of a contraindicated antithrombotic. Gastrointestinal bleeding is the most prevalent cause of bleeding in patients who received a contraindicated anti-thrombotic, whereas percutaneous bleeding was the most prevalent cause in those who did not receive a contra-indicated antithrombotic.
Approxi-mately one-third of patients had an al-ternative or unknown site of bleeding.
TABLE 3 shows the causes of
in-hospital death. As expected, most deaths were due to cardiac causes, and the data do not differentiate hemor-rhage-related deaths.
In unadjusted analysis, patients who received contraindicated anti-thrombotics experienced higher rates of in-hospital major bleeding (5.6% vs 2.9%; OR, 1.93; 95% confidence interval [CI], 1.66-2.23) and death (6.5% vs. 3.9%; OR, 1.68; 95% CI, 1.46-1.95). With multivariable regression analysis, there remained a significantly increased risk of major bleeding (adjusted OR, 1.66; 95% CI, 1.43-1.92) and death (adjusted OR, 1.24; 95% CI, 1.04-1.48) associated
with the use of contraindicated anti-thrombotics (FIGURE1).
The propensity analysis yielded 5079 matched pairs; baseline charac-teristics of these patients were well balanced without any significant dif-ferences. In the propensity-matched cohort, receipt of contraindicated antithrombotics was significantly associated with increased in-hospital major bleeding (OR, 1.63; 95% CI, 1.35-1.98), but no significant asso-ciation was found with in-hospital death (OR, 1.15; 95% CI, 0.97-1.36) (Figure 1).
In secondary analyses within anti-coagulant and antiplatelet classes, patients receiving enoxaparin had significantly higher rates of in-hospital major bleeding (5.0% vs
Table 2. Site of Major Bleedinga
Bleeding Site No. (%) P Value Total (n = 805) Contraindicated Antithrombotics (n = 280) No Contraindicated Antithrombotics (n = 525) Percutaneous entry site No 545 (67.70) 209 (74.64) 336 (64.00)
.002 Yes 260 (32.30) 71 (25.36) 189 (36.00) Retroperitoneal No 761 (94.53) 267 (95.36) 494 (94.10) .45 Yes 44 (5.47) 13 (4.64) 31 (5.90) Gastrointestinal No 557 (69.19) 169 (60.36) 388 (73.90) ⬍.001 Yes 248 (30.81) 111 (39.64) 137 (26.10) Genital-urinary No 781 (97.02) 271 (96.79) 510 (97.14) .78 Yes 24 (2.98) 9 (3.21) 15 (2.86) Other or unknown No 539 (66.96) 188 (67.14) 351 (66.86) .94 Yes 266 (33.04) 92 (32.86) 174 (33.14)
aCentral nervous system hemorrhage was not included in the major bleeding end point because it was included as
stroke in the complications section on the data form, which did not distinguish between hemorrhagic and ischemic strokes.
Table 3. Primary Cause of In-Hospital Deatha
Cause of Death No. (%) Total (n = 963) Contraindicated Antithrombotics (n = 306) No Contraindicated Antithrombotics (n = 657) Cardiac 621 (64.5) 193 (63.1) 428 (65.1) Neurologic 40 (4.2) 16 (5.2) 24 (3.7) Renal 54 (5.6) 12 (3.9) 42 (6.4) Vascular 18 (1.9) 5 (1.6) 13 (2.0) Infection 56 (5.8) 15 (4.9) 41 (6.2) Pulmonary 77 (8.0) 27 (8.8) 50 (7.6) Valvular 2 (0.2) 0 2 (0.3) Other 54 (5.6) 21 (6.9) 33 (5.0) Unknown 41 (4.3) 17 (5.6) 24 (3.7)
aP = .40 for all comparisons.
