A Retrospective Claims Database Study on Drug

Sep 23, 2016 - Abbvie GK, 3-5-27, Mita, Minato-ku, Tokyo ... Clinical trials have demonstrated the efficacy ... might differ from clinical trials, as ...

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Adv Ther (2016) 33:1947–1963 DOI 10.1007/s12325-016-0406-6

ORIGINAL RESEARCH

A Retrospective Claims Database Study on Drug Utilization in Japanese Patients with Crohn’s Disease Treated with Adalimumab or Infliximab Kaoru Yokoyama . Kiyotaka Yamazaki . Miiko Katafuchi . Sameh Ferchichi

Received: June 14, 2016 / Published online: September 23, 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com

ABSTRACT

or IFX prescriptions between January 2012 and

Introduction: Crohn’s disease (CD) is a chronic

February 2015 were included. Outcomes of interest were (1) failure in the induction phase

and progressive disease in which the long-term

(defined as switch or discontinuation) and (2)

management is important. This study sought to assess treatment persistence and dose escalation

persistence in the maintenance phase (defined as the absence of switch or discontinuation over

in the maintenance phase with adalimumab (ADA) or infliximab (IFX) in a Japanese

12 months since maintenance initiation). Results: Overall, 133 patients (53 ADA; 80 IFX)

real-world setting.

were included. Of them, treatment failed in 26

Methods: A retrospective analysis was conducted using the Japan Medical Data

patients (19.6%) in the induction phase. During the induction phase, there was a trend towards

Center database. CD patients with either ADA

fewer treatment failures with ADA than IFX (88.7% vs. 75.0%; p = 0.051). Of those who

Enhanced content To view enhanced content for this article go to http://www.medengine.com/Redeem/9E76 F06048096649.

completed induction, 64 patients (33 ADA; 31

Electronic supplementary material The online version of this article (doi:10.1007/s12325-016-0406-6) contains supplementary material, which is available to authorized users.

IFX) had at least 12 months of valid insurance enrolment after the initiation of maintenance and 13 (5 ADA; 8 IFX) had either switch or discontinuation within 12 months after the initiation of maintenance. Probabilities of

K. Yokoyama Department of Gastroenterology, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan K. Yamazaki (&)  M. Katafuchi Abbvie GK, 3-5-27, Mita, Minato-ku, Tokyo 108-6302, Japan e-mail: [email protected] S. Ferchichi Creativ-Ceutical, 215 rue du Faubourg Saint-Honore´, 75008 Paris, France

switch or discontinuation over 12 months after the maintenance date were 15.2% and 20.9% for ADA and IFX groups, respectively (p-log rank = 0.7764). Conclusion: Japanese patients have a high primary response to anti-tumor necrosis factor therapy in the real-world setting, in line with the

results

of

clinical

trials.

This

initial

Adv Ther (2016) 33:1947–1963

1948

therapeutic advantage can be lost during the

with immunosuppressants is associated with

maintenance phase, leading to dose escalation, treatment switch, or discontinuation. This

adverse events risk [4], and treatment with

study suggests that those events occurred in comparable proportions of patients treated with either ADA or IFX. However, these findings should be considered with caution given the retrospective nature and small size of the study.

corticosteroids is maintenance of

not adequate for clinical remission

the [5].

Monoclonal antibodies, targeting tumor necrosis factor (TNF)-a, are considered the treatment of choice in patients with CD [6].

Funding: Abbvie GK, Tokyo, Japan.

In Japan, the available anti-TNF treatments for CD are infliximab (IFX) and adalimumab

Keywords: Adalimumab;

(ADA). IFX was the first TNF-a chimeric monoclonal antibody introduced for the

Anti-TNF;

Crohn’s

disease; Discontinuation; Dose escalation; Gastroenterology; Infliximab; Persistence; Switch

treatment of CD in 2002. It is administered intravenously at a dose of 5 mg/kg body weight at weeks 0, 2, and 6 for induction. The standard dose of maintenance IFX therapy is 5 mg/kg of body weight administered every 8 weeks [7].

INTRODUCTION

ADA is administered subcutaneously and is

Crohn’s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract belonging

prescribed at an induction dose of 160 mg at week 0 and 80 mg at week 2. The standard

to the group of Inflammatory Bowel Diseases

maintenance dose is 40 mg administered every 2 weeks [8–10].

