Patterns of 6-mercaptopurine and azathioprine maintenance therapy among a cohort of commercially insured individuals diagnosed with Crohn’s disease in the United States

Figures & data

Figure 1 Illustration of the cohort of CD patients who initiated 6-mercaptopurine/azathioprine, and the three secondary outcomes of treatment, discontinuation, augmentation, and switch.

Abbreviations: 6-MP, 6-mercaptopurine; AZA, azathioprine; CD, Crohn’s disease; TNF, tumor necrosis factor.

Table 1 Characteristics of 3,657 Crohn’s disease patients initiating 6-MP/AZA from 2001–2008

Characteristic	Number of patients	Percentage of patients
Female	1,986	54.3%
Male	1,671	45.7%
Age (mean, SD)	42 (16.77)
0 to 18	575	15.7%
19 to 29	537	14.7%
30 to 39	618	16.9%
40 to 49	719	19.7%
50 to 59	809	22.1%
≥60	399	10.9%
Regiona
Northeast	443	12.1%
North Central	1,167	31.9%
South	1,463	40.0%
West	574	15.7%
Prior drug useb
Methotrexate	17	0.5%
Anti-TNFs	68	1.9%
Concomitant drug usec
Corticosteroids	2,149	58.8%
5-ASAs	2,637	72.1%
Antibiotics	2,333	63.8%
Measures of comorbidity
Charlson score, 0	2,903	79.4%
Charlson score, 1	484	13.2%
Charlson score, ≥2	270	7.4%
Prior rheumatologic condition	120	3.3%
Number of GI outpatient visits
0 visits	1,128	30.8%
1 to 2 visits	871	23.8%
≥3 visits	1,658	45.3%
Number of distinct generic drug prescriptions
1 to 4	523	14.3%
5 to 8	1,153	31.5%
9 to 12	973	26.6%
≥13	1,008	27.6%

Notes:

a Region was missing for ten individuals

b prior use was defined as occurring during the 3–12 months prior to 6-MP/AZA initiation

c concomitant use was defined as occurring during the 12 months prior to 6-MP/AZA initiation.

Abbreviations: 5-ASA, 5-aminosalicylate; 6-MP, 6-mercaptopurine; AZA, azathioprine; GI, gastrointestinal; SD, standard deviation; TNF, tumor necrosis factor.

Figure 2 Time-to-treatment noncontinuation of initial 6-MP/AZA maintenance therapy.

Notes: Nonparametric Kaplan–Meier survival curves estimate the time-to-noncontinuation of initial 6-MP/AZA maintenance therapy among a cohort of CD patients (n=3,657) initiating 6-MP/AZA maintenance therapy between January 1, 2001 and December 31, 2008, overall (A) and stratified by age (≤18 vs >18 years), (B). At 12, 24, and 36 months, the numbers of CD patients at risk were 1,544, 730, and 352. Stratified by age, the same numbers of patients at risk were 170, 67, and 32 and 1,374, 663, and 320 among those ≤18 years and >18, respectively.
Abbreviations: 6-MP, 6-mercaptopurine; AZA, azathioprine; CD, Crohn’s disease.

Table 2 Patient-level predictors of failure to continue initial 6-MP/AZA among 3,657 Crohn’s disease patients

Independent variable	Unadjusted HR (95% CI)	Adjusted HRc (95% CI)
Female vs male	0.87 (0.81–0.93)	0.92 (0.85–0.99)
19–29 years vs 0–18 years	1.47 (1.28–1.68)	1.39 (1.21–1.59)
30–39 years vs 0–18 years	1.35 (1.19–1.54)	1.25 (1.09–1.43)
40–49 years vs 0–18 years	1.27 (1.12–1.43)	1.16 (1.02–1.32)
50–59 years vs 0–18 years	1.17 (1.03–1.32)	1.04 (0.91–1.19)
≥60 years vs 0–18 years	1.20 (1.04–1.40)	1.07 (0.91–1.25)
Northeast vs South	0.81 (0.72–0.92)	0.86 (0.76–0.97)
North Central vs South	0.90 (0.82–0.98)	0.91 (0.84–1.00)
West vs South	0.93 (0.83–1.03)	0.95 (0.85–1.07)
Anti-TNF prescription prior to initiationa (yes vs no)	1.81 (1.40–2.33)	1.64 (1.26–2.13)
Methotrexate prescription prior to initiationa (yes vs no)	1.35 (0.82–2.25)	1.21 (0.73–2.03)
Salicylate prescription prior to initiationb (yes vs no)	0.96 (0.88–1.04)	0.94 (0.86–1.02)
Steroid prescription prior to initiationb (yes vs no)	1.00 (0.93–1.08)	0.95 (0.88–1.03)
Antibiotic prescription prior to initiation (yes vs no)	1.19 (1.10–1.28)	1.06 (0.96–1.16)
History of rheumatologic diseaseb (yes vs no)	1.27 (1.04–1.55)	1.23 (1.00–1.51)
5–8 vs 1–4 generic prescriptionsb	1.16 (1.03–1.31)	1.20 (1.05–1.37)
9–12 vs 1–4 generic prescriptionsb	1.24 (1.09–1.40)	1.28 (1.10–1.49)
≥13 vs 1–4 generic prescriptionsb	1.43 (1.27–1.62)	1.46 (1.23–1.73)

Notes:

a Prior use was defined as occurring during the 3–12 months prior to 6-MP/AZA initiation

b all variables were assessed during the 12 months prior to 6-MP/AZA initiation

c all estimates were adjusted for all the variables above in addition to year of initiation, Charlson score, number of office visits, number of gastrointestinal procedures, and number of hospitalizations.

Abbreviations: 6-MP, 6-mercaptopurine; AZA, azathioprine; CI, confidence interval; HR, hazard ratio; TNF, tumor necrosis factor; vs, versus.

