The effect of drug interactions on bleeding risk associated with warfarin therapy in hospitalized patients

Figures & data

Table

ATC	anatomical therapeutic chemical
B-ERYT	BLOOD ERYTHROCYTE COUNT
B-Throm	platelet count
CI	confidence interval
CYP2C9	cytochrome P450 2C9 isoenzyme
Hb	hemoglobin
HCT	hematocrit
ICD-10	International Classification of Diseases, 10th revision
INR	international normalized ratio
MCH	mean cellular hemoglobin
MCV	mean corpuscular volume
non-SSRI	non-selective serotonin re-uptake inhibitor.
NSAID	non-steroidal anti-inflammatory drug
OR	odds ratio
PPI	proton pump inhibitor
SSRI	selective serotonin re-uptake inhibitor
UGIB	upper gastrointestinal bleeding

Table I.  List of interacting drugs.

Platelet aggregation inhibitor	Frequency, n (%)
Acetylsalicylic acid	334 (71.4)
Dipyridamole	96 (20.5)
Clopidogrel	34 (7.3)
Ticlodipine	4 (0.9)
Total	468 (100)
No interactions were found for iloprost, combinations (acetylsalicylic acid and dipyridamole), abciximab, eptifibatide, and tirofiban.
SSRI	Frequency, n (%)
Citalopram	677 (78.5)
Fluoxetine	105 (12.2)
Sertraline	40 (4.6)
Paroxetine	33 (3.8)
Clomipramine	8 (0.9)
Total	863 (100)
No interactions were found for escitalopram.
SSRI = selective serotonin re-uptake inhibitor.
Non-SSRI	Frequency, n (%)
Mirtazapine	184 (90.6)
Moclobemide	19 (9.4)
Total	203 (100)
No interactions were found for reboxetine.
Non-SSRI = non-selective serotonin re-uptake inhibitor.
Non-selective NSAID	Frequency, n (%)
Ibuprofen	355 (27.9)
Diclofenac	216 (17.0)
Naproxen	201 (15.8)
Ketoprofen	164 (12.9)
Nimesulide	143 (11.2)
Indometacin	67 (5.3)
Meloxicam	50 (3.9)
Ketorolac	30 (2.4)
Nabumetone	13 (1.0)
Tolfenamic acid	13 (1.0)
Piroxicam	8 (0.6)
Etodolac	4 (0.3)
Tenoxicam	3 (0.2)
Tiaprofenic acid	3 (0.2)
Aceclofenac	2 (0.2)
Mefenamic acid	1 (0.1)
Total	1273 (100)
No interactions were found for lornoxicam, dexibuprofen, and dexketoprofen.
NSAID = non-steroidal anti-inflammatory drug.
Coxib	Frequency, n (%)
Rofecoxib	121 (49.2)
Celecoxib	105 (42.7)
Etoricoxib	17 (6.9)
Valdecoxib	3 (1.2)
Total	246 (100)
No interactions were found for parecoxib.
CYP2C9 inhibitor	Frequency, n (%)
Metronidazole	792 (41.1)
Fluconazole	435 (22.6)
Amiodarone	343 (17.8)
Phenytoin	170 (8.8)
Miconazole	55 (2.9)
Sulfamethoxazole	48 (2.5)
Tamoxifen	35 (1.8)
Zafirlukast	24 (1.2)
Gemfibrozil	17 (0.9)
Fluvoxamine	10 (0.5)
Total	1929 (100)

No interactions were found for voriconazole.

CYP2C9 = cytochrome P450 2C9 isoenzyme.

Table II.  The demographic characteristics of cases and controls.

	Platelet aggregation inhibitor	Antidepressant		NSAID
		SSRI	Non-SSRI	Non-selective	Coxib	CYP2C9 inhibitor	Control
Treatment periods, n (% of total)	468 (5.4)	863 (10.0)	203 (2.4)	1273 (14.8)	246 (2.9)	1929 (22.4)	3633 (42.2)
Patients, n (% of total)	396 (5.8)	828 (12.2)	199 (2.9)	1067 (15.8)	222 (3.3)	1407 (20.8)	3614 (53.4)
Sex, male/female	279/189^a	406/457^b	94/109^a	621/652^b	111/135^a	1051/878	1964/1669
Mean age, years (range)	69^a (22–94)	69^b (15–96)	67^b (15–87)	68^b (17–97)	68^b (24–92)	67^b (18–99)	66 (14–97)
Proportion (%) of treatment periods with concomitant exposure to PPI	25.9 ^b	36.7 ^b	43.4 ^b	27.7 ^b	42.3 ^b	38.5 ^b	13.8
Proportion (%) of treatment periods with concomitant exposure to oral glucocorticoid	18.8^b	26.7^b	32.5^b	43.4^b	44.7^b	47.2^b	1.5

