chemotherapy - induced nausea and vomiting ( cinv ) negatively impacts the quality of life in cancer patients   and may lead to nonadherence to or dose reductions in chemotherapy .
potential cardiac effects of antiemetics warrant special attention , given an estimated 1360% burden of cardiovascular - related diseases that increases with age , among cancer patients [ 35 ] .
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 728% incidence of heart failure , cisplatin has been associated with an 8.5% incidence of venous thromboembolism , including deep vein thrombosis and pulmonary embolism , and doxorubicin / daunorubicin has been associated with 0.53% incidence of arrhythmias .  
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 .
although aprepitant has been shown to be generally well tolerated in clinical trials , isolated cases of serious adverse events , such as bradycardia   and hypertension , 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 .
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 .
a retrospective cohort study of adult patients with select cancers , treated with hec and/or mec , was conducted using 20052007 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 study included several cancer types commonly treated with hec or mec , namely , breast , colorectal , head and neck , lung , and ovarian cancer patients ( table 4 ) , 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 
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 3090% of patients having emesis ( table 5 ) .
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 .
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 ( table 1 ) .
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 .  
overall , the frequencies of cardiovascular and thromboembolic - related events following any hec or mec treatment were mostly driven by the mec - only treatment group , comprising 90% of patients ( table 2 ) .
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 .  
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
stratified by the decision to include aprepitant in the antiemetic regimen ( table 3 ) , 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 .   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 ) .
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 , 19872001 ) , an annual incidence ( per 1000 persons ) of angina pectoris of 4 to over 8 among men ages 4554 and 65 + years , respectively , and 0.9 to over 4 among women ages 4554 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 , 20032006 ) .  
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 .
for example , cyclophosphamide is an anticancer agent that is metabolized to its active metabolites by cypa34   and is also associated with cardiac side effects such as acute heart failure , pericardial effusion , and arrhythmia .
coadministration with aprepitant causes a decrease in plasma concentrations of the active metabolites of cyclophosphamide by 5% , a level which may not be clinically significant .  
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 ) , 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 .
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 .  
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 .
the preliminary information on experiences of the aprepitant antiemetic group compared to nonusers was helpful but should be interpreted cautiously .
 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 20052007 impact national benchmark database were classified into emetogenic chemotherapy categories and cvd outcomes . among 5827 hec / mec - treated patients , 
 frequencies were highest for hypertension ( 1621% ) and composites of venous ( 712% ) and arterial thromboembolic events ( 47% ) . 
 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 . 
1. Background/Objective
2. Methods 
3. Results
4. Discussion 