Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website http://www.cardiologyres.org

Original Article

Volume 11, Number 1, February 2020, pages 15-21

Polypharmacy Is Associated With Accelerated Deterioration of Renal Function in Cardiovascular Outpatients

Figure 1. The numbers of drugs prescribed for the patients with each comorbidity as the median of each group. *P < 0.05, †P < 0.01 in Mann-Whitney U-test.

**Table 1.** Clinical Characteristics
	Classification of polypharmacy	P value
The data are presented as mean ± SD for normally distributed variables, median (first quartile, third quartile) for not normally distributed variables, or the number (percentage) for categorical variables. Differences in categorical variables between groups were assessed using Fisher’s exact test followed by Holm’s post hoc test. Differences in continuous variables between groups were assessed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test for normally distributed variables, or Kruskal-Wallis’s test followed by Steel-Dwass’s post hoc test for not normally distributed variables. BMI: body mass index; Cr: serum creatinine; CV: cardiovascular; CVD: cardiovascular disease; eGFR: estimated glomerular filtration rate; Hb: hemoglobin; Ht: hematocrit; IHD: ischemic heart disease; PAD: peripheral artery disease; Plt: platelet; PP: polypharmacy; RBC: red blood cells; RDW-CV: red blood cell distribution width-coefficient of variation; WBC: white blood cell. ^aP < 0.05, non-PP vs. PP; ^bP < 0.05, non-PP vs. hyper-PP; ^cP < 0.05, PP vs. hyper-PP.
N	259	68 (26.25)	132 (50.97)	59 (22.78)
Age (years)	72 (64, 78)	70 (63, 75)	72 (66, 78)	73 (62, 80)	0.057
Male gender (%)	173 (66.8)	38 (55.9)	95 (72.0)	40 (67.8)	0.075
BMI (kg/m²)	24.0 ± 3.9	23.2 ± 3.7	24.0 ± 3.9	24.8 ± 3.8	0.069
WBC (10²/µL)	60.6 ± 17.6	55.4 ± 13.4	62.6 ± 18.8^a	62.0 ± 18.1	0.017
Plt (10⁴/µL)	19.3 ± 5.4	19.8 ± 5.2	19.1 ± 5.3	19.0 ± 5.9	0.599
RBC (10⁴/µL)	441 ± 63	455 ± 47	444 ± 61	417 ± 78^{b, c}	0.002
Hb (g/dL)	13.5 ± 1.8	14.1 ± 1.4	13.6 ± 1.9	12.8 ± 1.8^{b, c}	< 0.001
Ht (%)	40.9 ± 5.0	42.3 ± 3.8	41.1 ± 5.3	39.1 ± 5.2^{b, c}	0.002
RDW-CV	13.6 (13.0, 14.1)	13.3 (12.8, 13.7)	13.7 (13.1, 14.1)^a	13.7 (13.1, 14.8)^b	< 0.001
Anemia (%)	74 (28.6)	6 (8.8)	37 (28.0)^a	31 (52.5)^{b, c}	< 0.001
Cr (mg/dL)	0.84 (0.68, 1.01)	0.72 (0.62, 0.84)	0.85 (0.70, 0.99)^a	1.01 (0.81, 1.32)^{b, c}	< 0.001
eGFR (mL/min/1.73 m²)	65.4 ± 20.9	73.8 ± 17.3	66.2 ± 19.1^a	54.0 ± 23.4^{b, c}	< 0.001
Number of CVDs or their risk factors	3 (2, 4)	2 (1, 2)	3 (2, 4)^a	4 (2, 5)^{b, c}	< 0.001
CVD or its risk factor
Atrial fibrillation (%)	47 (18.1)	10 (14.7)	22 (16.7)	15 (25.4)	0.262
Diabetes mellitus (%)	98 (37.8)	12 (17.6)	52 (39.4)^a	34 (57.6)^{b, c}	< 0.001
Dyslipidemia (%)	150 (57.9)	32 (47.1)	81 (61.4)	37 (62.7)	0.114
Heart failure (%)	56 (21.6)	7 (10.3)	24 (18.2)	25 (42.4)^{b, c}	< 0.001
Hypertension (%)	184 (71.0)	43 (63.2)	94 (71.2)	47 (79.7)	0.127
IHD (%)	129 (49.8)	20 (29.4)	71 (53.8)^a	38 (64.4)^b	< 0.001
PAD (%)	24 (9.3)	1 (1.5)	10 (7.6)	13 (22.0)^{b, c}	< 0.001
Stroke (%)	28 (10.8)	3 (4.4)	15 (11.4)	10 (16.9)	0.060

