# Cardiovascular Events in Cancer Patients Treated with Highly or Moderately Emetogenic Chemotherapy:  Results from a Population-Based Study

Authors: Thao T. Vo; Jeanenne J. Nelson
Journal: Journal of Cancer Epidemiology
 (2012)

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## Abstract

Studies on cardiovascular safety in cancer patients treated with highly or moderately emetogenic chemotherapy (HEC or MEC), who may have taken the antiemetic, aprepitant, have been limited to clinical trials and postmarketing spontaneous reports. Our study explored background rates of cardiovascular disease (CVD) events among HEC- or MEC-treated cancer patients in a population-based setting to contextualize events seen in a new drug development program and to determine at a high level whether rates differed by aprepitant usage. Medical and pharmacy claims data from the 2005–2007 IMPACT National Benchmark Database were classified into emetogenic chemotherapy categories and CVD outcomes. Among 5827 HEC/MEC-treated patients, frequencies were highest for hypertension (16–21%) and composites of venous (7–12%) and arterial thromboembolic events (4–7%). Aprepitant users generally did not experience higher frequencies of events compared to nonusers. Our study serves as a useful benchmark of background CVD event rates in a population-based setting of cancer patients.


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## Body

## 1. Background/Objective

Chemotherapy-induced nausea and vomiting (CINV) negatively impacts the quality of life in cancer patients [1] and may lead to nonadherence to or dose reductions in chemotherapy [2].  Potential cardiac effects of antiemetics warrant special attention, given an estimated 13–60% burden of cardiovascular-related diseases that increases with age, among cancer patients [3–5].  Cardiovascular disease (CVD) can be preexisting, a result or natural progression of the malignancy or an adverse event resulting from chemotherapeutic treatment, such as anthracyclines and alkylating agents [6, 7].  For example, cyclophosphamide treatment has been associated with a 7–28% incidence of heart failure, cisplatin has been associated with an 8.5% incidence of venous thromboembolism, including deep vein thrombosis and pulmonary embolism [8], and doxorubicin/daunorubicin has been associated with 0.5–3% incidence of arrhythmias [9].Aprepitant is currently the only FDA-approved neurokinin (NK1) receptor antagonist (RA) that, when coadministered with other antiemetics, such as corticosteroids (dexamethasone) and serotonin 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, and palonosetron), augments the prevention of acute and, particularly, delayed CINV [10].  Although aprepitant has been shown to be generally well tolerated in clinical trials [11], isolated cases of serious adverse events, such as bradycardia [12] and hypertension [13], have been reported in two highly emetogenic chemotherapy (HEC) studies comparing aprepitant plus ondansetron and dexamethasone to the standard regimen of ondansetron and dexamethasone, alone [14, 15].  Other cardiovascular events (>0.5% and greater than standard therapy), regardless of causality, have also been reported in patients treated with the aprepitant regimen in either HEC or MEC studies, including myocardial infarction, tachycardia, deep vein thrombosis,  flushing, hypertension, and hypotension [12].  However, results from clinical trials may not reflect those observed in clinical practice, and population-based studies of the cardiovascular effects of aprepitant are lacking.  We aimed to quantify background rates of several CVD-related events among HEC and/or MEC-treated cancer patients for two purposes:  to understand expected rates among cancer patients in order to contextualize events which may be seen in our clinical development program of a similar patient population with a similar drug and to further understand at a high level whether rates differed by the decision to treat with aprepitant, recognizing that users versus nonusers may differ with respect to disease severity, access to care, preexisting conditions, and other factors.  Therefore, the objective of this study was to use a large, US healthcare claims database to assess the frequency of CVD-related events among HEC and/or MEC-treated cancer patients and to determine if the frequency was impacted by the decision to treat with aprepitant.


