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					           Journal of Oncology Pharmacy Practice
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Impact of erythropoiesis-stimulating agent prescribing at an Asian cancer center, after release of safety
                                              advisories
                                         QingRu Chan and Alexandre Chan
                                 J Oncol Pharm Pract published online 21 July 2010
                                         DOI: 10.1177/1078155210378058

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              J Oncol Pharm Pract OnlineFirst, published on July 21, 2010 as doi:10.1177/1078155210378058
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Impact of erythropoiesis-stimulating                                                                           ! The Author(s) 2010
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agent prescribing at an Asian cancer                                                                           DOI: 10.1177/1078155210378058
                                                                                                               opp.sagepub.com
center, after release of safety advisories

QingRu Chan
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore

Alexandre Chan
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore;
Department of Pharmacy, National Cancer Centre Singapore, Singapore




Abstract
Background. Erythropoiesis-stimulating agents (ESAs) provide symptom relief and decrease blood transfusion support
among patients with chemotherapy-induced anemia. However, due to increased cardiovascular events associated with
off-labeled usage of ESAs, the FDA incorporated black box warnings in 2007 to include the following key points: (a) ESAs
should be used only to treat anemia due to concomitant chemotherapy of a noncurative intent and (b) target hemoglo-
blin level should not exceed 12 g/dL. Thus, this study was designed to compare the prescribing of epoetin alfa at National
Cancer Centre Singapore before and after FDA black box updates. The secondary objective of this study was to evaluate
the appropriateness of efficacy and toxicity monitoring of epoetin alfa.
Methods. This was a retrospective, single-centered, drug utilization review. Patients who received at least one dose of
epoetin alfa were included in this study. Utilization of epoetin alfa was segregated into two time periods: January 1, 2005
to October 15, 2007 (S1, Pre-safety advisories changes) and October 16, 2007 to December 10, 2009 (S2, Post-safety
advisories changes).
Results. A total of 171 patients were prescribed epoetin alfa at NCCS during the two time periods. However, only 139
patients were eligible for analysis, with 91 and 48 patients in S1 and S2 respectively. After safety advisory changes, there
were more (18.2%) metastatic patients and fewer (19.1%) patients with cardiovascular co-morbidities who were pre-
scribed epoetin alfa, the mean hemogloblin level when epoetin alfa was initiated was lowered by 0.46 g/dL, more (43%)
dose adjustments were made for ‘excessive’ responders and more (40.7%) patients had fewer blood transfusions after
epoetin alfa therapy (p < 0.05). However, blood pressure control, iron studies, and supplementation did not improve
(p > 0.05).
Conclusion. This study suggested that oncologists have generally adopted the new ESA safety warnings and adjusted
prescribing habits.


Keywords
anemia, cancer, epoetin alfa, erythropoiesis-stimulating agent, FDA black box warnings, prescribing practices



Introduction                                                                 contamination, and iron overload.4 Recombinant ery-
Chemotherapy-induced anemia (CIA) is a prevalent                             thropoiesis-stimulating agents (ESAs), on the other
side effect that occurs in 50–60% of cancer patients.1,2                      hand, stimulate erythropoiesis by binding to the
Untreated CIA is associated with marked fatigue, hence
affecting patient’s well-being and quality of life (QOL).3
CIA can be treated rapidly with red blood cell transfu-                      Corresponding author:
                                                                             Dr Alexandre Chan, Department of Pharmacy, Faculty of Science,
sions. However, blood transfusions are associated with                       National University of Singapore, Block S4, 18 Science Drive 4,
potential risks such as transfusion-related reactions,                       Singapore 117543
congestive heart failure, virus transmission, bacterial                      Email: phaac@nus.edu.sg