Table 1. Clinical Characteristics

Classification of polypharmacy

P value

All

non-PP (0 - 4)

PP (5 - 9)

hyper-PP (≥ 10)

The data are presented as mean ± SD for normally distributed variables, median (first quartile, third quartile) for not normally distributed variables, or the number (percentage) for categorical variables. Differences in categorical variables between groups were assessed using Fisher’s exact test followed by Holm’s post hoc test. Differences in continuous variables between groups were assessed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test for normally distributed variables, or Kruskal-Wallis’s test followed by Steel-Dwass’s post hoc test for not normally distributed variables. BMI: body mass index; Cr: serum creatinine; CV: cardiovascular; CVD: cardiovascular disease; eGFR: estimated glomerular filtration rate; Hb: hemoglobin; Ht: hematocrit; IHD: ischemic heart disease; PAD: peripheral artery disease; Plt: platelet; PP: polypharmacy; RBC: red blood cells; RDW-CV: red blood cell distribution width-coefficient of variation; WBC: white blood cell. ^aP < 0.05, non-PP vs. PP; ^bP < 0.05, non-PP vs. hyper-PP; ^cP < 0.05, PP vs. hyper-PP.

259

68 (26.25)

132 (50.97)

59 (22.78)

Age (years)

72 (64, 78)

70 (63, 75)

72 (66, 78)

73 (62, 80)

0.057

Male gender (%)

173 (66.8)

38 (55.9)

95 (72.0)

40 (67.8)

0.075

BMI (kg/m²)

24.0 ± 3.9

23.2 ± 3.7

24.0 ± 3.9

24.8 ± 3.8

0.069

WBC (10²/µL)

60.6 ± 17.6

55.4 ± 13.4

62.6 ± 18.8^a

62.0 ± 18.1

0.017

Plt (10⁴/µL)

19.3 ± 5.4

19.8 ± 5.2

19.1 ± 5.3

19.0 ± 5.9

0.599

RBC (10⁴/µL)

441 ± 63

455 ± 47

444 ± 61

417 ± 78^{b, c}

0.002

Hb (g/dL)

13.5 ± 1.8

14.1 ± 1.4

13.6 ± 1.9

12.8 ± 1.8^{b, c}

< 0.001

Ht (%)

40.9 ± 5.0

42.3 ± 3.8

41.1 ± 5.3

39.1 ± 5.2^{b, c}

0.002

RDW-CV

13.6 (13.0, 14.1)

13.3 (12.8, 13.7)

13.7 (13.1, 14.1)^a

13.7 (13.1, 14.8)^b

< 0.001

Anemia (%)

74 (28.6)

6 (8.8)

37 (28.0)^a

31 (52.5)^{b, c}

< 0.001

Cr (mg/dL)

0.84 (0.68, 1.01)

0.72 (0.62, 0.84)

0.85 (0.70, 0.99)^a

1.01 (0.81, 1.32)^{b, c}

< 0.001

eGFR (mL/min/1.73 m²)

65.4 ± 20.9

73.8 ± 17.3

66.2 ± 19.1^a

54.0 ± 23.4^{b, c}

< 0.001

Number of CVDs or their risk factors

3 (2, 4)

2 (1, 2)

3 (2, 4)^a

4 (2, 5)^{b, c}

< 0.001

CVD or its risk factor

Atrial fibrillation (%)

47 (18.1)

10 (14.7)

22 (16.7)

15 (25.4)

0.262

Diabetes mellitus (%)

98 (37.8)

12 (17.6)

52 (39.4)^a

34 (57.6)^{b, c}

< 0.001

Dyslipidemia (%)

150 (57.9)

32 (47.1)

81 (61.4)

37 (62.7)

0.114

Heart failure (%)

56 (21.6)

7 (10.3)

24 (18.2)

25 (42.4)^{b, c}

< 0.001

Hypertension (%)

184 (71.0)