(IBD) that results in a considerably decreased quality of life. The incidence and prevalence of

Clinical trials have demonstrated the efficacy and safety of ADA and IFX in the induction and

CD are increasing with time and in different regions around the world [1]. The highest

maintenance of remission in patients with

reported prevalence rates per 100,000 persons

moderate to severe CD, in particular in Japanese patients [7, 8, 11–13]. However,

were 322 in Europe, 318.5 in North America, and 67.9 in Asia and the Middle East [1]. In

treatment outcomes in the real-world setting might differ from clinical trials, as patients’

Japan, the prevalence of CD reached 26.8 per 100,000 in 2010 [2].

profiles may be more diverse and patients may

Given the chronic and progressive nature of

not strictly adhere to a regular injection schedule. Several real-world studies have

the disease, the main goal of the treatment is to stop progression, reduce and control symptoms,

demonstrated that despite the high response rate, the response to ADA or IFX is lost over

reduce the risks of complication, and maintain nourishment to improve the quality of life of

time, leading the efficacy of treatment waning

long-term

(and consequently dose increase) to treatment discontinuation or to treatment switch [14–22].

management as well as treatment persistence is very important.

However, to date, there is limited real-world Japan-specific evidence in the literature

CD management includes drug, nutritional and surgical therapies. However, it has been

regarding loss of response and treatment

patients

[3].

Therefore,

the

shown that the standard therapies for CD

persistence. The primary objectives of this study were: (1)

patients have several limitations; treatment

to estimate the probability of treatment failure

Adv Ther (2016) 33:1947–1963

1949

in the induction phase with ADA or IFX and (2)

defined

to estimate the probability of persistence in the

procedure codes [25, 26].

maintenance phase with ADA or IFX. The secondary objective was to estimate the

Ethical Considerations

probability of dose escalation maintenance phase with ADA

The

in or

the IFX.

Exploratory objectives were to estimate the probabilities of adverse events and surgical procedures in the maintenance phase.

using

protocol

Japan-specific

was

submitted

standardized

to

Kitasato

University Hospital’s Ethics Committee, but the study was exempted from ethical review, since no personally identifiable data were used

METHODS

in the JMDC extraction for the current study. Patients were identified via a unique

Study Design and Data Source

anonymized code assigned by JMDC and the authors did not have access to the original data containing personal information.

This study was a retrospective observational cohort analysis of CD patients enrolled in the Japan Medical Data Center (JMDC) database.

Study Population

The JMDC database is an administrative database comprising medical and pharmacy

The study population was identified based on

claims data for salaried workers of medium-to large-scale companies and their family members. This database included up to 2.3 million insured persons between 2005 and 2015, representing approximately 1.8% of the Japanese population. A database extract was used in the current study that included patients with at least one health insurance claim associated with a CD diagnosis and at least one prescription of ADA or IFX between December 2011 and May 2015. The database was completely anonymized and

contained

patient

demographic

information (gender, age, insurance type, and reason of withdrawal), inpatient and outpatient medical and pharmacy claims data, with clinical diagnoses coded under the International Classification of Diseases 10th revision (ICD-10) classification [23], Japan-specific standard disease codes [24], drug prescriptions information coded according to the Anatomical Therapeutic Chemical (ATC) classification, as well as health care procedures

members’ medical and pharmacy claims data. To meet the objectives of the study, two populations of interest were identified. The population #1—called induction analyses population—included patients who: (1) had a prescription of ADA or IFX between January 2012 and February 2015 (the first prescription date of ADA or IFX was called the ‘‘index date’’); who (2) had a claim associated with a confirmed diagnosis of CD before or at the same time than the index date, between January 2012 and February 2015; who had (3) no prescription of ADA or IFX, initiated or ongoing, in the 6 months before the index date, and (4) a minimum of 17 weeks of valid insurance status after the index date. A 17-week follow-up was required, as the discontinuation of IFX treatment was assessed up to 17 weeks after the index date. The population #2—called maintenance analyses population—was a subpopulation of population #1 who (1) completed the induction phase of ADA or IFX and entered the maintenance phase with the same treatment

Adv Ther (2016) 33:1947–1963

1950

and who (2) had at least 12 months of valid

(c) no fourth IFX prescription up to 10 weeks

insurance

of

after the third IFX injection. In short, patients

maintenance. In addition, two subgroups of interest were defined: patients with or without

were considered to discontinue in the case of deviation from the theoretical injection

immunosuppressant therapy after the index date.

schedule by more than 2 weeks. For ADA prescriptions, discontinuation in induction

status

after

the

initiation

phase was defined as: (1) the absence of the Definitions of Variables and Outcomes

third ADA injection up to 2 weeks after the expected date of the third injection and (2)

A confirmed CD diagnosis was identified in medical claims data, using the ICD-10 code

(a) no second ADA injection up to 4 weeks after the index date or (b) no third ADA injections up

‘‘K50’’ and a diagnosis without a suspicious flag in the database. Prescriptions of ADA or IFX

to 4 weeks after the second ADA injection.

were identified in the pharmacy claims data

In addition, if an event, such as infection, surgery, or immunostimulant(s) therapy,

based on ATC codes ‘‘L04B-’’. Patients’ demographic characteristics were

occurred between two prescription dates, then patients were allowed an additional 2 weeks of

directly available in the database, and included age, gender, type of insurance policy holder

delay before the next ADA or IFX prescription

(primary policy holder or family member), and

(for example, if a patient had an infection between the second and third injections, and

length of follow-up. Pharmacy claim records included prescribed dose (first, second, and

the third injection was within 8 weeks of the second one, then the patient was not classified

third), average dose intake in induction phase or maintenance phase, and average time

as discontinued IFX treatment).

between prescriptions.