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erythropoietin receptor on reticulocyte progenitor cells,                 This study was designed to determine the impact of
leading to the anti-apoptosis of reticulocytes and sub-                the safety advisories by comparing the prescribing pat-
sequently, the production of mature red blood cells.5                  terns of epoetin alfa at NCCS before and after the
The three ESAs namely, epoetin alfa, epoetin beta,                     release of safety advisories. This study was also
and darbepoetin alfa have shown to increase hemoglo-                   designed to evaluate the appropriateness of efficacy
bin levels, reduce blood transfusion rates, and improve                and toxicity monitoring of epoetin alfa at NCCS.
QOL in patients with CIA.6,7 Efficacy and safety                         Results from this study will highlight current prescrib-
profiles are shown to be similar for all three ESAs.8                   ing issues associated with epoetin alfa and may influ-
   Since 2005, numerous clinical trials and four large                 ence future prescribing and monitoring practices.
meta-analyses have shown an increase in cardiovascu-
lar events and tumor progression associated with ESA
due to off-labeled usage.9–12 In these trials, ESAs were                Methods
used either: (1) at higher than approved doses, (2) for
                                                                       Study design
anemia treatment in cancer patients who were not on
chemotherapy, or (3) to target a hemoglobin level                      This was a single-centered, retrospective, drug utiliza-
exceeding 12 g/dL. These off-labeled usages were spec-                  tion review. Study protocol approval was obtained
ulated to contribute to the increased thromboembolic                   from the Institutional Review Board at NCCS.
events and mortality that were associated with ESAs.
As a result, the U.S. Food and Drug Administration’s
                                                                       Data collection
(FDA) Oncologic Drugs and Advisory Committee has
discouraged such off-labeled usages of ESAs by man-                     Patients were identified from the pharmacy electronic
dating product label changes and incorporating black                   dispensing records of epoetin alfa 10,000 IU and
box warnings in March 2007 that were updated again in                  40,000 IU and the usage patterns of epoetin alfa were
November 2007.13–16 The new labeling states that (a)                   reviewed and documented. The eligibility criteria were
ESAs are not indicated for patients receiving myelosup-                cancer patients who received at least one dose of epoe-
pressive chemotherapy when the anticipated outcome is                  tin alfa at NCCS from January 1, 2005 to December 10,
cure, (b) ESA should be used only for treatment of                     2009. Patients who do not have complete data for anal-
anemia due to concomitant chemotherapy and it is                       ysis such as epoetin alfa dosing regimens and relevant
not indicated for the prevention of anemia, (c) therapy                lab values were excluded from the study. Utilization of
should not be initiated at hemoglobin levels more than                 epoetin alfa was segregated into two time periods:
10 g/dL, (d) the target hemogloblin level in cancer                    January 1, 2005 to October 15, 2007 (S1, Baseline,
patients if treated with ESAs should be up to 12 g/dL                  Pre-safety advisories changes) and October 16, 2007
and (e) ESA dose should be withheld when hemoglo-                      to December 10, 2009 (S2, Post-safety advisories
blin exceeds a level needed to avoid transfusion. The                  changes). Patients who have received epoetin alfa in
updated product label also warns against the continu-                  both time periods were excluded in the data for S2.
ation of ESA after completion of chemotherapy. In
view of the FDA safety warnings, organizations such
                                                                       Study end points
as the American Society of Hematology/American
Society of Clinical Oncology (ASH/ASCO) and the                           Demographics and baseline patient characteristics:
National Comprehensive Cancer Network (NCCN)                           Patient demographics such as gender, ethnicity, weight,
have also updated their practice guidelines since                      age, cancer diagnosis, medical history of cardiovascular
September 2007.4,17                                                    diseases, cancer stage, and chemotherapy regimens were
   A drug ultilization study reviewed the prescribing of               collected to determine the baseline characteristics of
epoetin alfa before FDA black box updates at the                       patients receiving epoetin alfa at NCCS.
National Cancer Centre Singapore (NCCS).18                                Evaluating prescribing of epoetin alfa: To evaluate
Findings showed that dose titrations of epoetin alfa                   the prescribing of epoetin alfa, end point measurements
did not conform to product insert recommendations                      included data such as: (1) hemoglobin initiation level,
and routine assessment of patient’s iron stores and                    (2) hemoglobin target level achieved, (3) epoetin alfa
oral iron supplementation was lacking. Furthermore,                    dose adjustments, (4) treatment duration, and (5) pres-
a substantial number of patients had uncontrolled                      ence of concomitant iron supplementation. The hemo-
blood pressure while on epoetin alfa therapy.                          globin target level of 11–12 g/dL was determined
   Hence, to provide an insight to whether prescribing                 according to NCCN guidelines for optimal target
and monitoring patterns have changed, this drug utili-                 hemogloblin levels in patients with CIA. To determine
zation review will examine the patterns of epoetin alfa                the response to initial epoetin alfa therapy and the need
utilization after release of safety advisories.                        for dose adjustments, patients were classified as ‘poor’,




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Chan and Chan                                                                                                                      3