43 (63.2)

94 (71.2)

47 (79.7)

0.127

IHD (%)

129 (49.8)

20 (29.4)

71 (53.8)^a

38 (64.4)^b

< 0.001

PAD (%)

24 (9.3)

1 (1.5)

10 (7.6)

13 (22.0)^{b, c}

< 0.001

Stroke (%)

28 (10.8)

3 (4.4)

15 (11.4)

10 (16.9)

0.060

**Table 2.** Drugs Administered in Each Category of Polypharmacy
	All	Classification of polypharmacy	P value
The data are presented as median (first quartile, third quartile) for not normally distributed variables, or the number (percentage) for categorical variables. Differences in categorical variables between groups were assessed using Fisher’s exact test followed by Holm’s post hoc test. Differences in continuous variables between groups were assessed using Kruskal-Wallis’s test followed by Steel-Dwass’s post hoc test for not normally distributed variables. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; CV: cardiovascular; H₂-blocker: histamine type 2 receptor blocker; NSAID: nonsteroidal anti- inflammatory drug; PP: polypharmacy; PPI: proton pump inhibitor; statins: HMG-CoA reductase inhibitor. ^aP < 0.05, non-PP vs. PP; ^bP < 0.05, non-PP vs. hyper-PP; ^cP < 0.05, PP vs. hyper-PP.
N	259	68 (26.25)	132 (50.97)	59 (22.78)
Number of drugs	7 (4, 9)	3 (1, 3)	7 (6, 8)^a	12 (10, 14)^{b, c}	< 0.001
Number of CV drugs	4 (3, 6)	2 (1, 3)	5 (4, 6)^a	8 (6, 9)^{b, c}	< 0.001
ACEI (%)	39 (15.1)	4 (5.9)	22 (16.7)	13 (22.0)^b	0.023
Antiarrhythmic agent	24 (9.3)	4 (5.9)	7 (5.3)	13 (22)^{b, c}	0.002
Anticoagulant (%)	67 (25.9)	8 (11.8)	37 (28.0)^a	22 (37.3)^b	0.002
Antiplatelet agents (%)	152 (58.7)	15 (22.1)	93 (70.5)^a	44 (74.6)^b	< 0.001
ARB (%)	141 (54.4)	22 (32.4)	78 (59.1)^a	41 (69.5)^b	< 0.001
Calcium channel blockers (%)	120 (46.3)	27 (39.7)	59 (44.7)	34 (57.6)	0.115
Cardiac stimulant	10 (3.9)	1 (1.5)	4 (3.0)	5 (8.5)	0.135
Diuretics (%)	80 (30.9)	6 (8.8)	39 (29.5)^a	35 (59.3)^{b, c}	< 0.001
Hypolipidemic agent other than statins	19 (7.3)	1 (1.5)	10 (7.6)	8 (13.6)^b	0.002
Insulin (%)	11 (4.2)	0 (0.0)	2 (1.5)^a	9 (15.3)^b	< 0.001
Oral hypoglycemic agents (%)	59 (22.8)	0 (0.0)	32 (24.2)^a	27 (45.8)^{b, c}	< 0.001
Statins (%)	120 (46.3)	10 (14.7)	78 (59.1)^a	32 (54.2)^b	< 0.001
Vasodilator agent	44 (17.0)	2 (2.9)	24 (18.2)^a	18 (30.5)^b	< 0.001
β-blockers (%)	124 (47.9)	16 (23.5)	67 (50.8)^a	41 (69.5)^{b, c}	< 0.001
Number of non-CV drugs	2 (1, 3)	0 (0, 1)	2 (1, 3)^a	3 (3, 7)^{b, c}	< 0.001
Antianxiety or hypnotic (%)	55 (21.2)	4 (5.9)	30 (22.7)^a	21 (35.6)^b	< 0.001
Cathartic (%)	52 (20.1)	3 (4.4)	22 (16.7)^a	27 (45.8)^{b, c}	< 0.001
H₂-blockers (%)	26 (10.0)	3 (4.4)	15 (11.4)	8 (13.6)	0.162
NSAIDs (%)	13 (5.0)	1 (1.5)	4 (3.0)^a	8 (13.6)^b	0.004
PPI (%)	88 (34.0)	4 (5.9)	49 (37.1)^a	35 (59.3)^{b, c}	< 0.001
Uric acid-lowering agents (%)	46 (17.8)	6 (8.8)	21 (15.9)	19 (32.2)^{b, c}	0.003