Persistence in the Maintenance Phase

Treatment Failure in the Induction Phase

Persistence in the maintenance phase was assessed among the population #2 and was

Treatment failure in the induction phase was assessed in the population #1, and was defined

defined as the absence of switch or discontinuation in the post-induction phase.

as switch or discontinuation in the induction phase. Switch in the induction phase was

Switch in the maintenance phase was

defined as at least one new prescription of

defined as at least one prescription of ADA within 2 weeks following an IFX prescription

ADA within 17 weeks among patients who had initiated induction on IFX treatment or vice

among patients initiating maintenance treatment with IFX, or vice versa.

versa. For the IFX group, discontinuation in the

For the IFX group, discontinuation in the

induction phase was defined as: (1) the absence

maintenance phase was defined as: (1) no IFX prescription up to 70 days (10 weeks) after the

of the fourth IFX injection, which is theoretically scheduled on week 16, over

last prescription date and (2) no infections, surgeries, or immunostimulant therapy within

17 weeks after the index date and (2) (a) no second IFX prescription up to 4 weeks after the

12 weeks from the last prescription date. For the ADA group, a patient was considered

index date, or (b) no third IFX prescription up to 6 weeks after the second IFX injection, or

to have discontinued treatment after the ‘nth’ prescription at time tn with a quantity qn if

Adv Ther (2016) 33:1947–1963

1951

there was: (1) no ADA prescription renewal up

system, and diseases of the digestive system.

to (tn ? 1 ? 14) days (tn ? 1 was defined as the

Adverse events were defined as confirmed

expected next prescription date, according to the quantity prescribed qn) and (2) no

diagnosis (without a suspicious flag) occurring for the first time in patient history, after the

infections, surgeries, or immunostimulant therapy within 12 weeks from the last

index date. Surgery was Japan-specific procedure

prescription

Immunostimulants,

date

tn .

In

other

words,

identified codes

using [26].

immunosuppressant,

discontinuation was assumed to occur if no prescription renewal occurred within 2 weeks

leucocyte removal therapy, and enteral nutrition therapies were identified using ATC

following the expected date of renewal and there was no infection justifying the delay to

codes. Complications (fistulas or obstructions) were assessed in the pre-index period (3 months

prescription renewal.

prior to the index date), and were defined using

Dose Escalation in Maintenance Phase

ICD-10 codes with a confirmed diagnosis. The full list of codes (ATC, ICD-10, and procedure

Dose escalation in the maintenance phase was assessed among population #2 and was defined

codes) is provided in the Supplementary Materials (Tables S5, S6, and S7).

as an increase in maintenance therapy dosage or a reduction in the interval between

Statistical Analyses

maintenance therapy prescriptions. For IFX prescriptions, dose escalation was defined as: (1) at least two successive

Categorical variables were compared between treatment groups using the Chi-square test or

prescriptions with a number of vials exceeding by 2 the number previously prescribed (e.g.,

Fisher’s exact test, and continuous variables were compared using the Student’s t or

three vials to five vials, three vials to six vials,

Wilcoxon tests. Study outcomes were described over 12 months and 24 months of

etc.), or at least two successive intervals between injections of less than 6 weeks (5 mg/kg every

follow-up,

respectively.

Times

from

6 weeks or shorter instead of 5 mg/kg every 8 weeks). For ADA prescriptions, dose escalation

maintenance date to switch, to discontinuation, and to dose escalation were

was defined as: (1) at least two successive

described using Kaplan–Meier survival curves, stratified by treatment group and for all patients

prescriptions which showed an increase in maintenance therapy dosage (e.g., from 40 mg

(ADA

or

IFX).