## 2. Methods

A retrospective cohort study of adult patients with select cancers, treated with HEC and/or MEC, was conducted using 2005–2007 data from the IMPACT National Benchmark Database (OptumInsight, Eden Prairie, MN), a comprehensive, deidentified healthcare claims database that is representative of the nonelderly, insurance-carrying population in the United States.  At the time of our analysis, the database contained inpatient/outpatient and pharmacy claims, a subset of lab results and enrolment information on over 82 million members from 45 healthcare plans serving nine census regions from 1997 to 2007.  The IMPACT database is HIPAA compliant and features encrypted member and provider IDs.The study included several cancer types commonly treated with HEC or MEC, namely, breast, colorectal, head and neck, lung, and ovarian cancer patients (Table4), in adults with ≤4 cycles of HEC and/or MEC as documented in one or more claims in the year 2006.  We choose ≤4 cycles because two-thirds of all treated patients had up to and including 4 cycles.  The study analysis period was defined as the first day of the first HEC and/or MEC cycle to 30 days past the first day of the last cycle.  The start of a new cycle of chemotherapy was defined by a period of more than 7 days but less than 45 days between cycles.  The start of treatment was the first HEC and/or MEC claim in 2006, with 3 months prior with no claim (“wash-in” period) to ensure that there was no CVD effect of HEC/MEC treatment in 2005 that was carried over into 2006.  The end of treatment was reached after 45 days of no additional HEC and/or MEC claim following the last claim (“wash-out” period) to ensure that all CVD effects from HEC/MEC treatment in 2006 were captured.  To illustrate, for patients whose first HEC or MEC claim was between January 1, 2006 and March 31, 2006, the enrolment criteria for inclusion in the study extended as far back as October 1, 2005.  For patients whose last claim in 2006 was seen after December 1, 2006, enrolment into 2007 to look for further treatment and the 45 day “wash-out” period was required.Data on aprepitant exposure and chemotherapy was obtained from the inpatient/outpatient and pharmacy claims.  Chemotherapeutic agents were defined as HEC if they were associated with >90% of treated patients having emesis, and MEC, if associated with 30–90% of patients having emesis (Table5). Chemotherapies were classified by a physician within our department using previously published criteria as guidance [16, 17].  Cardiovascular outcomes of interest included arterial and venous thromboembolic events, individually as well as a composite event, as well as cardiac arrest, hypertension, hypotension, increased platelets, sudden death, and syncope (Table 4). Patient characteristics included gender, age, tumor type, and prior history of cardiovascular disease.  Prior CVD was defined as the presence of a claim for hypertension, diabetes, coronary artery disease, myocardial infarction, congestive heart failure, ischemic stroke, transient ischemic attack, deep vein thrombosis, or pulmonary embolism anytime before HEC or MEC initiation.Subjects who used either HEC or MEC were categorized into 3 emetogenic chemotherapy groups:  HEC-only, MEC-only, or HEC/MEC combined.  All analyses, including the distribution (% or mean) of patient characteristics and the frequency of CVD outcomes of interest, were tabulated overall and stratified by aprepitant usage and emetogenic category of chemotherapy.  Analyses were not further stratified by number of chemotherapy cycles, however, due to insufficient sample size.  This study was purely descriptive, and therefore, no formal statistical comparison was made between aprepitant users and nonusers.  Rather, the data was visually inspected for noteworthy absolute differences of ≥5% or relative differences of ≥1.5 times.


## 3. Results

The number of cancer patients with the cancer types of interest who had at least 3 months of continuous enrolment and pharmacy benefit, at least one HEC or MEC claim, and ≤4 cycles of chemotherapy was 5827.  Among these patients, the distribution of patients by cancer type was 60.4% with breast, 25.7% with lung, 7.0% with colorectal, 5.9% with head and neck, and 5.6% with ovarian cancer (Table1).  Over 90% of patients had treatment by MEC-only, followed by 5.7% with HEC-only and 3.9% with both HEC and MEC.  Females comprised the majority across chemotherapy groups (55% HEC-only; 80% MEC-only; 58% HEC/MEC combination), and this gender difference was greater among those who took aprepitant compared to those who did not.  The mean age (~55 years) was similar across the chemotherapy groups, as was the percentage aged 60 years or older.  Those taking aprepitant, however, were 2 to 4.8 years younger, on average, and comprised fewer patients aged 60+ years compared to those who did not take aprepitant.  In HEC-only patients, 32% of aprepitant users were 60+ compared to 39% of nonusers; in MEC-only patients, the percentages were 20% versus 38%, respectively; and in the HEC/MEC combination group, the percentages were 35% versus 36%, respectively.  Using a more traditional cutpoint of age 65+ years, similar results were found with aprepitant users having a smaller proportion of older patients than nonusers.  Over half of patients had a history of CVD before their chemotherapy treatment, with the HEC-only group having a higher burden (62%) compared to the MEC-only group (50%) and HEC/MEC combined group (56%).  The proportion with a prior history of CVD was lower in aprepitant users compared to nonusers.Table 1
Characteristics of 5827 patients with select* cancers and ≤4 cycles of HEC, MEC, or HEC/MEC combined, 2005–2007 IMPACT National Benchmark Database (OptumInsight, Eden Prairie, MN).