‘excessive’, and ‘optimal’ responders. ‘Poor’ responders                   Mann–Whitney U nonparametric test as the duration
were patients who did not have an increase in hemo-                        of therapies were not normally distributed. Statistical
globin levels of more than 0.5 g/dL after 2–6 weeks of                     analyses were performed with the Statistical Package
therapy. ‘Excessive’ responders were patients who                          for Social Sciences version 17.0 (SPSS Inc, Chicago,
either had a hemogloblin rise of more than 1 g/dL                          IL, USA), using an -value of 0.05 for statistical
within any two week period during therapy or when                          significance.
their hemogloblin level exceeded 12 g/dL during epoetin
alfa therapy. ‘Optimal’ responders were defined to have
a stable hemoglobin level of 1–2 g/dL while receiving                      Results
chemotherapy and could continue on the same pre-
                                                                           Demographics and baseline patient characteristics
scribed dose of epoetin alfa. Treatment duration was
defined as the number of days from the first to the last                     A total of 171 patients were prescribed epoetin alfa at
dose of epoetin alfa.                                                      NCCS between January 1, 2005 and December 10,
    Evaluating the appropriateness of drug efficacy                          2009. However, only 139 patients were fit for the eligi-
monitoring: To evaluate the appropriateness of drug                        bility criteria and their patient records were reviewed.
efficacy monitoring, the following end points were doc-                      There were 91 patients receiving epoetin alfa before
umented: (1) number of blood transfusions needed                           release of safety advisories (S1) and 48 patients receiv-
before and after epoetin alfa therapy, (2) hemoglobin                      ing epoetin alfa after release of safety advisories (S2)
monitoring frequency, and (3) presence of serum iron                       (Figure 1). The number of prescriptions for epoetin alfa
monitoring. To evaluate whether there was a change in                      decreased after black box warning updates (S1: 0.83
patients’ blood transfusion requirements during epoetin                    prescriptions/week vs. S2: 0.5 prescriptions/week).
alfa therapy, the average weekly number of blood                           Baseline characteristics of patients were similar in the
transfusions required before and after epoetin alfa ini-                   two time periods except significantly more patients with
tiation was compared. Blood transfusions required                          sarcoma (S2: 14.6% vs. S1: 3.3%; p ¼ 0.032) and met-
2 weeks after termination of epoetin alfa therapy were                     astatic disease (S2: 89.6% vs. S1: 71.4%; p ¼ 0.018)
not documented.                                                            were prescribed epoetin alfa after introduction of
    Evaluating the appropriateness of drug toxicity                        safety guidelines (Table 1).
monitoring: To evaluate appropriateness of drug toxic-                        In both time periods, the majority of patients pre-
ity monitoring (1) the status of blood pressure control,                   scribed with epoetin alfa were female (66.2%), Chinese
(2) incidence of significant increase in blood pressure,                    (71.2%), manifested breast cancer (27.3%), had a mean
(3) blood pressure monitoring frequency, and (4) occur-                    weight of 55.3 kg and a mean age of 60.6 years. Private
rence of thromboembolic events were documented.                            patients form the majority (59%) of the patient popula-
Patients were defined to manifest ‘uncontrolled’ hyper-                     tion. A smaller proportion of patients in the later period
tension if their blood pressure at time of epoetin alfa                    (S2) manifested cardiovascular co-morbidities such as
initiation was not in accordance to the Singapore                          hypertension, hyperlipidemia, diabetes mellitus, and
Ministry of Health hypertension guidelines.19 Patients                     ischemic heart disease (S2: 47.9% vs. S1: 67.0%;
were documented to have a significant increase of sys-                      p ¼ 0.044). Four patients (2.9%) manifested iron and
tolic blood pressure after initiation of epoetin alfa if the               vitamin B12 deficiency anemia prior to chemotherapy.
increase was sustained at more than 10 mm Hg or had                        A larger proportion of patients (89.6%) presented with
exceeded their target blood pressure. Blood pressure                       metastatic disease in the later period. More than 90% of
readings were not documented after epoetin alfa ther-                      the patient population was on either concurrent chemo-
apy termination. Patients were documented to have an                       therapy, radiotherapy, or both and only nine patients
additional risk of thrombosis if they had prior venous                     (6.5%) did not receive chemotherapy or radiotherapy
thromboembolism, hypercoagulability, recent surgery                        while on epoetin alfa treatment (Table 1). The majority
(i.e., within 6 months), and prolonged inactivity (i.e.,                   (87.5%), of the patients were prescribed epoetin alfa
more than 1 month) by hospitalization.                                     with chemotherapy that was noncurative intent. A start-
                                                                           ing epoetin alfa dose of 40,000 IU once weekly was pre-
                                                                           scribed to 75% of patients and the other common
Statistical analyses
                                                                           starting dosing regimens were 10,000 IU once every 10
Frequencies and percentages were used to summarize                         days and 10,000 IU thrice weekly.
categorical data. Chi-Square/Fisher’s Exact Test and
the two-sided independent samples t-test were utilized
                                                                           Prescribing patterns of epoetin alfa
to evaluate categorical variables and continuous vari-
ables, respectively. Statistical comparison with respect                   The mean hemoglobin level that epoetin alfa was
to duration of therapies was conducted using the                           initiated was significantly lowered after changes in




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                                            S1                                                                     S2

                     Cancer patients who received at least 1 dose of                Cancer patients who received at least 1 dose of
                      epoetin alfa from January 1, 2005 to October                 epoetin alfa from October 16, 2007 to December
                        15, 2007 at the National Cancer Centre                         10, 2009 at the National Cancer Centre
                                         Singapore                                                     Singapore

                        Represents the patient population that was                    Represents the patient population that was
                       prescribed epoetin alfa before the release of                  prescribed epoetin alfa after the release of
                                    safety advisories                                              safety advisories

                                          n =121                                                               n= 56


                                                                                                                   Patients who were repeat
                                                                                                                       patients from S1
                         Patients who had
                      incomplete information                                                                                 n=6
                           for analysis

                                 n = 30



                                                                                                                      Patients who had
                                                                                                                   incomplete information
                                                                                                                        for analysis

                                                                                                                             n=2




                        Patients who were eligible for complete                          Patients who were eligible for complete
                                information for analysis                                         information for analysis

                                          n= 91                                                               n= 48




Figure 1. Patient disposition.