Kaplan–Meier curves

compared between Log-rank test.

of prescriptions, defined as an increase in the

Only the month and year were available for the date of claims and diagnoses in the JMDC

number of prescribed syringes per prescribed duration.

treatments

using

were

every 2 weeks to 80 mg every 2 weeks) or (2) at least two successive reductions in the frequency

the

database. However, the full date including the

Exploratory Outcomes

day (DD/MM/YYYY) was available for the majority of prescriptions (dates were missing

Adverse events were identified in medical claims data using ICD-10 codes; these included

in 6% of ADA and IFX prescriptions) and health care procedures (dates were missing in 9% of

infections, anemia, neoplasms, nutritional and

procedures). An imputation algorithm was

metabolic diseases, diseases of the respiratory

created to complete missing dates of ADA and

Adv Ther (2016) 33:1947–1963

1952

IFX prescriptions, based on the theoretical delay

Around 32% of patients were prescribed

between prescriptions (the detailed algorithm is

immunosuppressant therapy after the index

provided in the Supplementary Material [Fig. S10]). The other missing days (dates of

date in both treatment groups. Nutrition prescriptions were frequent; 71.7% of patients

prescriptions other than ADA or IFX and dates of procedures and diagnoses) were imputed

who initiated their treatment with ADA had enteral nutrition prescription after the index

using the corresponding claim date when

date, compared to 66.2% in IFX group (Table 1).

available; alternatively, the 15th of the month was used.

Failure in Induction Phase

A sensitivity analysis was conducted to assess the impact of changing the definition of

Among patients who initiated their treatment

discontinuation on the results of persistence in the maintenance phase. The time window in the definition was varied by ±7 days (i.e., for

with ADA or IFX (population #1—133 patients), 26 patients (19.6%) switched or discontinued their treatment during the induction phase.

the IFX group, the time widow was varied from 63 to 77 days; and for the ADA group, it was

Among patients who initiated their treatment with ADA, 88.7% completed induction phase

varied from (tn ? 1 ? 7) days to (tn ? 1 ? 21)

and moved to maintenance phase with the same treatment, compared to 75.0% for IFX group

days). Analyses were conducted using the SAS statistical software version 9.3 (SAS Inc., Cary, NC, USA).

RESULTS

(p = 0.051) (Table 2). Treatment discontinuation occurred in 11.3% and 21.3% of patients in the ADA and IFX groups, respectively. No patient in the ADA group switched treatment during induction phase (Table 2).

Study Population

Persistence in Maintenance Phase

From January 2012 to February 2015, 150 CD

Among patients who had completed induction

patients treated with ADA or IFX met the inclusion and exclusion criteria. Of these

phase and entered maintenance phase with the

patients, 133 (53 ADA; 80 IFX) had at least 17 weeks of follow-up after the index date (Fig. S1, Supplementary Material). The majority of patients were male (84.2%), with individual-level insurance, and the mean age was 34.4 years (SD = 13.0. The mean follow-up time was 18.4 months (SD = 9.7). The average number of biologics prescriptions after the index date was 17.1 (SD = 12.5) for patients initiating their treatment with ADA and 10.3 (SD = 5.8) for the IFX group (Table 1).

same treatment (107 patients), 64 patients (33 ADA, 31 IFX) had at least 12 months of valid insurance enrolment after the initiation of maintenance (population #2). Of these, 13 patients (5 ADA, 8 IFX) had at least either a switch or discontinuation event within 12 months after the initiation of maintenance (Table S1, Supplementary Material). Over 12 months following the initiation of maintenance, the probability of a switch or discontinuation was 15.2% for the ADA group versus 20.9% for IFX group (p-log rank = 0.7764) (Fig. 1).

69 (86.3%)

Male

32.5

Median

56 (70.0%)

Individual

33 (62.3%)

20 (37.7%)

34

35.2 (12.9)

43 (81.1%)

10 (18.9%)

89 (66.9%)

44 (33.1%)

33

34.4 (13.0)

112 (84.2%)

21 (15.8%)

0.35

0.58

0.43

8

Median

14

17.1 (12.5)

17.5

Median

9 (17.0%)

18.1

19.2 (9.8)

1 (1.9%)

1 (0.8%)

24 (18.1%)

18

18.40 (9.6)

11

13.0 (9.7)

26 (32.5%)

17 (32.1%)

43 (32.3%)

Immunosuppressant prescription after the index date, n (%)

0

Immunostimulants after the index date, n (%)

15 (18.8%)

Surgery after the index date, n (%)

17.8 (9.5)

Mean (SD)

Follow-up time after the index date, months

10.3 (5.8)

Mean (SD)

0.96

0.40

0.80

0.41

0.001

Number of prescriptions of ADA or IFX after the index date (index date included)

24 (30.0%)

Family

Type of insurance, n (%)

33.9 (13.2)

Mean (SD)

Age at the index date, years

11 (13.8%)

Female

Gender, n (%)

p value*

17 (28.3%)



10 (16.7%)

16.9

17.9 (9.6)

9

10.8 (5.3)

41 (68.3%)

19 (31.7%)

32

32.9 (12.6)

52 (86.7%)

8 (13.3%)