Table 3 Maintenance therapy changes among 2,845 patients diagnosed with Crohn’s disease who failed to continue initial 6-MP/AZA therapy

Treatment strategy	Number of patients (%)
Discontinued all therapy	2,108 (74.02)
Switched to another therapy
Natalizumab	0 (0.00)
Methotrexate	45 (1.58)
Anti-TNF	203 (7.13)
Anti-TNF + methotrexate	5 (0.18)
Augmented with another therapy
6-MP/AZA + anti-TNF	484 (16.99)

Abbreviations: 6-MP, 6-mercaptopurine; AZA, azathioprine; TNF, tumor necrosis factor.

Table 4 Clinical events occurring among 2,845 CD patients during the 60 days prior to failure of initial 6-MP/AZA treatment continuation

Event of interest	Number of patients (%a)
Possible indicator of intolerance	105 (3.6)
Pancreatitis diagnosis	71 (2.4)
Liver toxicity diagnosis	17 (0.6)
Low white blood cell count diagnosis	18 (0.6)
Possible indicator of active disease	1,128 (38.6)
Oral steroid prescription	799 (27.4)
GI surgery procedure	480 (16.4)
Hospitalization related to CD	246 (8.4)
Both	56 (1.9)

Notes:

a Individuals can experience multiple events in each category, therefore the column percentages do not sum to 100%.

Abbreviations: 6-MP, 6-mercaptopurine; AZA, azathioprine; CD, Crohn’s disease; GI, gastrointestinal.

Table S1 Administrative codes used to identify an initial 6-MP/AZA treatment discontinuation, switch, and augmentation

Source	Description	Codes
NDC, HCPCS	Azathioprine	49452078301 51552077902 51552077904 51927225800 00173059871 55390060020 60976059871 65483055101 65649024141 66591024141 00054408425 00054808425 00081059756 00173059755 00378100501 00406200301 00781105901 00781507501 23490511009 52959007900 54868092101 54868092104 54868531000 54868531001 54868531002 54868531004 57866902101 60976059755 65483059010 66479030110 66591022141 68084022901 68084022911 68382000301 68382000305 68462050201 65649023141 66591023141 38779031203 38779031206 49452078201 49452078203 49452078302
		C9436 J7500 J7501 K0119 K0120
NDC, HCPCS	6-MP	00054458111 00054458127 00081080725 00081080765 00093551006 00173080725 00173080765 00378354725 00378354752 38779142703 38779142704 38779142706 49884092202 49884092204 51927200000 54868528200 57844052206 57844052207 57844052252 68084032521 68258910301
		S0108
NDC, HCPCS	Methotrexate	49452460002 49452460003 49452460102 49452460104 51552105401 51552105409 51927156500 00205532618 63323012140 58406068318 61703040804 63323012104 66479013613 00555092901 51285036801 00555094501 51285036901 55390014301 58406067105 63323012250 66479013929 00005450704 00005450705 00005450707 00005450709 00005450723 00005450791 00054455015 00054455025 00054855003 00054855005 00054855006 00054855007 00054855010 00054855025 00182153901 00182153995 00364249901 00364249936 00378001401 00378001450 00405464301 00405464336 00536399801 00536399836 00555057202 00555057235 00555057245 00555057246 00555057247 00555057248 00555057249 00603449921 00677161001 00781107601 00781107636 00904174960 00904174973 00904601260 23490588900 49999038024 51079067001 51079067005 51079067086 51079067087 51285050902 51432052203 52959024400 54569181800 54868382600 54868382601 54868382602 54868382603 54868382604 54868382605 54868382606 54868382607 55289092430 59911587401 62701094036 62701094099 67253032010 67253032036 67253058042 67253058043 67253058044 67253058045 67253058046 68115063200 58406068312 63323012108 58406067301 66479013721 54868471600 58406068316 63323012110 63323012310 66479013619 00186142013 00205455626 00469288030 10019094001 10019094002 10019094101 10139006202 10139006210 10139006240 53905003110 53905003210 53905003410 55390003110 55390003210 55390003310 55390003410 58406068114 58406068117 61703035038 61703040707 61703040732 61703040813 61703040822 61703040832 61703040841 61703040858 66479013501 66479013509 66758004002 66758004008 66758004101 00205933792 54569452500 54868017301 54868479600 58406068315 61703040807 63323012102 63323012302 66479013611 00555092701 51285036601 00555092801 51285036701 38779003503 38779003504 38779003506 38779003511 62991120001 62991120002 63370015410 63370015415 63370015425
		J8610 J9250 J9260
NDC, HCPCS	Natalizumab	59075073015, C9126, J2323, Q4079
NDC, HCPCS	Anti-TNFs	50474070062 50474071079 00074379902 00074433902 00074433906 00074433907 00074937402 54569552400 54868482200 57894003001
		C9249 J0135 J0718 J1745 S9359

Abbreviations: NDC, National Drug Code; HCPCS, Healthcare Common Procedural Coding System; TNF, tumor necrosis factor.

Table S2 Administrative codes used to identify possible indicators of intolerance or active disease

Source	Description	Codes
ICD-9 CM	Acute pancreatitis	577.0
ICD-9 CM	Liver toxicity	570, 790.4
ICD-9 CM	Low white blood cell count	288.5, 288.0
ICD-9 CM	GI procedures	43200–43273, 44360–44397, 45300–45392, 46600–46615
NDC	Oral steroid prescription	Codes
ICD-9 CM	Crohn’s disease-related hospitalization	555.0, 555.1, 555.2, 555.9

Abbreviations: NDC, National Drug Code; ICD-9 CM, International Classification of Diseases, ninth revision codes; GI, gastrointestinal.