safety guidelines. (S2: 8.52 g/dL vs. S1: 8.98 g/dL;                             had a ‘poor’ response to epoetin alfa was comparable
p ¼ 0.032). None of the patients in the later period                             in both treatment periods (S1: 7.1% vs. S2: 6.3%;
were started on epoetin alfa when their hemoglobin                               p ¼ 1.000). Similar proportions of ‘poor’ responders to
level was more than 12 g/dL. On the other hand,                                  epoetin alfa had their epoetin alfa dose prematurely
during S1, one patient (1.1%) was prescribed epoetin                             discontinued (S1: 57.1% vs. S2: 68.8%; p ¼ 0.333).
alfa at high hemogloblin levels (i.e., more than 12 g/dL)                        The proportion of patients who achieved the optimal
(Figure 2). The median duration of epoetin alfa therapy                          target hemoglobin level at 11–12 g/dL before the dis-
was similar at 17 days (IQR: 8–110) and 20 days (IQR:                            continuation of epoetin alfa therapy was alike (S1:
5.75–91.75) for S1 and S2 respectively. (p ¼ 0.844)                              34.1% vs. S2: 33.3%; p ¼ 1.000).
(Table 2). Before release of safety advisories, there                               The proportion of patients who were prescribed oral
were three patients (3.3%) whose epoetin alfa therapy                            iron supplementation with epoetin alfa was similar (S1:
lasted for more than 17 months. On the other hand,                               59.3% vs. S2: 66.6%; p ¼ 0.464). The most common
none of the patients in the later period was prescribed                          (94.2%) iron supplement prescribed was ferrous gluco-
epoetin alfa therapy for more than 17 months.                                    nate. Twenty-three patients (16.5%) were prescribed
   Table 2 shows the response to epoetin alfa therapy                            both iron and folic acid, while nine (6.5%) patients
within 2–6 weeks of treatment. Similar number of                                 were prescribed iron, folic acid, and vitamin B12.
patients achieved ‘poor’, ‘optimal’, or ‘excessive’                              None of the patients received intravenous iron.
response to epoetin alfa therapy in both treatment per-
iods (p ¼ 0.713). More patients had their dose adjusted                          Evaluating appropriateness of drug efficacy
by the oncologists when they had an ‘excessive’
                                                                                 monitoring
response to epoetin alfa during the later period (S2:
75% vs. S1: 32%; p ¼ 0.032). The proportion of                                   Out of the 14 (29.2%) patients who received blood
patients who had dose adjustment made when they                                  transfusions due to CIA prior to epoetin alfa therapy




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Chan and Chan                                                                                                                               5

Table 1. Demographics and baseline characterstics of study population

                                                                         S1                                     S2                 Total
Characteristics                                               Patients, No. (%)                          Patients, No. (%)   Patients, No. (%)

Total                                                         91 (100%)                                  48 (100%)           139 (100%)
Gender
  Male                                                        29 (31.9)                                  18 (37.5)           47 (33.8)
  Female                                                      62 (68.1)                                  30 (62.5)           92 (66.2)
Ethnicity
  Chinese                                                     62 (73.6)                                  37 (77.1)           99 (71.2)
  Malay                                                       4 (4.4)                                    3 (6.3)             7 (5.0)
  Indian                                                      7 (7.7)                                    2 (4.2)             9 (6.5)
  Others                                                      18 (14.3)                                  6 (12.5)            24 (17.3)
Mean weight in kg (SD)                                        55.8 (9.1)                                 54.3 (11.6)         55.3 (10.1)
Mean age in years (SD)                                        60.9 (12.3)                                60.0 (13.3)         60.6 (12.6)
Malignancy
  Breast                                                      29 (31.9)                                  9 (18.8)            38 (27.3)
  Ear, Nose, and Throat                                       5 (5.5)                                    2 (4.2)             7 (5.0)
  Gastrointestinal                                            12 (13.2)                                  7 (14.6)            19 (13.7)
  Genitourinary                                               5 (5.5)                                    1 (2.1)             6 (4.3)
  Lung                                                        8 (8.8)                                    6 (12.5)            14 (10.1)
  Pancreas                                                    5 (5.5)                                    2 (4.2)             7 (5.0)
  Ovary                                                       14 (15.4)                                  8 (16.7)            22 (15.8)
  Sarcoma*                                                    3 (3.3)                                    7 (14.6)            10 (7.2)
  Others                                                      10 (11.0)                                  6 (12.5)            16 (11.5)
Presence of metastatic disease*                               65 (71.4)                                  43 (89.6)           108 (77.7)
Medical history
  Hypertension                                                43 (43.3)                                  19 (39.6)           62 (44.6)
  Hyperlipidemia                                              11(12.1)                                   9 (18.8)            20 (14.4)
  Diabetes mellitus                                           16 (17.6)                                  11 (22.9)           27 (19.4)
  Cardiac arrhythmia                                          1 (1.1)                                    1 (2.1)             2 (1.4)
  Myocardial infarct                                          1 (1.1)                                    1 (2.1)             2 (1.4)
  Ischemic stroke                                             1 (1.1)                                    0 (0.0)             1 (0.7)
  Ischemic heart disease                                      5 (5.5)                                    3 (6.3)             8 (5.8)
  Anemia                                                      3 (3.3)                                    1 (2.1)             4 (2.9)
Cardiovascular co-morbidity*                                  61 (67.0)                                  23 (47.9)           84 (60.4)
Therapy regimen
  Concurrent chemotherapy only                                75 (82.4)                                  37 (77.1)           112 (80.6)
  Concurrent radiotherapy only                                5 (5.5)                                    4 (8.3)             9 (6.5)
  Concurrent chemotherapy and radiotherapy                    5 (5.5)                                    4 (8.3)             9 (6.5)
  Not on chemotherapy or radiotherapy                         6 (6.6)                                    3 (6.3)             9 (6.5)
*p < 0.05.