CharacteristicHEC and/or MECHEC onlyMEC onlyHEC/MEC combined(N=5827)(N=330)(N=5269)(N=228)TotalNo AprepAprepTotalNo AprepAprepTotalNo AprepAprepTotalNo AprepAprep% Male21.9027.5611.1445.4552.7338.1819.5725.597.5241.6747.4832.58% Female78.1072.4488.8654.5547.2761.8280.4374.4192.4858.3352.5267.42Mean age (yrs)54.756.351.754.855.853.854.656.251.456.257.154.8% Age ≥6032.5238.2221.6935.1538.7931.5232.2338.2920.1035.5335.9734.83% Age ≥6514.3518.316.8214.8516.9712.7314.2218.335.9816.6719.4212.36% Breast cancer60.4150.9878.3126.6719.3933.9464.0753.7484.7424.5618.7133.71% Colorectal cancer7.009.302.646.976.677.276.959.451.948.338.637.87% Head and neck cancer5.855.746.0726.9726.6727.273.934.183.4219.7420.1419.10% Lung cancer25.7332.9112.0936.6744.8528.4824.0531.519.1148.6853.9640.45% Ovarian cancer5.596.473.936.677.276.065.606.553.703.953.604.49% Prior history of CVD‡50.7655.2842.1961.5264.8558.1849.8654.6840.2156.1458.9951.69*Breast, colorectal, head and neck, lung, and ovarian cancers.‡Prior history of CVD is defined as a diagnosis of any of the following prior to the start of HEC and/or MEC:  hypertension, diabetes, coronary artery disease, myocardial infarction, congestive heart failure, stroke, transient ischemic attack, deep vein thrombosis (DVT), and pulmonary embolism (PE).Note: percentage by type of cancer may add to >100% due to patients having multiple cancer types.Overall, the frequencies of cardiovascular and thromboembolic-related eventsfollowing any HEC or MEC treatment were mostly driven by the MEC-only treatment group, comprising 90% of patients (Table 2).  There were no sudden deaths.  The frequencies of increased platelets, arterial disorder, arterial occlusive disease, cardiac disorder, cardiogenic shock, iliac artery embolism, intermittent claudication and peripheral ischemia were low (n≤10) in this cohort.Table 2
Cardiovascular-related events in 5827 patients with select* cancers and ≤4 cycles of HEC, MEC, or HEC/MEC combined, 2005–2007 IMPACT National Benchmark Database (OptumInsight, Eden Prairie, MN).
Cardiovascular and thromboembolic eventsHEC and/or MECHEC onlyMEC onlyHEC plus MEC(N=5827)(N=330)(N=5269)(N=228)n%n%n%n%Angina pectoris320.5530.91280.5310.44Arterial disorder90.1520.6170.130—Arterial occlusive disease20.030—20.040—Arterial thromboembolic (excluding chest pain/discomfort)2544.36236.972204.18114.82Arterial thromboembolic (including chest pain/discomfort)88115.127221.8275414.315524.12Cardiac arrest250.4341.21190.3620.88Cardiac disorder30.050—30.060—Cardio-respiratory arrest270.4641.21210.4020.88Cardiogenic shock10.020—10.020—Cerebral ischemia621.0682.42531.0110.44Cerebrovascular accident520.8930.91490.930—Chest pain or discomfort71912.346218.7961011.584720.61Circulatory collapse140.2410.30130.250—Embolism971.6682.42831.5862.63Hypertension96616.586820.6185416.214419.30Hypotension1492.56113.331262.39125.26Iliac artery embolism20.0310.3010.020—Increased platelets70.120—70.130—Intermittent claudication90.1520.6140.0831.32Myocardial infarction110.1910.30100.190—Myocardial ischemia110.190—110.210—Peripheral embolism380.6541.21300.5741.75Peripheral ischemia——0—0—0—Sudden death——0—0—0—Syncope1402.40123.641172.22114.82Venous thromboembolic4507.724012.123837.272711.84*Breast, colorectal, head and neck, lung, and ovarian cancers.Hypertension occurred in 16% of the MEC-only chemotherapy group and was slightly higher among the smaller HEC-only and HEC/MEC combination groups.  Chest pain or discomfort occurred in 12% of the MEC-only patients, in 19% of HEC-only patients, and in 21% of combined HEC/MEC patients.  All other single adverse CVD events occurred at a frequency less than 5%, including MI and cerebrovascular accident, with the exception of hypotension, which occurred in 5.3% of those treated with HEC/MEC combined.  The composite measure for arterial thromboembolic events, excluding chest pain and discomfort, ranged from 4% among the MEC-only group to 7% in the HEC-only group.  The composite of venous thromboembolic events was 12% for the HEC-only and the HEC/MEC combined groups and 7% for the MEC-only group.Stratified by the decision to include aprepitant in the antiemetic regimen (Table3), the analysis demonstrated that in the MEC-only treated group, the composite of arterial thromboembolic events (without chest pain and discomfort), cardiac arrest, cardiorespsiratory arrest, cerebral ischemia, cerebrovascular accident, embolism, hypotension, and hypertension were more frequent (≥1.5 times or ≥5% absolute difference) among those who did not use aprepitant compared to those who did.  Though based on small numbers (n≤10), nonusers also had a higher rate of circulatory collapse (10 versus 3), increased platelet (6 versus 1), intermittent claudication (3 versus 1), and myocardial ischemia (9 versus 2). In all but two events (arterial disorder and arterial occlusive disorder) of the CVD-related categories among the MEC-only treated group, the frequency of CVD events was lower among aprepitant users versus nonusers.Table 3
Cardiovascular-related events in 5827 patients with select* cancers and ≤4 cycles of HEC, MEC, or HEC/MEC combined, by aprepitant status, 2005–2007 IMPACT National Benchmark Database (OptumInsight, Eden Prairie, MN).
