Increased risk of hospitalization for ultrarapid metabolizers of cytochrome P450 2D6

Figures & data

Table 1 Characteristics of patients by CYP2D6 metabolizer phenotype

CYP2D6 phenotypes
Feature	Overall cohort	Ultrarapid	Extensive to ultrarapid	Extensive	Intermediate to extensive	Intermediate	Poor to intermediate	Poor	P-value
Patients, n (%)	929 (100)	74 (8.0)	145 (16)	195 (21)	179 (19)	203 (22)	64 (6.9)	69 (7.4)	–
Age, median (IQR), years	49 (46–52)	49 (45–52)	48 (47–52)	48 (45–52)	49 (46–51)	49 (45–52)	49 (47–51)	50 (46–52)	0.46
Female, %	54	62	50	53	49	62	53	49	0.08
Minnesota tier, %									0.03
0	13	11	5.6	13	18	17	7.8	8.8
1	62	53	65	64	56	63	73	65
2	20	27	26	19	19	15	14	22
3	4.9	6.8	2.8	4.7	6.2	5.0	4.7	4.4
4	0.5	2.7	6.9	0	0.6	0.5	0	0
Disease,a %
Depression	7.0	9.4	8.9	5.8	6.1	6.9	2.7	10.5	0.44
Arthritis	5.7	10.6	5.7	4.8	5.1	6.5	5.4	2.6	0.45
Coronary artery disease	1.2	1.2	1.3	1.4	1.5	1.4	0	0	0.90
Congestive heart failure	0	0	0	0	0	0	0	0	–
Smoking status,b %									0.72
Current	3.6	5.9	2.6	3.9	2.1	3.3	5.4	5.3
Former smoker	28.3	31.8	28.2	31.9	28.7	26.5	25.7	21.3
Never	68.1	62.4	69.2	64.3	69.2	70.2	68.9	73.3
Alcohol consumption,b %									0.28
Never	14.5	16.5	10.3	12.1	19.1	15.9	17.6	9.2
Once monthly or less	22.3	22.4	19.9	24.2	20.1	21.5	32.4	19.7
2–4 times monthly	27.7	24.7	32.7	29.5	25.8	26.2	21.6	31.6
2–5 times weekly	27.5	30.6	23.7	28.0	28.4	29.4	20.3	30.3
≥6 times weekly	8.0	5.9	13.5	6.3	6.7	7.0	8.1	9.2
Medication use,c %
Oxycodone	53.3	63.5	54.4	52.4	50.0	54.6	47.3	52.6	0.44
Codeine	38.9	43.5	34.2	39.9	38.3	38.9	48.6	32.9	0.37
Hydrocodone	35.9	45.9	39.2	34.1	33.7	32.9	32.4	40.8	0.30
Tramadol	26.4	28.2	27.2	23.1	24.0	30.6	23.0	28.9	0.60
Morphine	10.9	22.4	9.5	10.6	11.7	10.2	8.1	3.9	0.01
Metoprolol	10.5	11.8	13.3	11.1	8.2	9.7	9.5	10.5	0.82
Amitriptyline	6.2	9.4	10.1	3.4	3.6	7.4	5.4	6.6	0.07

Notes:

a The proportion for each disease was calculated by using January 1, 2005 as the prevalence date and searching the electronic medical records for the 5 years preceding the prevalence date.

b Frequency data were collected upon enrollment in the Mayo Clinic Biobank.

c The proportion for each medication was calculated from the medication prescription history (≥1 prescription for each medication) in the electronic health record.

Abbreviations: CYP2D6, cytochrome P450 2D6; IQR, interquartile range.

Figure 1 Proportion of hospitalizations and ED visits among 929 patients according to CYP2D6 phenotype.

Notes: A higher proportion of patients with the ultrarapid metabolizer phenotype were hospitalized or visited the ED, compared to patients with the extensive metabolizer phenotype.
Abbreviations: CYP2D6, cytochrome P450 2D6; ED, emergency department.

Figure 2 Survival analysis according to CYP2D6 phenotype.