during S2, one patient (7.1%) required more blood                           patients receiving fewer blood transfusions (S2: 78.6%
transfusions, eleven patients (78.6%) required fewer                        vs. S1: 37.9%; p ¼ 0.022), and significantly fewer
blood transfusion, and two patients (14.3%) required                        patients receiving more blood transfusions (S2: 7.1%
the same number of blood transfusions after initiation                      vs. S1: 44.8%; p ¼ 0.016) (Table 2).
of epoetin alfa therapy (Figure 3). During the later                           Frequency of hemogloblin monitoring was similar in
period, there was a significantly greater proportion of                      both time periods. Majority of the patients had full




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6                                                                                                                                                             J Oncol Pharm Practice 0(0)


                                 40.0
                                                                                                                            (DVT) 3 months after the initiation of epoetin alfa, and
                                               37.5                                                                         they all were started on anticoagulation therapy. Before
                                                        35.2 35.4                    S1 (Jan 05 to Oct 07)
                                 35.0                                                n = 91                                 safety guideline updates, three patients (3.3%) devel-
                                                                                                                            oped DVT at an average of 4.7 months (1–8 months)
                                 30.0                                  28.6
                                                                                     S2 (Oct 07 to Dec 09)
                                                                                                                            after epoetin alfa initiation. There was no significant
                                                                                                                            difference in the proportions of patients who developed
    Proportion of patients (%)




                                                                                     n = 48
                                 25.0
                                        22.0                                                                                DVT after epoetin alfa therapy in the two time periods
                                 20.0
                                                                                                                            (p ¼ 1.000).

                                                                              14.6
                                 15.0                                                13.2
                                                                                            12.5                            Discussion
                                 10.0                                                                                       To our knowledge, this is the first drug ultilization
                                                                                                                            study assessing the impact of safety advisories on
                                  5.0
                                                                                                                            ESA prescribing for patients with CIA in Singapore.
                                                                                                     1.1

                                  0.0
                                                                                                             0              This investigation at NCCS revealed that after release
                                          ≤8             8.1–9         9.1–10        10.1–12          >12                   of safety advisories, (1) there was an overall decrease in
                                                      Hemogloblin initiation level (g/dL)                                   number of patients who were prescribed epoetin alfa,
                                                                                                                            (2) fewer patients with cardiovascular co-morbidities
Figure 2. Comparison of the hemogloblin initiation level at first                                                           were started on epoetin alfa, (3) the mean hemoglobin
dose of epoetin alfa.                                                                                                       level at which epoetin alfa was initiated had decreased,
                                                                                                                            (4) there were more dose adjustments made for patients
blood counts reviewed at least fortnightly (S1: 76.9%                                                                       who had an ‘excessive’ response to epoetin alfa, and
vs. S2: 68.8%; p ¼ 0.314) (Table 2).                                                                                        (5) there were more patients who had fewer blood
   Proportions of patients who had baseline serum                                                                           transfusions after epoetin alfa therapy.
iron, folate, and vitamin B12 studies done prior to                                                                             Present findings demonstrated a reduction of more
epoetin alfa initiation were similar (Iron indices S1:                                                                      than 50% in the number of prescriptions for epoetin
12.1% vs. S2: 10.4%; p ¼ 1.000, folate and vitamin                                                                          alfa at NCCS. This decrease concurs with a market
B12 studies S1: 14.3% vs. S2: 10.4%; p ¼ 0.604)                                                                             report that quotes a 10% decline in worldwide sales
(Table 2).                                                                                                                  of ESAs from 2006 to 2007.20 This decrease in overall
                                                                                                                            epoetin alfa usage may be due to the new warnings
Evaluating appropriateness of drug toxicity                                                                                 highlighting the increase of thromboembolic events
                                                                                                                            and disease progression associated with epoetin alfa
monitoring                                                                                                                  usage. Hence, oncologists may defer from prescribing
At time of epoetin alfa initiation, the proportion of                                                                       epoetin alfa for patients with CIA.
patients who manifested hypertension at the start of                                                                            After release of safety advisories, the baseline pro-
epoetin alfa therapy was comparable between the two                                                                         files of the patients receiving epoetin alfa at NCCS
time periods (S1: 47.3% vs. S2: 39.6%; p ¼ 0.473)                                                                           remain the same in terms of gender, ethnicity, age,
(Table 2).                                                                                                                  and weight. Patients were mostly female, Chinese,
   Majority of hypertensive patients had their blood                                                                        with a mean age and weight of 60.6 years old and
pressure monitored on a monthly basis in both time                                                                          55.3 kg respectively. Breast cancer patients formed the
periods. Of the 19 patients in the later period who man-                                                                    largest group of patients receiving epoetin alfa therapy.
ifested hypertension during epoetin alfa initiation, 14                                                                     Female cancer patients were more afflicted by CIA, and
patients (73.7%) had regular blood pressure monitor-                                                                        expectedly, they formed the majority of patients receiv-
ing. Comparatively, before safety guideline changes,                                                                        ing epoetin alfa therapy.21 This patient profile corre-
only 29 (67.4%) out of 43 hypertensive patients had                                                                         lates with the trends in cancer incidences in Singapore
regular blood pressure monitoring. However, the differ-                                                                      where breast cancer is the most common cancer diag-
ence was not statistically significant (p ¼ 0.768) The                                                                       nosis in the female Chinese population.22 However,
proportion of patients who had a sustained increase                                                                         there was a significant number of metastatic patients
in systolic blood pressure of more than 10 mmHg or                                                                          who were treated with epoetin alfa; this was not unan-
had exceeded their target blood pressure goal after                                                                         ticipated as new guidelines state that patient’s chemo-
epoetin alfa initiation was similar in both time periods                                                                    therapy regimen should be of a noncurative intent.4
(S1: 9.9% vs. S2: 14.6%; p ¼ 0.415) (Table 2).                                                                                  The mean hemoglobin level at which epoetin
   After safety advisory changes, two patients (4.2%)                                                                       alfa was initiated after safety advisory changes was
developed thromboembolic events after epoetin alfa                                                                          8.52 g/dL, which was significantly lower than the
therapy. Both patients developed deep vein thrombosis                                                                       mean hemoglobin initiation levels before the release