Cardiovascular and thromboembolic eventsHEC and/or MECHEC onlyMEC onlyHEC/MEC combinedNo AprepAprepNo AprepAprepNo AprepAprepNo AprepAprep(N=2010)(N=3817)(N=165)(N=165)(N=1756)(N=3513)(N=89)(N=139)n%n%n%n%n%n%n%n%Angina pectoris200.52120.6021.2110.61180.51100.570—11.12Arterial disorder30.0860.3010.6110.6120.0650.280—0—Arterial occlusive disease10.0310.050—0—10.0310.060—0—Arterial thromboembolic (excludes chest pain/discomfort)1965.13582.89148.4895.451754.98452.5675.0444.49Arterial thromboembolic  (includes chest pain/discomfort)61116.0127013.434024.243219.3953415.2022012.533726.621820.22Cardiac arrest220.5830.1521.2121.21180.5110.0621.440—Cardiac disorder20.0510.050—0—20.0610.060—0—Cardio-respiratory arrest240.6330.1521.2121.21200.5710.0621.440—Cardiogenic shock10.030—0—0—10.030—0—0—Cerebral ischemia501.31120.6042.4242.42451.2880.4610.720—Cerebrovascular accident461.2160.3031.820—431.2260.340—0—Chest pain or discomfort48812.7823111.493621.822615.7642011.9619010.823223.021516.85Circulatory collapse110.2930.1510.610—100.2830.170—0—Embolism772.02201.0053.0331.82681.94150.8542.8822.25Hypertension69718.2626913.384124.852716.3662917.9022512.812719.421719.10Hypotension1173.07321.5974.2442.421042.96221.2564.3266.74Iliac artery embolism10.0310.050—10.6110.030—0—0—Increased platelets60.1610.050—0—60.1710.060—0—Intermittent claudication50.1340.2010.6110.6130.0910.0610.7222.25Myocardial infarction110.290—10.610—100.280—0—0—Myocardial ischemia90.2420.100—0—90.2620.110—0—Peripheral embolism250.65130.6521.2121.21210.6090.5121.4422.25Peripheral ischemia0—0—0—0—0—0—0—0—Sudden death0—0—0—0—0—0—0—0—Syncope962.52442.1942.4284.85862.45311.7764.3255.62Venous thromboembolic3088.071427.062414.55169.702687.631156.551611.511112.36*Breast, colorectal, head and neck, lung, and ovarian cancers.Table 4
ICD-9 codes for selected cancers and cardiovascular-related events.
CancerICD-9-CM code(s)Breast174.0-174.6, 174.8, 174.9, 175, 175.0, 175.9Colorectal153, 153.0-153.9, 154, 154.0-154.3, 154.8, 230.3-230.6Head and neck140.0-140.9, 141.0-141.9, 142.0-142.9, 143.0-143.9, 144.0-144.9, 145.0-145.9, 146.0-146.9, 147.0-147.9, 148.0-148.9, 149.0-149.9, 161.0-161.9Lung162.2-162.5, 162.8, 162.9Ovarian183.0CVD-related eventsICD-9-CM code(s)Arterial Thromboembolic eventsAngina pectoris413.xArterial disorder459.9Arterial occlusive disease362.34Cardiac disorder997.1Cardio-respiratory arrest427.5, 799.1Cardiogenic shock785.51Cerebral ischemia435, 435.8, 435.9, 437.1Cerebrovascular accident436, 437Chest pain or discomfort586.5xCirculatory collapse785.5, 785.50Embolism433, 434.x, 444.0–444.2, 444.21, 444.22, 444.81, 444.89, 444.9, 445, 445.01, 445.02, 445.81, 445.89Iliac artery embolism444.81Intermittent claudication440.21Myocardial infarction410.xMyocardial ischemia414.8Peripheral embolism444.xPeripheral ischemia414Cardiac Arrest427.5Hypertension401.x, 405.x, 401.0, 401.1, 401.9, 796.2Hypotension458.xIncreased platelets238.71, 287.1Sudden death798, 798.2Syncope780.0, 780.2, 780.9Venous thromboembolic eventsDeep vein thrombosis451.1, 451.11, 451.19, 451.2, 451.81, 451.83, 451.84, 453.1–453.4, 453.41, 453.42, 453.8, 453.9Phlebitis451.xPhlebitis superficial451.1Pulmonary embolism415.1, 415.11, 415.12, 415.19Superior vena cava occlusion459.2, 901.2, 38.8Thrombophlebitis451.x4Thrombophlebitis superficial451.0, 451.82, 671.2xVaricophlebitis454.1, 454.2, 454.8Vena cava thrombosis453.2Venous thrombosis453.0, 453.4, 453.9Table 5
Chemotherapeutic agents according to HEC or MEC status.