3.9% vs 3.0%, P⬍ .001) and death (6.0% vs 5.4% vs 3.0%, P⬍ .001) compared with patients who re-ceived unfractionated heparin or bivalirudin, respectively. After risk
adjustment, receipt of enoxaparin remained associated with in-hospital major bleeding (adjusted OR, 1.28; 95% CI, 1.04-1.59) and in-hospital death (adjusted OR, 1.35; 95% CI,
1.06-1.72) compared with unfrac-tionated heparin. Compared with patients who received bivalirudin, patients receiving enoxaparin did not have a significantly higher risk of major bleeding (adjusted OR, 1.17; 95% CI, 0.93-1.47) but had a significantly higher risk of death (adjusted OR, 1.44; 95% CI, 1.11-1.88). The use of eptifibatide was not significantly associated with a higher risk of unadjusted in-hospital major bleeding (6.2% vs 5.4%; OR, 1.20; 95% CI, 0.93-1.54) or death (6.8% vs 7.1%; OR, 0.96; 95% CI, 0.76-1.20). After adjustment, the use of eptifibatide was not signifi-cantly associated with in-hospital major bleeding (adjusted OR, 1.23; 95% CI, 0.95-1.61) or in-hospital death (adjusted OR, 1.04; 95% CI, 0.78-1.37).
In analyses stratified by ACS status, among patients undergoing PCI in the setting of ACS, the use of any contra-indicated antithrombotic (adjusted OR, 1.82; 95% CI, 1.52-2.17), enoxa-parin vs unfractionated heenoxa-parin (ad-justed OR, 1.28; 95% CI, 1.01-1.62), or eptifibatide vs abciximab (adjusted OR, 1.39; 95% CI, 1.04-1.85) was associated with an increased risk o f i n - h o s p i t a l m a j o r b l e e d i n g (FIGURE2). Similarly, the use of any
contraindicated antithrombotic (ad-justed OR, 1.20; 95% CI, 1.00-1.46), enoxaparin vs unfractionated heparin (adjusted OR, 1.36; 95% CI, 1.05-1.74), or enoxaparin vs bivalirudin (adjusted OR, 1.51; 95% CI, 1.15-1.98) was associated with an increase in in-hospital death. However, there was no significant association with in-hospital major bleeding in the enoxaparin vs bivalirudin group (ad-justed OR, 1.14; 95% CI, 0.88-1.47) or with in-hospital death in the epti-fibatide vs abciximab group (ad-justed OR, 1.13; 95% CI, 0.84-1.51). In the non-ACS PCI strata, all com-parisons were nonsignificant (data not shown); however, the test for interaction was nonsignificant, and thus effect modification by ACS sta-tus was not confirmed.
Figure 1. Multivariable and Propensity Odds Ratios of In-Hospital Death and In-Hospital Bleeding Increased Bleeding 1 2 0.5 OR (95% CI) Increased Death 1 2 0.5 OR (95% CI) 306/4727 305/4723
No. of Events/No. of Patients In-hospital bleeding Contraindicated Antithrombotics 280/5041 279/5036 No Contraindicated Antithrombotics 525/17 596 179/5036 657/16 727 268/4718 Multivariable analysis Propensity analysis Multivariable analysis Propensity analysis OR (95% CI) 1.66 (1.43-1.92) 1.63 (1.35-1.98) No. of Events/No. of Patients
In-hospital death Contraindicated Antithrombotics No Contraindicated Antithrombotics OR (95% CI) 1.24 (1.04-1.48) 1.15 (0.97-1.36)
OR indicates odds ratio; CI, confidence interval.
