Factors affecting the development of adverse drug reactions to β-blockers in hospitalized cardiac patient population

Figures & data

Table 1 Baseline data of the patients

Characteristic	Patients on β-blocker therapy (n=138)
Age (years), mean ± SD	59.5±9.8
Males, n (%)	98 (71)
Body mass index (kg/m^2), mean ± SD	28.2±3.8
Active smokers, n (%)	55 (39.9)
Arterial hypertension, n (%)	106 (76.8)
Diabetes mellitus, n (%)	32 (23.2)
Hypercholesterolemia, n (%)	63 (45.7)
Family history of CAD, n (%)	49 (35.5)
Obesity, n (%)	34 (24.6)
Number of drugs, median (range)	8 (2–16)
Duration of hospitalization	6 (1–29)
(days), median (range)
ADRs, n (%)	15 (10.9)

Abbreviations: SD, standard deviation; CAD, coronary artery disease; ADR, adverse drug reaction.

Table 2 Frequencies of CYP2D6 gene variations, alleles, and genotypes in Montenegrin patients on β-blocker therapy

Population genetics parameters	Observed frequency	95% confidence interval
Gene variation
2549delA	0.033 (9/276)	0.017–0.062
1846G>A	0.181 (50/276)	0.140–0.231
Gene deletion	0.014 (4/276)	0.004–0.038
1707delT	0.025 (7/276)	0.011–0.053
100C>T	0.130 (36/276)	0.096–0.176
Allele
CYP2D6*1	0.739 (204/276)	0.684–0.787
CYP2D6*3	0.029 (8/276)	0.014–0.057
CYP2D6*4	0.178 (49/276)	0.137–0.227
CYP2D6*5	0.014 (4/276)	0.004–0.038
CYP2D6*6	0.025 (7/276)	0.011–0.053
CYP2D6*10	0.014 (4/276)	0.004–0.038
Genotype
Extensive metabolizer
CYP2D6*1/*1	0.543 (10/138)	0.460–0.624
Intermediate metabolizer
CYP2D6*1/*10	0.014 (2/138)	0.001–0.055
Poor metabolizer
CYP2D6*1/*3	0.051 (7/138)	0.023–0.103
CYP2D6*1/*4	0.275 (38/138)	0.208–0.355
CYP2D6*1/*5	0.014 (2/138)	0.001–0.055
CYP2D6*1/*6	0.036 (5/138)	0.014–0.085
Very poor metabolizer
CYP2D6*4/*10	0.014 (2/138)	0.001–0.055
No enzyme activity
CYP2D6*3/*5	0.007 (1/138)	0.000–0.045
CYP2D6*4/*4	0.022 (3/138)	0.005–0.065
CYP2D6*4/*5	0.007 (1/138)	0.000–0.045
CYP2D6*4/*6	0.014 (2/138)	0.001–0.055

Table 3 Characteristics of detected ADRs

Characteristic	ADRs in patients on β-blocker therapy (n=15) (%)
Type
Type A	15 (100)
Type B	0 (0)
Type C	0 (0)
Causality
Certain	0 (0)
Probable	3 (20)
Possible	12 (80)
Level of intervention
Level 1 (no change in dose)	3 (20)
Level 2 (dose changed or drug stopped)	10 (66.66)
Level 3 (drug stopped + additional therapy)	2 (13.33)
Level 4 (transfer to intensive care unit)	0 (0)
Severity
Serious ADRs	4 (26.66)
Nonserious ADRs	11 (73.33)
Outcome
Recovery without consequences	15 (100)
Recovery with consequences	0 (0)

Abbreviation: ADR, adverse drug reaction.

Figure 1 Distribution of ADRs of β-blockers according to CYP2D6 enzyme activity.

Abbreviations: ADR, adverse drug reaction; CYP2D6, cytochrome P450 2D6.

Table 4 Multivariate logistic regression with ADRs on β-blockers as the dependent variable

Independent variable	Multivariate logistic regression
	OR (95% CI)	P-value
Number of days of hospitalization	1.13 (1.03–1.24)	0.008
Enzyme activity (two categories)	34.60 (4.80–49.31)	<0.001
Concomitant use of other drugs that are metabolized by the same CYP enzyme system	25.44 (5.01–29.29)	<0.001

Abbreviations: ADR, adverse drug reaction; OR, odds ratio; CI, confidence interval; CYP, cytochrome P450.

Figure S1 Questionnaire regarding adverse drug reaction.

Abbreviation: BMI, body mass index.