HEC or MECChemotherapeutic agentStrengthNDC or J-codeOralMEC (low)Arsenic10 MG/10 ML60553011110MEC (low)Arsenic10 MG/10 ML63459060010MEC (low)Carboplatin50 MG/0 ML15321030MEC (low)Carboplatin150 MG/10 ML15321130MEC (low)Carboplatin450 MG/40 ML15321230MEC (low)Carboplatin50 MG15321330MEC (low)Carboplatin150 MG15321430MEC (low)Carboplatin450 MG15321530MEC (low)Carboplatin10 MG/ML591333712MEC (low)Carboplatin10 MG/ML591333889MEC (low)Carboplatin10 MG/ML703324411MEC (low)Carboplatin10 MG/ML703324611MEC (low)Carboplatin10 MG/ML703324811MEC (low)Carboplatin10 MG/ML703324911MEC (low)Carboplatin50 MG703326401MEC (low)Carboplatin150 MG703326601MEC (low)Carboplatin450 MG703326801MEC (low)Carboplatin10 MG/ML703424401MEC (low)Carboplatin10 MG/ML703424601MEC (low)Carboplatin10 MG/ML703424801MEC (low)Carboplatin10 MG/ML10019091202MEC (low)Carboplatin10 MG/ML10019091203MEC (low)Carboplatin50 MG10019091501MEC (low)Carboplatin150 MG10019091601MEC (low)Carboplatin450 MG10019091701MEC (low)Carboplatin50 MG50111096576MEC (low)Carboplatin150 MG50111096676MEC (low)Carboplatin450 MG50111096776MEC (low)Carboplatin50 MG55390015001MEC (low)Carboplatin150 MG55390015101MEC (low)Carboplatin450 MG55390015201MEC (low)Carboplatin10 MG/ML55390015301MEC (low)Carboplatin10 MG/ML55390015401MEC (low)Carboplatin10 MG/ML55390015501MEC (low)Carboplatin10 MG/ML61703033918MEC (low)Carboplatin10 MG/ML61703033922MEC (low)Carboplatin10 MG/ML61703033950MEC (low)Carboplatin10 MG/ML61703033956MEC (low)Carboplatin150 MG63323016721MEC (low)Carboplatin450 MG63323016800MEC (low)Carboplatin10 MG/ML63323016905MEC (low)Carboplatin10 MG/ML63323016915MEC (low)Carboplatin10 MG/ML63323016945MEC (low)Carboplatin10 MG/ML63323017245MEC (low)Cyclophosphamide100 MG13560693MEC (low)Cyclophosphamide200 MG13561693MEC (low)Cyclophosphamide500 MG13562693MEC (low)Cyclophosphamide500 MG15050241MEC (low)Cyclophosphamide50 MG15050301MEC (low)Cyclophosphamide50 MG15050302MEC (low)Cyclophosphamide25 MG15050401MEC (low)Cyclophosphamide100 MG15053941MEC (low)Cyclophosphamide200 MG15054641MEC (low)Cyclophosphamide500 MG15054741MEC (low)Cyclophosphamide25 MG54412925MEC (low)Cyclophosphamide50 MG54413025MEC (low)Cyclophosphamide25 MG54808925MEC (low)Cyclophosphamide50 MG54813025MEC (low)Cyclophosphamide500 MG10019095501MEC (low)Cytarabine1 GM9329501MEC (low)Cytarabine1 GM703519401MEC (low)Cytarabine1 GM55390013301MEC (low)Cytarabine1 GM55390080801MEC (low)Daunorubicin20 MG703503203MEC (low)Daunorubicin20 MG/4ML55390010810MEC (low)Daunorubicin20 MG55390028110MEC (low)Daunorubicin2 MG/ML56146030101MEC (low)Daunorubicin2 MG/ML61958030101MEC (low)Doxorubicin20 MG13109691MEC (low)Doxorubicin20 MG13109694MEC (low)Doxorubicin20 MG/10 ML13114691MEC (low)Doxorubicin20 MG/10 ML13114694MEC (low)Doxorubicin20 MG/10 ML13124691MEC (low)Doxorubicin50 MG/20 ML13115679MEC (low)Doxorubicin50 MG/20 ML13125679MEC (low)Doxorubicin50 MG186153101MEC (low)Doxorubicin50 MG10019092102MEC (low)Doxorubicin50 MG55390023301MEC (low)Doxorubicin50 MG55390024301MEC (low)Epirubicin2 MG/ML9509101MEC (low)Epirubicin2 MG/ML9509301MEC (low)Epirubicin50 MG61703034735MEC (low)Idarubicin5 MG13250694MEC (low)Idarubicin20 MG13252686MEC (low)Idarubicin1 MG/ML13253678MEC (low)Idarubicin1 MG/ML13255667MEC (low)Idarubicin1 MG/ML13259691MEC (low)Ifosfamide1 GM15055605MEC (low)Ifosfamide1 GM15055611MEC (low)Ifosfamide1 GM15055641MEC (low)Ifosfamide3 GM15055741MEC (low)Ifosfamide5 GM/3 GM703410048MEC (low)Ifosfamide1 GM63323014210MEC (low)Irinotecan20 MG/ML9752901MEC (low)Irinotecan20 MG/ML9752902MEC (low)Pentostatin10 MG62701080001MEC (low)Temozolomide5 MG85124801MEC (low)Temozolomide5 MG85124802MEC (low)Temozolomide5 MG85124803MEC (low)Temozolomide20 MG85124401MEC (low)Temozolomide20 MG85124402MEC (low)Temozolomide250 MG85125201MEC (low)Temozolomide250 MG85125202MEC (low)Temozolomide100 MG85125901MEC (low)Temozolomide100 MG85125902MEC (low)Temozolomide100 MG85136601MEC (low)Temozolomide100 MG85136602MEC (low)Temozolomide250 MG85141701MEC (low)Temozolomide140 MG85142501MEC (low)Temozolomide140 MG85142502MEC (low)Temozolomide180 MG85143001MEC (low)Temozolomide180 MG85143002MEC (low)Temozolomide20 MG85151901MEC (low)Temozolomide20 MG85151902MEC (low)Temozolomide20 MG54868414205MEC (low)Temozolomide20 MG54868414206MEC (low)Temozolomide5 MG54868534801MEC (low)Temozolomide100 MG54868535002MEC (low)Temozolomide250 MG54868535400MEC (high)Carmustine100 MG15301238MEC (high)Carmustine100 MG15301297MEC (high)Cisplatin50 MG/50 ML15322022MEC (high)Cisplatin50 MG/50 ML15322097MEC (high)Cisplatin1 MG/ML703574711MEC (high)Cisplatin1 MG/ML703574811MEC (high)Cisplatin1 MG/ML10019091001MEC (high)Cisplatin1 MG/ML10019091002MEC (high)Cisplatin50 MG/50 ML55390011250MEC (high)Cisplatin50 MG/50 ML55390041450MEC (high)Cisplatin1 MG/ML63323010351MEC (high)Cisplatin1 MG/ML63323010364MEC (high)Cisplatin1 MG/ML63323010365MEC (high)Cyclophosphamide1 GM13563670MEC (high)Cyclophosphamide1 GM15050541MEC (high)Cyclophosphamide1 GM15054812MEC (high)Cyclophosphamide1 GM15054841MEC (high)Cyclophosphamide1 GM10019095601MEC (high)Cytarabine2GM55390013401MEC (high)Cytarabine2GM55390080901MEC (high)Cytarabine2000 MG/20 ML61703031922MEC (high)Cytarabine2000 MG/20 ML61703031922MEC (high)Dactinomycin0.5 MG6329822MEC (high)Dactinomycin0.5 MG67386081155MEC (high)Doxorubicin200 MG/100 ML13116683MEC (high)Doxorubicin75 MG/37.0 ML13117687MEC (high)Etoposide500 MG/20 ML15306120MEC (high)Etoposide1 GM/50 ML15306220MEC (high)Etoposide500 MG/20 ML55390029201MEC (high)Etoposide1000 MG/50 ML55390029301MEC (high)Etoposide500 MG/20 ML55390049201MEC (high)Etoposide1000 MG/50 ML55390049301MEC (high)Melphalan2 MG81004535MEC (high)Melphalan2 MG173004535MEC (high)Melphalan50 MG173013093MEC (high)Melphalan50 MG173013093MEC (high)Melphalan2 MG54868433901MEC (high)Melphalan2 MG54868433902MEC (high)Melphalan2 MG59572030250MEC (high)Methotrexate1 GM55390014301MEC (high)Methotrexate1000 MG/40 ML63323012140MEC (high)Methotrexate1 GM63323012250MEC (high)Methotrexate1 GM66479013929MEC (high)Procarbazine50 MG4005301MEC (high)Procarbazine50 MG54482005301HECCisplatin100 MG/100 ML15322122HECCisplatin100 MG/100 ML55390011299HECCyclophosphamide2GM13564670HECCyclophosphamide2GM15050641HECCyclophosphamide2GM15054941HECCyclophosphamide2GM10019095701HECDacarbazine200 