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Chan and Chan                                                                                                                                          7

Table 2. Prescribing and monitoring of epoetin alfa treatment

                                                                                                       No. (%) of patients

                                                                                                       S1 (n ¼ 91)           S2 (n ¼ 48)       p-Value

1. Evaluate appropriateness of prescribing of epoetin alfa
   (a) Response
       Poor                                                                                            28 (30.8)             16 (33.3)
       Excessive                                                                                       25 (27.5)             12 (25.0)         0.713
       Optimal                                                                                         38 (41.8)             20 (41.6)
   (b) Dose adjustments made
       ‘Poor’ responders                                                                               2 (7.1)               1 (6.3)           1.000
       ‘Excessive’ responders                                                                          8 (32.0)              9 (75.0)          0.032
   (c) Premature discontinuation of epoetin alfa in ‘poor’                                             16 (57.1)             11(68.8)          0.333
       responders to epoetin alfa
   (d) Mean hemogloblin initiation level in g/dL (SD)                                                  8.98 (1.27)           8.52 (1.18)       0.032
   (e) Achieved optimal hemogloblin target before epoetin                                              31 (34.1)             16 (33.3)         1.000
       alfa discontinuation
   (f) Median duration of epoetin alfa therapy in days (IQR)                                           17 (8–110)            20 (5.75–91.75)   0.844
   (g) Prescribed oral iron supplementation                                                            54 (59.3)             32 (66.6)         0.464
2. Evaluate appropriateness of drug efficacy monitoring
   (a) Received blood transfusions after epoetin alfa therapy
       More                                                                                            13 (44.8)             1 (7.1)           0.016
       Fewer                                                                                           11 (37.9)             11 (78.6)         0.022
       Same                                                                                            5 (17.2)              2 (14.3)          1.000
   (b) Fortnightly hemogloblin monitoring                                                              70 (76.9)             33 (68.8)         0.314
   (c) Baseline blood serum studies done prior to epoetin alfa initiation
       Iron                                                                                            11 (12.1)             5 (10.4)          1.000
       Folate and Vitamin B12                                                                          13 (14.3)             5 (10.4)          0.604
3. Evaluate appropriateness of drug toxicity monitoring
   (a) Manifested hypertension at time of epoetin alfa initiation                                      43 (47.3)             19 (39.6)         0.473
   (b) Monthly blood pressure monitoring in hypertensive patients                                      29 (67.4)             14 (73.7)         0.768
   (c) Significant increase in blood pressure                                                          9 (9.9)               7 (14.6)          0.415
   (d) Development of thromboembolic events                                                            3 (3.3)               2 (4.2)           1.000
SD ¼ Standard deviation; IQR ¼ Inter-quartile range.