14 (29.8%)



8 (17.0%)

18.6

19.4 (9.7)

15

18.5 (12.4)

29 (61.7%)

18 (38.3%)

33

33.7 (12.7)

39 (83.0%)

8 (17.0%)

ADA (n 5 47)

IFX (n 5 60)

Total (n 5 133)

IFX (n 5 80)

ADA (n 5 53)

Population #2 (n 5 107)

Population #1 (n 5 133)

Table 1 Patient demographic and clinical characteristics

31 (29.0%)



18 (16.8%)

18.1

18.6 (9.6)

12

14.2 (9.9)

70 (65.4%)

37 (34.6%)

32

33.2 (12.6)

91 (85.1%)

16 (15.0%)

Total (n 5 107)

0.87

0.96

0.96

0.43

0.001

0.47

0.76

0.60

p value*

Adv Ther (2016) 33:1947–1963 1953

p value*

38 (71.7%)

14

Median

14

14.3 (9.6) 14

19.7 (21.3)

91 (68.4%)

28

Median

15

22.4 (17.7) 28

31.6 (23.1)

0.0001

0.02

0.51



Median

3

Median

Mean (SD)

3.3 (1.0)

Average induction dose

3

Median

a

3.2 (1.3)

Mean (SD)

Third dosea

3.3 (1.0)

Mean (SD)

Second dose

3

Median

a

3.3 (0.9)

Mean (SD)

First dosea



Mean (SD)

3.1 (0.8)

2

2.2 (1.5)

2

2.5 (1.3)

4

3.7 (0.9)









































Average time between two successive prescriptions during maintenance phase, days

37.7 (24.4)

Mean (SD)

Time between the second and the third prescriptions, days

23.2 (25.8)

Mean (SD)

Time between the first and second prescriptions, days

53 (66.3%)

Enteral nutrition prescription after the index date, n (%)

3.2 (0.7)

3

3.2 (0.8)

3

3.2 (0.7)

3

3.2 (0.7)

33.5

31.1 (14.4)

28

30.3 (7.4)

14

16.6 (9.1)

40 (66.7%)

3.2 (0.8)

2

2.3 (1.4)

2

2.6 (1.2)

4

3.8 (0.8)

27

27.5 (12.3)

16

21.7 (12.5)

14

13.8 (7.7)

35 (74.5%)

ADA (n 5 47)

IFX (n 5 60)

Total (n 5 133)

IFX (n 5 80)

ADA (n 5 53)

Population #2 (n 5 107)

Population #1 (n 5 133)

Table 1 continued















28.3

29.5 (13.6)

28

26.5 (10.8)

14

15.4 (8.6)

75 (70.1%)

Total (n 5 107)









0.18

\0.0001

0.10

0.38

p value*

1954 Adv Ther (2016) 33:1947–1963

– Median

– Mean (SD)

Average maintenance dose

ADA adalimumab, IFX infliximab, SD standard deviation * Continuous variables were compared using the student test or the Wilcoxon test; categorical variables were compared using the Chi-square test or the Fisher’s exact test a Dose unit: for ADA, 1 dose = Injection 40 mg Syringe 0.8 mL and for IFX, 1 dose = I.V Infusion 100 mg

– 2 2 – – –

3











3

2.3 (1.1)

3

2.1 (0.9)







1955

a

3 Median

ADA (n 5 47) IFX (n 5 60) ADA (n 5 53) IFX (n 5 80)

Population #1 (n 5 133)

Table 1 continued

Total (n 5 133)

p value*

Population #2 (n 5 107)

Total (n 5 107)

p value*

Adv Ther (2016) 33:1947–1963

The sensitivity analyses showed that the difference in the probability of switch or discontinuation remained non-significant when the time window was decreased or increased by 7 days (decreased time window: 28.0% vs 23.4% for ADA and IFX, respectively, p-log rank = 0.2142; increased time window: 13.1% vs 19.0% for ADA and IFX, respectively, p-log rank = 0.7572). Dose Escalation in Maintenance Phase Among population #2, eight patients (12.5%) had dose escalation within 12 months after the initiation of maintenance. The probabilities of dose escalation at 12 months after the initiation of maintenance were 5.0% and 20.7% for ADA and IFX, respectively (p-log rank = 0.0762) (Fig. 2). For each treatment group, dose escalation was assessed for patients treated with or without immunosuppressant therapy after the index date. For patients treated with IFX, the 12-month probability of dose escalation was significantly higher in patients treated with immunosuppressant compared to patients not treated with immunosuppressant (60.6% vs. 7.1%, respectively; p-log rank \0.0001). Dose escalation occurred in one ADA patient without immunosuppressant prescription, and in no patients

treated

with

immunosuppressant

(Table S2, Supplementary Material). Complications and Concomitant Therapies The probability of surgical procedures over 12 months following the index date was 15.4% and 17.5% for ADA and IFX groups, respectively. Two patients in the IFX group had leucocyte removal therapy within 12 months after the index date (beginning of