Notes: (A) Probability of survival free of hospitalization according to CYP2D6 phenotype of 929 patients. Patients with the ultrarapid metabolizer phenotype had a higher rate of hospitalization compared to patients with the extensive metabolizer phenotype. (B) Probability of survival free of ED visit according to CYP2D6 phenotype of 929 patients. Patients with the ultrarapid metabolizer phenotype had a higher rate of ED use compared to patients with the extensive metabolizer phenotype.
Abbreviations: CYP2D6, cytochrome P450 2D6; ED, emergency department.

Table 2 Association between CYP2D6 metabolizer phenotype and the risk of hospitalization or an ED visit for 929 adultsa

CYP2D6 metabolizer phenotype	Hospitalization		ED visit
	Patients, n (%)	Hazard ratio (95% CI) b	Patients, n (%)	Hazard ratio (95% CI) c
Ultrarapid (n=74)	35 (47)	1.69 (1.11–2.57)	46 (62)	1.50 (1.05–2.14)
Extensive to ultrarapid (n=145)	47 (32)	1.05 (0.72–1.54)	85 (59)	1.35 (1.00–1.80)
Extensive (n=195)	59 (30)	Reference	95 (49)	Reference
Intermediate to extensive (n=179)	45 (25)	0.78 (0.53–1.16)	88 (49)	1.04 (0.78–1.38)
Intermediate (n=203)	58 (29)	0.91 (0.63–1.31)	108 (53)	1.14 (0.87–1.51)
Poor to intermediate (n=64)	20 (31)	1.04 (0.63–1.73)	31 (48)	1.02 (0.68–1.53)
Poor (n=69)	21 (30)	0.95 (0.58–1.56)	43 (62)	1.38 (0.96–1.98)

Notes:

a Adjusted for age and sex.

b Overall P=0.07.

c Overall P=0.14

Abbreviations: CI, confidence interval; CYP2D6, cytochrome P450 2D6; ED, emergency department.

Table 3 Association between CYP2D6 metabolizer phenotype and the risk of hospitalization or an ED visit for 929 adults, stratified by comorbidity levela,b

Outcome	Overall cohort (N =929)			Lower comorbidity (n =686c)			Higher comorbidity (n =232c)
	Patients, n	Events, n (%)	HRd (95% CI)	Patients, n	Events, n (%)	HRd (95% CI)	Patients, n	Events, n (%)	HRd (95% CI)
Hospitalization			P=0.004			P=0.03			P=0.23
Ultrarapid	74	35 (47)	1.80 (1.26–2.57)	47	19 (40)	1.85 (1.14–3.00)	27	16 (59)	1.38 (0.80–2.35)
Other 5 categoriese	786	229 (29)	Reference	589	139 (24)		187	86 (46)	Reference
Poor	69	21 (30)	1.09 (0.86–1.38)	50	16 (32)	Reference 1.31 (0.78–2.20)	18	5 (28)	0.57 (0.23–1.40)
ED visit			P=0.08			P=0.67			P=0.10
Ultrarapid	74	46 (62)	1.35 (1.00–1.84)	47	25 (53)	1.14 (0.76–1.72)	27	21 (78)	1.51 (0.94–2.41)
Other 5 categoriese	786	407 (52)	Reference	589	290 (49)	Reference	187	113 (60)	Reference
Poor	69	43 (62)	1.24 (0.91–1.71)	50	28 (56)	1.15 (0.78–1.70)	18	15 (83)	1.56 (0.91–2.68)

Notes:

a Comorbidity levels were based on Minnesota tiers (higher ≥2; lower 0 or 1).

b All analyses were adjusted for age and sex.

c Comorbidity levels were available for 918 patients.

d Hazard ratio compared ultrarapid metabolizer to the other 5 phenotypes.

e The other 5 categories were 1) extensive to ultrarapid, 2) extensive, 3) intermediate to extensive, 4) intermediate, and 5) poor to intermediate.

Abbreviations: CI, confidence interval; CYP2D6, cytochrome P450 2D6; ED, emergency department; HR, hazard ratio.