SSRI = selective serotonin re-uptake inhibitor; Non-SSRI = non-selective serotonin re-uptake inhibitor; NSAID = non-steroidal anti-inflammatory drug; CYP2C9 = cytochrome P450 2C9 isoenzyme; PPI = proton pump inhibitor.

^aP<0.05 for comparison to the control.

^bP<0.001 for comparison to the control.

Table III.  The frequencies of warfarin treatment periods linked with a bleeding diagnosis and the bleeding risks caused by co-medications.

	All bleeding diagnoses			Upper GI bleeding diagnoses			Lower GI bleeding diagnoses			Intracranial bleeding diagnoses
	n (% of total)	OR	(95% CI)	n (% of total)	OR	(95% CI)	n (% of total)	OR	(95% CI)	n (% of total)	OR	(95% CI)
Platelet aggregation inhibitor	13 (2.8)	1.62	(0.84–3.13)	3 (0.6)	2.18	(0.56–8.45)	1 (0.2)	0.83	(0.10–7.05)	0 (0)
Antidepressant
SSRI	35 (4.1)	2.57^b	(1.54–4.28)	13 (1.5)	5.49^a	(1.79–16.85)	3 (0.3)	1.33	(0.33–5.36)	3 (0.3)	1.47	(0.35–6.17)
Non–SSRI	4 (2.0)	1.15	(0.31–4.25)	0 (0)			0 (0)			1 (0.0)	2.12	(0.24–18.69)
NSAID
Non-selective	44 (3.5)	2.57^b	(1.56–4.23)	8 (0.6)	2.79	(0.88–8.91)	10 (0.8)	3.96 ^a	(1.13–13.93)	5 (0.4)	1.68	(0.47–6.02)
Coxib	12 (4.9)	3.10^b	(1.44–6.67)	2 (0.8)	2.91	(0.33–25.79)	1 (0.4)	1.73	(0.24–12.51)			0 (0)
CYP2C9 inhibitor	104 (5.4)	3.64^b	(2.36–5.62)	29 (1.5)	5.71 ^b	(2.17–15.01)	13 (0.7)	3.12 ^a	(1.04–9.28)	11 (0.6)	2.39	(0.64–8.86)
Control	53 (1.5)			8 (0.2)			9 (0.2)					8 (0.2)

Multivariate logistic regression, adjusted for age, sex, ward, proton pump inhibitor and oral glucocorticoid medications. Adjustment for ward was impossible in lower GI and intracranial bleeding categories because the number of diagnoses in some specialities was zero.

OR = odds ratio; CI = confidence interval; GI = gastrointestinal; SSRI = selective serotonin re-uptake inhibitor; non-SSRI = non-selective serotonin re-uptake inhibitor; NSAID = non-steroidal anti-inflammatory drug; CYP2C9 = cytochrome P450 2C9 isoenzyme.

^aP<0.05 for comparison to the control.

^bP<0.001 for comparison to the control.

Table IV.  The means of the laboratory variables.