Table 2. Drugs Administered in Each Category of Polypharmacy

All

Classification of polypharmacy

P value

non-PP (0 - 4)

PP (5 - 9)

hyper-PP (≥ 10)

The data are presented as median (first quartile, third quartile) for not normally distributed variables, or the number (percentage) for categorical variables. Differences in categorical variables between groups were assessed using Fisher’s exact test followed by Holm’s post hoc test. Differences in continuous variables between groups were assessed using Kruskal-Wallis’s test followed by Steel-Dwass’s post hoc test for not normally distributed variables. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; CV: cardiovascular; H₂-blocker: histamine type 2 receptor blocker; NSAID: nonsteroidal anti- inflammatory drug; PP: polypharmacy; PPI: proton pump inhibitor; statins: HMG-CoA reductase inhibitor. ^aP < 0.05, non-PP vs. PP; ^bP < 0.05, non-PP vs. hyper-PP; ^cP < 0.05, PP vs. hyper-PP.

259

68 (26.25)

132 (50.97)

59 (22.78)

Number of drugs

7 (4, 9)

3 (1, 3)

7 (6, 8)^a

12 (10, 14)^{b, c}

< 0.001

Number of CV drugs

4 (3, 6)

2 (1, 3)

5 (4, 6)^a

8 (6, 9)^{b, c}

< 0.001

ACEI (%)

39 (15.1)

4 (5.9)

22 (16.7)

13 (22.0)^b

0.023

Antiarrhythmic agent

24 (9.3)

4 (5.9)

7 (5.3)

13 (22)^{b, c}

0.002

Anticoagulant (%)

67 (25.9)

8 (11.8)

37 (28.0)^a

22 (37.3)^b

0.002

Antiplatelet agents (%)

152 (58.7)

15 (22.1)

93 (70.5)^a

44 (74.6)^b

< 0.001

ARB (%)

141 (54.4)

22 (32.4)

78 (59.1)^a

41 (69.5)^b

< 0.001

Calcium channel blockers (%)

120 (46.3)

27 (39.7)

59 (44.7)

34 (57.6)

0.115

Cardiac stimulant

10 (3.9)

1 (1.5)

4 (3.0)

5 (8.5)

0.135

Diuretics (%)

80 (30.9)

6 (8.8)

39 (29.5)^a

35 (59.3)^{b, c}

< 0.001

Hypolipidemic agent other than statins

19 (7.3)

1 (1.5)

10 (7.6)

8 (13.6)^b

0.002

Insulin (%)

11 (4.2)

0 (0.0)

2 (1.5)^a

9 (15.3)^b

< 0.001

Oral hypoglycemic agents (%)

59 (22.8)

0 (0.0)

32 (24.2)^a

27 (45.8)^{b, c}

< 0.001

Statins (%)

120 (46.3)

10 (14.7)

78 (59.1)^a

32 (54.2)^b

< 0.001

Vasodilator agent

44 (17.0)

2 (2.9)

24 (18.2)^a

18 (30.5)^b

< 0.001

β-blockers (%)

124 (47.9)

16 (23.5)

67 (50.8)^a

41 (69.5)^{b, c}

< 0.001

Number of non-CV drugs

2 (1, 3)

0 (0, 1)

2 (1, 3)^a

3 (3, 7)^{b, c}

< 0.001

Antianxiety or hypnotic (%)

55 (21.2)

4 (5.9)

30 (22.7)^a

21 (35.6)^b

< 0.001

Cathartic (%)

52 (20.1)

3 (4.4)

22 (16.7)^a

27 (45.8)^{b, c}

< 0.001

H₂-blockers (%)

26 (10.0)

3 (4.4)

15 (11.4)

8 (13.6)

0.162

NSAIDs (%)

13 (5.0)

1 (1.5)

4 (3.0)^a

8 (13.6)^b

0.004

PPI (%)

88 (34.0)

4 (5.9)

49 (37.1)^a

35 (59.3)^{b, c}

< 0.001

Uric acid-lowering agents (%)

46 (17.8)