MG26815120HECDacarbazine200 MG703507501HECDacarbazine200 MG703507503HECDacarbazine200 MG55390009010HECDacarbazine200 MG61703032722HECDacarbazine100 MG63323012710HECDacarbazine200 MG63323012820HECMechlorethamine10 MG6775331HECMechlorethamine10 MG67386091151HECStreptozocin1 GM9084401HECStreptozocin1 GM703463601InjectablesMEC (low)Cyclophosphamide; oral25 MGJ8530MEC (low)Injection, arsenic trioxide1 MGJ9017MEC (low)Cyclophosphamide100 MGJ9070MEC (low)Cyclophosphamide200 MGJ9080MEC (low)Cyclophosphamide500 MGJ9090MEC (low)Cyclophosphamide, lyopholized100 MGJ9093MEC (low)Cyclophosphamide, lyopholized200 MGJ9094MEC (low)Cyclophosphamide, lyopholized500 MGJ9095MEC (low)Injection, epirubicin HCL2 MGJ9178MEC (low)Injection, irinotecan20 MGJ9206MEC (low)Injection, ifosfamide1 GMJ9208MEC (low)Injection, idarubicin hydrochloride5 MGJ9211MEC (low)Injection, mitoxantrone hydrochloridePer 5 MGJ9293MEC (low)Lomustine, oral10 MGS0178MEC (high)Injection, carboplatin50 MGJ9045MEC (high)Injection, carmustine100 MGJ9050MEC (high)Cisplatin, powder or solutionPER 10 MGJ9060MEC (high)Cyclophosphamide1.0 GMJ9091MEC (high)Cyclophosphamide, lyophilized1.0 GMJ9096MEC (high)Injection, dactinomycin0.5 MGJ9120MEC (high)Injection, melphalan hydrochloride50 MGJ9245MEC (high)Pracarbazine hydrochloride, oral50 MGS0182HECCisplatin50 MGJ9062HECCyclophosphamide2.0 GMJ9092HECCyclophosphamide, lyophilized2.0 GMJ9097HECDacarbazine100 MGJ9130HECDacarbazine200 MGJ9140HECInjection, mechlorethamine hydrochloride (nitrogen mustard)10 MGJ9230HECInjection, streptozocin1 GMJ9320MEC (low): moderately emetogenic chemotherapy associated with 30–60% of patients having emesis, MEC (high): moderately emetogenic chemotherapy associated with 60–90% of patients having emesis, HEC: highly emetogenic chemotherapy associated with >90% of patients having emesis.For the HEC-only and the combined HEC/MEC chemotherapy groups, the numbers of individual cardiovascular-related events were generally too small (n≤10) to make reliable comparisons across aprepitant status.  However, where cells sizes were larger, HEC-only-treated patients who did not use aprepitant compared to users had a higher frequency of chest pain/discomfort as a diagnosis,  a composite diagnosis of arterial thromboembolic events, excluding chest pain and discomfort, hypertension, and a composite measure of venous thromboembolic events. Though rare (n≤10), additional events that were more frequent among nonusers compared to aprepitant users included angina pectoris (2 cases versus 1), embolism (5 versus 3), and hypotension (7 versus 4); in contrast, aprepitant users had a higher frequency of syncope (4 cases versus 8) than nonusers.Among patients treated with both HEC and MEC, there was a higher frequency of chest pain and discomfort as a diagnosis and a composite diagnosis of arterial thromboembolic events, including chest pain, in nonusers of aprepitant compared to users.  Users had a higher frequency of hypotension (6 cases versus 6), intermittent claudication (2 versus 1), and peripheral embolism (2 versus 2).