	Platelet aggregation inhibitor	Antidepressant		NSAID
		SSRI	Non-SSRI	Non-selective	Coxib	CYP2C9 inhibitor	Control
Hb, g/L	128^b	126^b	128 ^a	123^b	124^b	119^b	133
(range)	(89–179)	(77–184)	(91–180)	(70–171)	(85–174)	(60–181)	(78–197)
Min Hb, g/L	115^a	110^b	111^b	107^b	108^b	108^b	121
(range)	(58–175)	(48–184)	(71–172)	(45–167)	(55–173)	(51–181)	(42–197)
HCT	0.38^b	0.38^b	0.38^b	0.37^b	0.37^b	0.36^b	0.39
(range)	(0.26–0.52)	(0.23–0.53)	(0.27–0.53)	(0.20–0.51)	(0.24–0.52)	(0.17–0.56)	(0.24–0.57)
B-Eryt, ×10^12/L	4.14^b	4.11^b	4.15^b	4.05^b	4.07^b	3.91^b	4.32
(range)	(2.61–6.09)	(2.53–5.76)	(2.90–5.65)	(2.37–6.46)	(2.60–5.70)	(2.31–6.68)	(2.49–8.47)
MCH, pg/cell	31	31	31	31	31	31	31
(range)	(21–38)	(24–38)	(25–37)	(23–38)	(25–38)	(22–40)	(18–40)
MCV, fL	92	92	91	91	91	91	91
(range)	(65–136)	(75–111)	(78–108)	(73–109)	(79–110)	(72–117)	(59–118)
B-Throm, ×10^9/L	247^a	244^a	259	250^b	247	259^b	232
(range)	(89–906)	(29–751)	(35–550)	(29–864)	(86–667)	(9–1011)	(9–1223)
INR	2.3	2.4	2.3	2.4	2.3	2.6^b	2.3
(range)	(0.9–4.6)	(0.9–5.5)	(0.9–4.3)	(0.9–5.2)	(0.9–4.6)	(0.9–7.0)	(0.8–7.0)

Adjusted for age, sex, ward, and concomitant exposure to proton pump inhibitor and oral glucocorticoid medications.

SSRI = selective serotonin re-uptake inhibitor; non-SSRI = non-selective serotonin re-uptake inhibitor; NSAID = non-steroidal anti-inflammatory drug; CYP2C9 = cytochrome P450 2C9 isoenzyme; Hb = hemoglobin; HCT = hematocrit; B-Eryt = erythrocyte count; MCH = mean cellular hemoglobin; MCV = mean corpuscular volume; B-Throm = platelet count; INR = international normalized ratio.

^aP<0.05 for comparison to the control.

^bP<0.001 for comparison to the control.

Table V.  The proportions of the treatment periods with Hb and Min Hb below, and B-Throm and INR above the target range, and the risk for these extra-target range values.

	Hb			Min Hb			B-Throm			INR
	% of total	OR	(95% CI)	% of total	OR	(95% CI)	% of total	OR	(95% CI)	% of total	OR	(95% CI)
Platelet aggregation inhibitor	39.3	1.50^a	(1.16–1.92)	55.8	1.37^a	(1.06–1.76)	6.8	1.75^a	(1.11–2.74)	7.1	1.14	(0.75–1.72)
Antidepressant
SSRI	43.8	1.71^b	(1.43–2.03)	68.4	2.10^b	(1.74–2.52)	6.6	1.29	(0.93–1.80)	7.1	1.09	(0.80–1.48)
Non-SSRI	36.5	1.11	(0.80–1.54)	70.0	2.11^b	(1.47–3.03)	12.8	2.37^b	(1.48–3.80)	5.9	0.90	(0.49–1.65)
NSAID
Non-selective	49.3	1.90^b	(1.60–2.26)	73.4	2.49^b	(2.08–2.98)	8.1	1.58^b	(1.18–2.12)	7.2	1.07	(0.81–1.42)
Coxib	49.6	1.91^b	(1.41–2.58)	71.1	2.05^b	(1.46–2.87)	6.9	1.29	(0.70–2.38)	6.9	1.07	(0.62–1.82)
CYP2C9 inhibitor	57.8	2.85^b	(2.44–3.33)	71.5	2.43^b	(2.06–2.86)	13.5	3.12^b	(2.41–4.05)	15.7	2.85^b	(2.30–3.54)
Control	27.9			46.7			4.5			5.9

Adjusted for age, sex, ward, and concomitant exposure to proton pump inhibitor and oral glucocorticoid medications.

OR = odds ratio; CI = confidence interval; SSRI = selective serotonin re-uptake inhibitor; non-SSRI = non-selective serotonin re-uptake inhibitor; NSAID = non-steroidal anti-inflammatory drug; CYP2C9 = cytochrome P450 2C9 isoenzyme; Hb = hemoglobin; HCT = hematocrit; B-Eryt = erythrocyte count; MCH = mean cellular hemoglobin; MCV = mean corpuscular volume; B-Throm = platelet count; INR = international normalized ratio.

^aP<0.05 for comparison to the control.

^bP<0.001 for comparison to the control.