Figure 2. Multivariable-Adjusted Odds Ratios of In-Hospital Bleeding and In-Hospital Death in Patients With Acute Coronary Syndrome
In-hospital bleeding Increased Bleeding 1 2 0.5 OR (95% CI) No. of Events/No. of Patients OR (95% CI) 229/3309 335/9598 Contraindicated antithrombotics No contraindicated antithrombotics 1.82 (1.52-2.17) 94/1839 407/6013 Enoxaparin Unfractionated heparin 1.28 (1.01-1.62) 94/1839 193/4361 Enoxaparin Bivalirudin 1.14 (0.88-1.47) 167/2208 112/1777 Eptifibatide Abciximab 1.39 (1.04-1.85) In-hospital death Increased Death 1 2 0.5 OR (95% CI) No. of Events/No. of Patients OR (95% CI) 261/3309 519/9598 Contraindicated antithrombotics No contraindicated antithrombotics 1.20 (1.00-1.46) 112/1839 559/6013 Enoxaparin Unfractionated heparin 1.36 (1.05-1.74) 112/1839 228/4361 Enoxaparin Bivalirudin 1.51 (1.15-1.98) 178/2208 151/1777 Eptifibatide Abciximab 1.13 (0.84-1.51)
COMMENT
Using data from the NCDR, we found that approximately 20% of dialysis pa-tients undergoing PCI received enoxa-parin, eptifibatide, or both, which are contraindicated or not recommended for use in patients receiving dialysis. In risk-adjusted analyses, the use of these medications was associated with in-creased in-hospital major bleeding and possibly in-hospital death. These find-ings were consistent in the overall co-hort using multivariable regression and in a propensity-matched cohort analy-sis. The associations were particularly evident among patients undergoing PCI in the setting of ACS. This study there-fore demonstrates that these medica-tions are used in clinical practice de-spite FDA-directed labeling, and their use is associated with adverse patient outcomes.
The results of this study illustrate the problem of medication errors in the United States, as well as the need to make patient safety a priority on the health care agenda.16Few prior
studies have evaluated this aspect of medication errors, namely the use of contraindicated medications in spe-cific patient subgroups and the asso-ciation of such medication use with patient outcomes. Among patients receiving chronic dialysis, prior stud-ies have identified inappropriate medication dosing and selection in ambulatory dialysis centers.7 , 1 7 , 1 8
These studies have been limited by small numbers of patients, and the association between receipt of medi-cations and outcomes has been largely unknown. The current study is the first, to our knowledge, to evaluate the increasing population of dialysis patients undergoing PCI with regard to receipt of contraindicated medica-tions and their outcomes.
There are several potential reasons for the use of enoxaparin and eptifi-batide among dialysis patients under-going PCI. One is the ease of adminis-tration of enoxaparin compared with unfractionated heparin. Enoxaparin is administered either as an intravenous bolus or a subcutaneous injection
without a continuous intravenous drip, which simplifies emergency and inpatient management as well as transfer protocols. As a result, enoxa-parin is a common drug choice in pre-printed order sets for ACS manage-m e n t . S e c o n d , c o manage-m p a r e d w i t h abciximab, eptifibatide is often less expensive and more widely available in many hospitals and has generally become the predominant glycoprotein inhibitor for PCI.19 Third, despite
FDA-guided warnings in the medica-tion package inserts and Internet-based pharmacy resources noting that these agents are not recommended for use in dialysis patients,13 there is a
paucity of direct evidence from clini-cal trial data regarding the use of these agents because dialysis patients are usually excluded from such trials. Moreover, there have been no previ-ous large studies on the use and out-comes of these agents in routine clini-cal practice. The lack of trial evidence and prior studies may have contrib-uted to the use of these agents despite labeling.
There are several important consid-erations when interpreting the results of this study. First, patients and hos-pitals participating in the NCDR may not be representative of all US prac-tice. However, the CathPCI registry rep-resents more than 800 hospitals across the United States and thus captures a significant portion of PCI procedures nationally. Furthermore, hospitals en-rolled in registry programs like Cath-PCI may be more committed to qual-ity assurance, which could mean that the use of contraindicated antithrom-botics in dialysis patients found in this study is underestimated. Second, the CathPCI registry does not capture the dosage or timing (before or during the PCI laboratory visit) of medica-tion administramedica-tion and cannot evalu-ate for dosing errors or distinguish be-tween patients who received more than 1 class of antithrombotic medication at the same time or in succession (ie, on admission and then in the catheteriza-tion laboratory). However, eptifi-batide and enoxaparin, independent of
their dose and timing of administra-tion, are considered contraindicated in dialysis patients.