Adv Ther (2016) 33:1947–1963

1956

Table 2 Probabilities of failure and persistence in induction phase by treatment group IFX (n 5 80)

ADA (n 5 53)

Total (n 5 133)

p value*

0.14

Discontinuation, n (%) No

63 (78.8%)

47 (88.7%)

110 (82.7%)

Yes

17 (21.3%)

6 (11.3%)

23 (17.3%)

No

77 (96.3%)

53 (100.0%)

Yes

3 (3.8%)

Switch, n (%)

0

130 (97.7%)

0.28

3 (2.3%)

Persistence, n (%) No

20 (25.0%)

6 (11.3%)

26 (19.6%)

Yes

60 (75.0%)

47 (88.7%)

107 (80.5%)

0.051

ADA adalimumab, IFX infliximab * Continuous variables were compared using the student test or the Wilcoxon test; categorical variables were compared using the Chi-square test or the Fisher’s exact test

Fig. 1 Kaplan–Meier plot of time to switch or discontinuation by treatment group. ADA adalimumab, IFX infliximab the induction phase), the data provided in the

12 months after the maintenance start date

Supplementary Material (Figs. S7 and S8). The probabilities of any adverse event within

were 51.4% and 69.4%, respectively, in ADA and IFX groups. The most frequent adverse

Adv Ther (2016) 33:1947–1963

1957

Fig. 2 Kaplan–Meier plot of time to dose escalation by treatment group. ADA adalimumab, IFX infliximab events were infections (24.4% of patients), anemia (20.9%), and diseases of the respiratory

this study is the provision of real-world data which could be seen to be of higher relevance in

system (12.7%) (Table 3).

terms of understanding actual clinical practice compared to clinical trial or single center

DISCUSSION

studies.

This retrospective analysis of data from the JMDC claims database for 150 Japanese patients with CD treated with ADA or IFX between 2012 and 2015 showed trends towards less instances of treatment failure during the induction phase and higher persistence and lower probability of dose escalation during the maintenance phase in ADA, compared to IFX. However, the differences were not statistically significant (p = 0.051). To the best of our knowledge, this is the first retrospective study that describes ADA and IFX treatment-related events based on Japan-specific claims data. The added value of

In the current study, patients were considered to have failed induction treatment if they switched or discontinued index treatment within 4 or 14 weeks, for ADA and IFX initiators, respectively. In the literature, failure in the induction phase was most often called primary non-response and defined as no clinical improvement at the end of the anti-TNF induction phase [22, 27]. Our data showed that &20% of patients did not complete induction therapy on ADA or IFX, which is in agreement with previously published clinical data on the efficacy of anti-TNFs [22, 23, 28]. A recent study by Viazis et al. (Greece) reported that among 161 CD patients treated with ADA

Adv Ther (2016) 33:1947–1963

1958

Table 3 Adverse events occurrence over 12 months after the index date (patients with at least 12 months of follow-up after ADA or IFX treatment initiation) IFX (n 5 49)

ADA (n 5 37)

Total (n 5 86)

p value*

Adverse events (at least one event), n (%)

34 (69.4%)

19 (51.4%)

53 (61.6%)

0.09

Certain infectious and parasitic diseases, n (%)

15 (30.6%)

6 (16.2%)

21 (24.4%)

0.12

Intestinal infectious diseases

5 (10.2%)

1 (2.7%)

6 (7.0%)

0.23

Mycoses

3 (6.1%)

5 (13.5%)

8 (9.3%)

0.28

Other infection

8 (16.3%)

0

8 (9.3%)

0.01

Anemia, n (%)

10 (20.4%)

8 (21.6%)

18 (20.9%)

0.89

Diseases of the digestive system, n (%)

3 (6.1%)

1 (2.7%)

4 (4.7%)

0.63

Diseases of the respiratory system, n (%)

8 (16.3%)

3 (8.1%)

11 (12.8%)

0.34

Malignant neoplasms, n (%)

0

1 (2.7%)

1 (1.2%)

0.43

10 (20.4%)

5 (13.5%)

15 (17.4%)

0.40

Other adverse events, n (%)

a

ADA adalimumab, IFX infliximab * Continuous variables were compared using the student test or the Wilcoxon test; categorical variables were compared using the Chi-square test or the Fisher’s exact test a List of other adverse events: Endocrine, nutritional and metabolic diseases, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, diseases of the genitourinary system, symptoms, signs and abnormal clinical and laboratory findings, injury, poisoning, and certain other consequences of external causes of IFX, 29 (18%) were considered as primary

from 15% to 35% [15, 20, 29]. Gonzaga et al.