6 (8.8)

21 (15.9)

19 (32.2)^{b, c}

0.003

**Table 3.** Univariate Analyses of Factors Associated With the Number of Drugs
Factor	ρ	P value
Correlations between each variable were examined using Spearman’s rank correlation coefficient rho (ρ). BMI: body mass index; CVD: cardiovascular disease; eGFR: estimated glomerular filtration rate; Hb: hemoglobin; Plt: platelet; WBC: white blood cell.
Number of CVDs or their risk factors	0.484	< 0.001
eGFR (mL/min/1.73 m²)	-0.336	< 0.001
Hb (g/dL)	-0.217	< 0.001
Plt (10⁴/µL)	-0.153	0.014
Age (years)	0.151	0.015
WBC (10²/µL)	0.143	0.021
BMI (kg/m²)	0.127	0.041

Table 3. Univariate Analyses of Factors Associated With the Number of Drugs

Factor

P value

Correlations between each variable were examined using Spearman’s rank correlation coefficient rho (ρ). BMI: body mass index; CVD: cardiovascular disease; eGFR: estimated glomerular filtration rate; Hb: hemoglobin; Plt: platelet; WBC: white blood cell.

Number of CVDs or their risk factors

0.484

< 0.001

eGFR (mL/min/1.73 m²)

-0.336

< 0.001

Hb (g/dL)

-0.217

< 0.001

Plt (10⁴/µL)

-0.153

0.014

Age (years)

0.151

0.015

WBC (10²/µL)

0.143

0.021

BMI (kg/m²)

0.127

0.041

**Table 4.** Multivariate Analysis of Factors Which Were Independently Associated With the Number of Drugs
Factor	β	P value
Factors which were independently associated with the number of drugs were examined using linear regression analysis. CVD: cardiovascular disease; CKD: chronic kidney disease; WBC: white blood cell; Plt: platelet; BMI: body mass index.
Number of CVDs or their risk factors	1.033	< 0.001
Anemia	1.722	< 0.001
CKD stage 3b or higher	1.923	0.002
WBC (10²/µL)	0.022	0.081
Plt (10⁴/µL)	-0.049	0.229
Male	0.504	0.244
BMI (kg/m²)	0.025	0.638
Age (years)	-0.009	0.672

Table 4. Multivariate Analysis of Factors Which Were Independently Associated With the Number of Drugs

Factor

P value

Factors which were independently associated with the number of drugs were examined using linear regression analysis. CVD: cardiovascular disease; CKD: chronic kidney disease; WBC: white blood cell; Plt: platelet; BMI: body mass index.

Number of CVDs or their risk factors

1.033

< 0.001

Anemia

1.722

< 0.001

CKD stage 3b or higher

1.923

0.002

WBC (10²/µL)

0.022

0.081

Plt (10⁴/µL)

-0.049

0.229

Male

0.504

0.244

BMI (kg/m²)

0.025

0.638

Age (years)

-0.009

0.672

**Table 5.** The Factors Which Correlated With the Changing Rate of eGFR
Factor	ρ	P value
The factors which correlated with the changing rate of eGFR were examined using Spearman’s rank correlation coefficient. eGFR: estimated glomerular filtration rate; Plt: platelet; Hb: hemoglobin; CVD: cardiovascular disease; WBC: white blood cell; BMI: body mass index.
Number of prescribed drugs	0.151	0.030
Age	0.087	0.213
Plt	-0.072	0.298
Hb	-0.065	0.353
eGFR	-0.061	0.378
Number of CVDs or their risk factors	0.050	0.473
WBC	-0.048	0.494
BMI	0.024	0.728

Table 5. The Factors Which Correlated With the Changing Rate of eGFR

Factor

P value

The factors which correlated with the changing rate of eGFR were examined using Spearman’s rank correlation coefficient. eGFR: estimated glomerular filtration rate; Plt: platelet; Hb: hemoglobin; CVD: cardiovascular disease; WBC: white blood cell; BMI: body mass index.

Number of prescribed drugs

0.151

0.030

Age

0.087

0.213

Plt

-0.072

0.298

-0.065

0.353

eGFR

-0.061

0.378

Number of CVDs or their risk factors

0.050

0.473

WBC

-0.048

0.494

BMI

0.024

0.728