of safety advisories. Furthermore, fewer patients were                              responders of epoetin alfa had their epoetin alfa dose
started on epoetin alfa when their hemoglobin levels                                prematurely discontinued. Fewer patients were on long
were more than 10 g/dL. In addition, more dose adjust-                              durations of epoetin alfa therapy; and this trend is in
ments were made for ‘excessive’ responders to epoetin                               accordance to recent guidelines stating that epoetin alfa
alfa. The above trends were not unforeseen, as ESAs                                 should be discontinued when patients have a poor
were associated with increased incidence of fatal throm-                            response after 6–8 weeks of therapy or when chemo-
botic events in patients with metastatic breast cancer                              therapy has completed.4,17 After safety guideline
receiving chemotherapy when administered at hemo-                                   changes, only one out of 16 ‘poor’ responders (6.3%)
globin levels of more than 12 g/dL and targeted at                                  had his/her epoetin alfa dose adjusted according to
hemoglobin levels of 12–14 g/dL.23 None of the patients                             product insert recommendation; similar trends were
in the later time period were started on epoetin alfa                               also observed in ‘poor’ responders to epoetin alfa
when their hemoglobin level was more than 12 g/dL;                                  before guideline changes. This may have been due to
this decline in number of patients suggest that oncolo-                             lack of prescriber knowledge, clinical circumstances, or
gists are more aware that high initiation hemoglobin                                patient demand. Epoetin alfa is costly (approximately
levels are associated with higher risk of fatality. It is                           S$100 per vial of EprexÕ 10,000 IU) and to increase the
important to highlight that majority of the ‘poor’                                  dosage may have been financially difficult.




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8                                                                                                                                                          J Oncol Pharm Practice 0(0)


                                 90
                                                                                                                         Evidence has shown that functional iron deficiency
                                                                                                                         should be treated with intravenous iron as it may provide
                                 80
                                                   78.6                           S1 (Jan 05 to Oct 07)                  better response as compared to oral forms.27 However,
                                                                                  n = 29
                                                                                                                         iron supplementation in intravenous form is not a
                                 70                                               S2 (Oct 07 to Oct 09)
                                                                                                                         common practice at NCCS.
                                                                                  n = 14                                     After guideline changes, patients who were prescribed
                                                                                                                         epoetin alfa manifested fewer cardiovascular co-morbid
                                 60
    Proportion of patients (%)




                                                                                                                         conditions. Physicians may have been more conservative
                                                                                                                         to initiate epoetin alfa in cancer patients with cardiovas-
                                 50
                                                                                            44.8                         cular co-morbidities in view of increasing evidence of car-
                                            37.9
                                                                                                                         diovascular and thromboembolic events associated with
                                 40
                                                                                                                         ESA use. Blood pressure was monitored monthly for the
                                                                                                                         majority of hypertensive patients, which fit into the
                                 30
                                                                                                                         monthly chemotherapy cycles. However, blood pressure
                                                                                                                         control and monitoring in hypertensive patients on epoe-
                                 20                                 17.2
                                                                           14.3
                                                                                                                         tin alfa did not significantly improve after guideline
                                                                                                                         changes. Blood pressure should be closely monitored as
                                 10                                                                 7.1
                                                                                                                         hypertension is the most common side effect of epoetin
                                                                                                                         alfa.28 In addition, blood pressure should also be well
                                  0
                                          Fewer                     Same                       More
                                                                                                                         controlled before initiation of epoetin alfa to prevent
                                      Frequency of blood transfusions required after epoetin alfa initiation             exacerbation of blood pressure.4,16 The proportion of
                                                                                                                         patients who developed thromboembolic events after ini-
                                                                                                                         tiation of epoetin alfa therapy remained the same after the
Figure 3. Comparison between numbers of blood transfusion
required after epoetin alfa initiation.                                                                                  FDA black box warnings were implemented. None of the
                                                                                                                         thromboembolic events resulted in death of any patient.
                                                                                                                         There was no information on whether the thromboem-
   Following changes in ESA prescribing guidelines,                                                                      bolic events occurred as a result of epoetin alfa therapy. In
other studies indicated that a decreased usage of epoe-                                                                  addition, approximately a quarter of patients were iden-
tin alfa correlates with a subsequent increase in blood                                                                  tified to have an additional risk of thromboembolism
transfusions.24,25 However, our results showed other-                                                                    prior to epoetin alfa therapy initiation. Hence, it is incon-
wise; in our study, there was a significant decrease of                                                                   clusive to whether epoetin alfa therapy resulted in vascu-
blood transfusion requirements in patients on epoetin                                                                    lar events in this study.
alfa therapy instead. This result demonstrates that a                                                                        This study is limited because of its retrospective
more favorable usage of epoetin alfa in individual                                                                       nature, information about patient’s symptoms and
patients is now in place, for the primary advantage of                                                                   treatment decisions are typically unstructured and not
epoetin alfa usage was to decrease transfusion rates in                                                                  readily included in the patients’ database and, therefore
patients with CIA.7                                                                                                      inaccessible for analysis. Hence, patients with high
   The past study highlighted that routine iron studies                                                                  hemoglobin levels may have been treated for signs
and iron supplementation were among the poor epoetin                                                                     and symptoms, and at the physician’s discretion.
alfa prescribing practices at NCCS.18 However, present                                                                   Despite these limitations, this analysis provides a
findings show that the monitoring of serum iron indices                                                                   useful perspective of epoetin alfa use in NCCS after
and provision of oral iron supplementation were still                                                                    the release of safety advisories. This study suggests
lacking in patients receiving epoetin alfa at NCCS. This                                                                 that oncologists have generally adopted the new
result concurs with a study at the Chicago Academic                                                                      safety warnings with ESAs and adjusted prescribing
Medical Center which revealed that majority of patients                                                                  habits especially in dosage adjustments.
with CIA who were on ESA therapy did not have iron                                                                           However, suboptimal prescribing practice high-
indices monitored and provision of iron supplementation                                                                  lighted in the past study such as monitoring of iron
was lacking in their institution.26 With continued ESA                                                                   indices, prescribing of iron supplementation, blood
use, iron deficiency would result and iron supplementa-                                                                   pressure monitoring, and control did not significantly
tion will eventually be needed to maintain optimal eryth-                                                                improve. Nonetheless, it is encouraging to observe pos-
ropoiesis.4 It is unclear why the practice of iron                                                                       itive trends for the above-mentioned areas except the
supplementation and serum iron studies did not improve.                                                                  monitoring of iron indices. The practice of monitoring
It is postulated that patients may not have manifested                                                                   iron indices was observed to be a declining trend
clinical presentations of iron deficiency as many                                                                         instead. Such suboptimal prescribing practices provide
patients were not on long-term epoetin alfa treatment.                                                                   opportunities for pharmacists to proactively review