Third, as in all observational stud-ies, unmeasured confounders that could influence the receipt of contraindi-cated antithrombotics must be consid-ered. However, a wide array of vari-ables was available for risk adjustment, and multivariable regression in the overall cohort and the propensity-matched analysis yielded similar re-sults. Fourth, hemorrhagic strokes were not differentiated from ischemic strokes on the data collection form and thus were not included in the major bleed-ing end point. The rate of bleedbleed-ing events may therefore be underesti-mated. Fifth, we were unable to assess long-term outcomes following dis-charge. However, the CathPCI regis-try, with its large numbers of patients, is well suited to address safety issues in patient subsets poorly represented in smaller registries. Finally, this study does not attempt to define the optimal antithrombotic therapy in dialysis pa-tients undergoing PCI. However, our study addresses a clinically relevant safety issue in a growing subset of pa-tients undergoing PCI.
CONCLUSIONS
In a large national cohort study, we found that approximately 20% of di-alysis patients undergoing PCI re-ceived eptifibatide or enoxaparin. The use of these medications was associ-ated with increased risk of in-hospital major bleeding. These results appear to validate the FDA-directed labeling of eptifibatide and enoxaparin as contra-indicated or not recommended for use in dialysis patients. Because non– renally cleared antithrombotic alterna-tives are available, this study supports avoiding the use of enoxaparin and ep-tifibatide in dialysis patients undergo-ing PCI. Educational efforts targetundergo-ing clinicians who prescribe these medica-tions and quality improvement inter-ventions, such as amending clinical pathway order sets to include consid-eration of renal function, are urgently needed.
Author Contributions: Dr Tsai had full access to all
of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design:Tsai, Ho, Rumsfeld.
Acquisition of data:Roe.
Analysis and interpretation of data:Tsai, Maddox, Roe, Dai, Alexander, Messenger, Nallamothu, Peterson.
Drafting of the manuscript:Tsai, Maddox, Dai.
Critical revision of the manuscript for important intellectual content:Tsai, Roe, Alexander, Ho, Messenger, Nallamothu, Peterson, Rumsfeld.
Statistical analysis:Dai.
Administrative, technical, or material support:Tsai, Roe, Ho, Messenger, Rumsfeld.
Study supervision:Maddox, Roe, Ho, Messenger, Rumsfeld.
Financial Disclosures: Dr Roe reported receiving
sig-nificant research support from Bristol-Meyers Squibb, Sanofi-Aventis, Schering Plough, and Eli Lilly and serv-ing as a consultant to Scherserv-ing Plough and the speak-ers’ bureaus for Schering Plough, Bristol-Meyers Squibb, and Sanofi-Aventis. Dr Peterson reported receiving sig-nificant research support from the partnership be-tween Bristol-Myers Squibb and Sanofi and from Sch-ering Plough. No other disclosures were reported.
Funding/Support: This analysis was funded by the
NCDR CathPCI Registry, which oversees the collec-tion and management of data in the registry. Dr Ho is supported by a VA Health Services Research and De-velopment Service (HSR&D) Career DeDe-velopment Award.
Role of the Sponsor: The funding agency had no role
in the design and conduct of the study; in the analysis and interpretation of the data; or in the preparation of the manuscript. The Research and Publications com-mittee for the NCDR CathPCI Registry reviewed and approved the final version of the manuscript.
Disclaimer: Dr Peterson, a contributing editor for
JAMA, was not involved in the editorial review of or the decision to publish this article.
Previous Presentation: Presented in part at the 2009
Scientific Sessions of the American Heart Associa-tion; November 14-18, 2009; Orlando, Florida.
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