## 4. Discussion

The proportion of patients with CVD events was low (≤5%) for many events across all chemotherapy groups, except for hypertension and the composite measures for arterial thromboembolic and venous thromboembolic events.  This is in line with population-based data showing an annual incidence (per 1000 persons) of myocardial infarction of about 4 for men and 2 for women (Atherosclerosis Risk In Communities Surveillance data, 1987–2001), an annual incidence (per 1000 persons) of angina pectoris of 4 to over 8 among men ages 45–54 and 65+ years, respectively, and 0.9 to over 4 among women ages 45–54 and 65+ years, respectively (National Heart, Lung, and Blood Institute data, 2006), and a 33.6% prevalence of hypertension among US adults 20 years and older (National Health and Nutrition Examination Survey data, 2003–2006) [18].CVD occurrences were slighter higher for those treated with HEC only or HEC/MEC combined than those treated with MEC-only.  In addition, the HEC/MEC combined group experienced a slightly elevated frequency of hypotension compared to the HEC-only or MEC-only groups.  It is noteworthy that sample sizes for the HEC-only and HEC/MEC combination groups are orders of magnitude smaller than the MEC-only group, and, thus, slightly higher percentages observed in these two groups may be due to sample variability.Those who did not use aprepitant compared to those who did generally experienced higher frequencies of certain CVD-related events, namely, cardiac arrest, hypertension, hypotension, the composite of arterial thromboembolic events without chest pain/discomfort, and, in particular, cardio-respiratory arrest, cerebral ischemia, cerebrovascular accident, and embolism among the MEC-only treated group; arterial thromboembolic events with chest pain among the HEC/MEC combined chemotherapy groups; arterial thromboembolic events without chest pain, hypertension, and venous thromboembolic events in the HEC-only treated group.  While there were some CVD-related events that occurred at a higher frequency among aprepitant users compared to nonusers, the absolute number of events was small, and most events were either similar across the two groups or higher in the nonaprepitant user group.  In particular, in the MEC-only group, with its large numbers of users and nonusers, arterial disorder was higher among aprepitant users but the occurrence of all other events was either similar or lower among aprepitant users compared to nonusers.  This may be explained by the fact that nonusers were more likely than users to be older and have a prior history of cardiovascular disease.Aprepitant is a substrate and dose-dependent inhibitor and inducer of the cytochrome P4503A4 (CYP3A4) isoenzyme, and drugs metabolized by CYPA34 can have a potential drug interaction with aprepitant [19].  For example, cyclophosphamide is an anticancer agent that is metabolized to its active metabolites by CYPA34 [10] and is also associated with cardiac side effects such as acute heart failure, pericardial effusion, and arrhythmia [7].  Coadministration with aprepitant causes a decrease in plasma concentrations of the active metabolites of cyclophosphamide by 5% [20], a level which may not be clinically significant [10].Some 5-HT3 RA antiemetics (e.g., dolasetron, granisetron and ondansetron) have been associated with reversible, clinically insignificant changes to electrocardiographic (ECG) parameters (i.e., PR, QTS, QT, and JT intervals) [21], and their coadministration could have a diluting or enhancing effect on the occurrence of cardiovascular events.As with all administrative databases, the claims data collected were not designed for research purposes, and, thus, are limited in scope and lack detailed clinical information available in medical records, such as ECG readings and lab data on MI-induced elevations of troponin, and so forth.  A claim may represent a condition to be ruled out rather than diagnosis of the condition, itself.  Discharge diagnosis for the identification of cardiovascular and thromboembolic events can have several sources of error, including variation in coding procedures, coding errors, incomplete coding, lack of specificity in available codes, and error in clinical diagnosis [22].  Misclassification of outcomes could lead to biased results.  Nevertheless, the usefulness of claims data for certain CVD events has been assessed by other investigators.  For example, a validation study of claim codes from a commercial insurance claims database, similar to IMPACT, against the gold standard medical records, showed a positive predictive value of 88% for both myocardial infarction and ischemic stroke [23].This was a high-level analysis performed to provide overall background rates in a population of cancer patients similar to those under study in our clinical development program.  It was not designed to draw causal inferences in differences between users of aprepitant and nonusers.  The decision whether to treat with aprepitant most likely depends on many factors, such as the ability to pay for medications, physician experience, emetogenic potential of the chemotherapeutic agent, drug-drug interactions, and whether treatment is for acute or delayed CINV [24, 25].  We did not attempt to unmask or correct for potential channeling bias, nor did we consider other possible confounding factors between the aprepitant user and nonuser groups, including drug severity and comorbidity.  Our comparisons did not take into account possible confounding due to drug-drug interactions with specific cardiotoxic chemotherapeutic agents or other coadministered antiemetics.  We did not account for chemotherapeutic drug dosages and did not have adequate sample size for assessing effects among individual cycles of chemotherapy.  As a next step, we would have corrected for as many of these shortcomings as possible in a subsequent, more rigorous pharmacoepidemiology study had our clinical development program advanced.Despite these limitations, this analysis provided a “real world” clinical practice baseline picture of the frequency of CVD-related events that occur during use of highly or moderately emetogenic chemotherapy, serving as a useful benchmark for safety signals identified during one of our clinical trial programs.  Results should also serve for future supportive care studies.  The preliminary information on experiences of the aprepitant antiemetic group compared to nonusers was helpful but should be interpreted cautiously.



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*Source: 529357-2012-04-12.xml*