non responders to induction therapy [22]. Farkas et al. (Hungary) reported that 88% of

(US) reported that 27% of 153 CD patients, who received maintenance therapy with IFX,

CD patients completed induction therapy with

discontinued

IFX [28]. In Vermeire et al. (Belgium), 74% of CD patients responded to IFX induction

12 months of maintenance therapy [15]. A recent multicenter retrospective study in the

therapy [23]. This suggests that our definition of treatment failure, based on claims data only,

US by Rosh et al. showed that the 12-month probability of discontinuation after ADA

provides a good proxy of primary non-response.

initiation in IBD patients was approximately

However, our analysis also showed that frequent changes in treatment occurred during

15% (Kaplan–Meir estimate) [20]. A recent Italian administrative database study in CD

the maintenance phases: switches, discontinuations, or dose escalations. Overall,

adult patients treated with anti-TNFs (ADA, IFX, and etanercept) showed that treatment

the probability of switch or discontinuation

persistence (defined as the absence of switches

over 12 months following the initial response to induction therapy was 20.3% (15.2% for ADA

or treatment interruptions after anti-TNF treatment initiation) was somewhat lower

group and 25.8% for IFX group). These rates are consistent with published data on anti-TNF

than in our study for ADA patients: 78% for IFX and 65% for ADA [29].

persistence from retrospective studies in other

The secondary outcome assessed in the

countries—rates

of

discontinuation

ranged

their

treatment

within

current study was the rate of dose escalation,

Adv Ther (2016) 33:1947–1963

which may be interpreted as a proxy of

1959

Although

treatment or

dose

switches,

secondary loss of response. In our study,

discontinuations

escalations

eight patients, representing 12.5% of the study population entering the maintenance

interpreted as events of failure or non-response to the treatment and that the definition of

phase, required dose increase and or interval reduction between ADA or IFX prescriptions

those events took into account intercurrent infections, concomitant surgeries, or

during a 12-month follow-up period. This rate

immunostimulant

is lower than that obtained from previously published clinical trial data (12-month rates

noted that a proportion of these events could have occurred for other factors, such as patient

ranged between 23% and 46%) [30]. This wide variability in loss of response rates across

compliance, medication reactions, choices made by practitioners, or patient preference.

therapies,

it

were

should

be

studies could be explained by the diversity of

In the current study, a minority of patients

definitions of this outcome. In 2011, a literature review by Ben-Horin et al. discussed

had immunosuppressant prescriptions after anti-TNF treatment initiation (32%

the disparity in the definitions of loss of response across studies on anti-TNF efficacy;

approximately in both groups). Several studies suggested that the risk–benefit profile of

some authors defined loss of response as a

immunosuppressants therapy is different in

quantifiable re-emergence of symptoms (for example, a change in the CD Activity Index

Japanese patients compared to Western patients [24, 25, 34], and thus, in the

[CDAI]), and others qualified dose escalation as a ‘‘decisive definition’’, while others

real-world setting, physicians may be cautious on adding immunosuppressant. Furthermore,

characterized it by switch, discontinuation, or an occurrence of a surgical intervention [30].

the results showed that among patients treated with IFX, there was a significantly higher

On the other hand, when we compared our

probability of dose escalation in patients who

study results to real-world published data, where authors adopted dose escalation as a

were prescribed immunosuppressant therapy compared to those without

definition of loss of response, we found also higher rates ranging from 23% to 55%

immunosuppressants. The addition of immunosuppressants, such as azathioprine, is

[14, 16, 17, 19, 21, 22, 31], but the majority

expected to reduce the risk of loss of response

of those studies had a longer follow-up compared to our study. The rate of dose

[35]. However, the higher rate of dose escalation in our study, interpreted as proxy of loss of

escalation for IFX (22.6% over 12 months) is close to the lower end of the range reported

response, in patients treated with the combination could be explained by the fact

above. Under the current definition of dose

that

escalation, patients treated with IFX who started their dosage at 10 mg/kg were not

immunosuppressants before increasing the IFX dose in patients with worsening symptoms (in

considered as dose escalated, since the weight was not available in JMDC database. For ADA

other words, patients treated with combination and IFX only were

group, the rate of dose escalation was found to

comparable). In addition, IFX patients not

be lower, which likely results from the fact that the higher dose has not yet been approved in

treated with immunosuppressants could have been switched to other treatments instead of

Japan [32, 33].

having their IFX dose increased.

physicians

may

have

prescribed

the not

Adv Ther (2016) 33:1947–1963

1960

The male-to-female ratio was 4:1 in our

studies

showing

higher

rates

of

loss

of

JMDC extract, and 5:1 in the 133 patients

response [14, 16–19, 21, 22, 30, 31].