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Chan and Chan                                                                                                                              9

the use of ESAs and collaborate with physicians in the                        7. Seidenfeld J, Piper M, Flamm C, et al. Epoetin treat-
management of ESAs in their institution. A pharmacist-                           ment of anemia associated with cancer therapy: A system-
run-clinic at Erie Veteran’s Affairs Medical Center suc-                          atic review and meta-analysis of controlled clinical trials.
ceeded in improving ESA usage, monitoring, and reduc-                            J Natl Cancer Inst 2001; 93: 1204–1214.
ing overall ESA therapy costs when pharmacists were                           8. Schwartzberg L, Shiffman R, Tomita D, Stolshek B,
                                                                                 Rossi G and Adamson R. A multicenter retrospective
authorized to order baseline and follow-up laboratory
                                                                                 cohort study of practice patterns and clinical outcomes of
tests as well as to adjust ESA doses accordingly.29
                                                                                 the use of darbepoetin alfa and epoetin alfa for chemo-
    As of February 16, 2010, the US FDA has approved                             therapy-induced anemia. Clin Ther 2003; 25: 2781–2796.
a risk evaluation and mitigation strategy (REMS) to                           9. Bennett CL, Silver SM, Djulbegovic B, et al. Venous
ensure the safe use of ESAs. Under the ESA                                       thromboembolism and mortality associated with recom-
APPRISE (Assisting Providers and Cancer Patients                                 binant erythropoietin and darbepoetin administration for
with Risk Information for Safe use of ESAs)                                      the treatment of cancer-associated anemia. JAMA 2008;
Oncology program, only those hospitals and healthcare                            299: 914–924.
professionals who have enrolled and completed training                       10. Glaspy J, Crawford J, Vansteenkiste J, et al.
in the program will prescribe and dispense ESAs to                               Erythropoiesis-stimulating agents in oncology: a study-
cancer patients.30 Once this new initiative is proven to                         level meta-analysis of survival and other safety outcomes.
improve ESA prescribing and decrease off-label usage,                             Br J Cancer 2010; 102: 301–315.
it is hoped that a similar mode of prescribing could be                      11. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant
implemented in Singapore as well.                                                human erythropoietins and cancer patients: updated
                                                                                 meta-analysis of 57 studies including 9353 patients.
                                                                                 J Natl Cancer Inst 2006; 98: 708–714.
Conclusions                                                                  12. Seidenfeld J, Piper M, Bohlius J, et al. ‘Comparative
                                                                                 Effectiveness of Epoetin and Darbepoetin for Managing
This investigation revealed that epoetin alfa prescribing                        Anemia in Patients Undergoing Cancer Treatment.
has generally improved after the release of safety advi-                         Comparative Effectiveness Review No. 3’, (Prepared by
sories at NCCS. Although ESAs have been associated                               Blue Cross and Blue Shield Association Technology
with negative publicity over the last 5 years, their ben-                        Evaluation Center Evidence-based Practice Center
efits still outweigh their risk in anemic cancer patients                         under Contract No. 290-02-0026). Agency for
with metastatic disease.31 With the current safety warn-                         Healthcare Research and Quality, Rockville, MD,
ings, it is crucial that clinicians continually re-examine                       http://effectivehealthcare.ahrq.gov/repFiles/EPO%20Final.
the literature to treat and monitor patients on ESAs                             pdf (2006, accessed March 2, 2010).
with their best interest in mind.                                            13. US FDA Postmarket Drug Safety Information for
                                                                                 Patients and Providers. ‘Erythropoiesis Stimulating
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