meeting selection criteria. This ratio is higher than those reported by Japan-specific

In the current study, the probability of adverse events was investigated in an

epidemiological studies (2.6:1–2.3:1) [36, 37]. However, given that the JMDC data contain

exploratory manner, based on the claims database. Due to the nature of the JMDC data,

26% more males compared to Japan census, we

the oldest reported diagnosis of an adverse

would expect to have a 3-to-1 male-to-female ratio approximately. The higher proportion of

event did not necessarily correspond the first date of the symptoms appearance, which would

males in our sample is probably attributable to sampling variability.

have led an overestimation of adverse events. Nevertheless, further evaluation of this

several

outcome is required based on data from

limitations of our study should be noted. First, the sensitivity analysis demonstrated that the

prospective studies or chart reviews. Another limitation of this study is that the

results were sensitive to a change in the definition of discontinuation during

results were based on crude comparison between ADA and IFX groups. The possibility

maintenance

the

of performing a matched comparison was

probability of discontinuation increased in both the groups when the time window

considered, but the sample size was too small. Although the clinical status of patients could

decreased. However, the difference in discontinuation rate between the treatment

not be obtained, patients’ demographic and clinical characteristics were similar between

groups remained non-significant. Second, given the nature of the data

treatment groups (Table 1 and Table S4). In addition, given the retrospective nature of the

available in the JMDC database, we did not

study and the small sample size, the results

have any clinical record, such as CDAI or physician’s assessment of severity, and could

should be interpreted with caution. Finally, some limitations related to the

only develop proxies of treatment failure in induction phase or loss of response in

nature of claims databases should also be mentioned; diagnostic codes are for a

maintenance phase. However, the comparison

reimbursement

of results to the literature suggests that those proxies were actually informative. Besides,

different from diagnosis in a chart. Only the month and the year of medical and claims data

although surgeries might indicate a loss of response [38], it was not possible to make the

were available. The full dates were missing for 6% of the prescriptions and 9% of the

distinction between surgeries performed for

procedures,

treating intestinal complications due to loss of response or for treating lesion which pre-existed

however, were unlikely to differ across groups or outcomes.

before the index date. Although the rate of pre-index date surgical treatments was similar

CONCLUSION

Besides

the

small

phase.

sample

As

size,

expected,

purpose

respectively.

which

These

may

be

issues,

to both the groups (Table S4, Supplementary Material), these factors may have led to an underestimation of loss of response rates

This is the first retrospective study that describes ADA and IFX treatment-related

observed in this study compared to other

events based on a real-life claims database in

Adv Ther (2016) 33:1947–1963

1961

Japan. The current study demonstrated that Japanese CD patients have a high primary response to ADA and IFX therapy in the real-world setting, and suggests that outcomes achieved in the real world are comparable to those observed in clinical trials. However, response can be lost during the maintenance phase in a certain number of patients, leading to treatment switch, discontinuation, or dose escalation. This study further suggests that treatment persistence was similar to patients treated with ADA compared to those treated with IFX. However, the results should be considered with caution due to the retrospective nature and small size of the study. Given that CD is a chronic and a progressive disease, further research on the causes of discontinuations and ways to improve persistence are recommended for the

the final approval to the version to be published. Disclosures. Kaoru Yokoyama has served as a speaker for AbbVie GK, Kyowa Hakko Kirin, Tanabe Mitsubishi, Asahi Kasei, and EA Pharma, and consulting fee from Kyorin and her institution received research grant from JIMRO, Yakult, Eisai, Tsumura, Chugai, MDS, Taiho, Tanabe Mitsubishi, and Shionogi outside the submitted work. Kiyotaka Yamazaki is a full-time employee of Abbvie GK, which funded the study. Miiko Katafuchi is a full-time employee of Abbvie GK, which funded the study. Sameh Ferchichi is a full-time employee of Creativ-Ceutical, which received funding from Abbvie GK. Compliance with Ethics Guidelines. The protocol was submitted to Kitasato University

future.

Hospital’s Ethics Committee, but the study was exempted from ethical review, since no personally

ACKNOWLEDGMENTS

identifiable data were used in the JMDC extraction Sponsorship, article processing charges and the open access charge for this study were funded

for the current study. Patients were identified via a unique anonymized code assigned by JMDC, and

by Abbvie GK, Tokyo, Japan. The study sponsor was involved in all the stages of the study

the authors did not have access to the original data containing personal information.

research and manuscript preparation, but all the authors participated in the design of the study and

contributed

to

the

manuscript

development. All the authors had full access to all the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given

Open Access. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Adv Ther (2016) 33:1947–1963

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