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  • Open Access

Hypertension control among euvolemic hypertensive hemodialysis patients in Malaysia: a prospective follow-up study

Journal of Pharmaceutical Policy and Practice201912:10

https://doi.org/10.1186/s40545-019-0169-y

  • Received: 3 October 2018
  • Accepted: 15 March 2019
  • Published:

Abstract

Objectives

Existing literature does not provide enough information on evaluation of factors associated with pre-dialysis controlled hypertension among euvolemic hemodialysis (HD) patients. We conducted a study to evaluate the rate and factors influencing pre-dialysis controlled hypertension among euvolemic HD patients.

Design

A multicenter prospective follow-up study.

Setting

Tertiary care teaching hospital and its associated private dialysis centers.

Participants

This study included 145 euvolemic eligible hypertensive patients. Various sociodemographic, clinical factors and drugs were investigated and analyzed by using appropriate statistical methods to determine the factors influencing hypertension control among the study participants.

Results

On baseline visit, the mean pre-dialysis systolic and diastolic BP (mmHg) of study participants was 161.2 ± 24. and 79.21 ± 11.8 retrospectively, and 30 (20.6%) patients were on pre-dialysis goal BP. At the end of the 6-months follow-up, the mean pre-dialysis systolic BP and diastolic BP (mmHg) of the patients was 154.6 ± 18.3 and 79.2 ± 11.8 respectively, and 42 (28.9%) were on pre-dialysis goal BP. In multivariate analysis, the use of calcium channel blockers (CCBs) was the only variable which had statistically significant association with pre-dialysis controlled hypertension at baseline (OR = 7.530, p-value = 0.001) and final (OR = 8.988, p-value < 0.001) visits.

Conclusions

In present study, the positive association observed between CCBs and controlled hypertension suggests that CCBs are effective antihypertensive drugs in the management of hypertension among euvolemic HD patients.

Strengths and limitations of this study

  • This study involved a group of patients from tertiary-level teaching hospital and its associated private dialysis centers of Malaysia.

  • To the best of the authors’ knowledge, this is the first study to assess the factors influencing pre-dialysis controlled hypertension in a cohort of 145 euvolemic HD patients in a Malaysian setting.

  • For determining the factors influencing hypertenion control multivariate analysis was conducted.

  • Being a prospective follow-up study, the findings of the present study need to be interpreted with caution since it is limited to only 6 months follow up.

  • Nevertheless, a multicenter study with a large sample size and longer follow up time is needed to confirm the findings of the current study.

Keywords

  • Calcium channel blockers
  • Euvolemic
  • Hemodialysis
  • Hypertension

Background

Hypertension is common and often poorly controlled among hemodialysis (HD) patients. In fact, volume overload is considered as an important cause of hypertension where patients may remain hypertensive even after thrice weekly HD sessions. In such patients, non-volume mechanisms such as activation of the renin angiotensin system and/or sympatho-adrenal activities, are important contributors to hypertension [13]. Due to their safety, tolerability and good therapeutic efficacies, renin angiotensin aldosterone system (RAAS) inhibitors are also considered as the first line agents in the treatment of hypertension among HD patients [4]. The national kidney foundation disease outcomes quality initiative (KDOQI) guidelines also recommend the use of RAAS inhibitors among dialysis patients having diabetic and heart failures [5].

A literature suggests that systolic BP is associated with cardiovascular adverse events [6]. Studies by Moist et al. and Efrati et al. concluded that the use of angiotensin converting enzyme (ACE) inhibitors is associated with improved survival [7, 8]. In fact, blood pressure (BP) control and cardiovascular outcomes can be improved by combining ACE inhibitors and angiotensin receptor blockers (ARBs) therapies [9]. Calcium channel blockers (CCB)s and other vasodilators are also considered to be effective in managing BP where CCBs are often widely applied in patients with volume overload and can very useful for lowering the BP among HD patients [10]. A recent randomized controlled trial reported that amlodipine can lower systolic BP  10 mmHg as compared with placebo (7% vs. 13%, respectively) without introducing an intradialytic hypotension [11]. Nevertheless, there is limited literature available on the role of CCBs regarding the management of hypertension among HD patients.

Among the general population, studies investigating CCBs use indicated mixed findings regarding their effects on patient’s outcome [1218]. For example, the use of short acting dihydropyridines leads to a higher risk of developing myocardial infarction while the longer acting CCBs pose some mortality risks as also seen with the use of other antihypertensive medications [10]. Generally, CCBs are commonly prescribed to patients with end stage renal disease (ESRD), mainly for BP control though it may have different effects in ESRD patients [10]. CCBs inhibit vasoconstriction as well as both the hypertrophic and hyperplastic effects of angiotensin II and other mitogens on the mesangial and vascular smooth muscle cells by blocking calcium-dependent mechanisms [1921]. The USA national clinical practice guideline (2005), recommended a pre-dialysis BP of less than 140/90 mmHg and post-dialysis BP of less than 130/80 mmHg [22]. However, achieving these standards in clinical practice remains a challenge. In this study, an observational analysis to evaluate the factors influencing pre-dialysis controlled hypertension among euvolemic HD patients is conducted.

Materials and methods

Study location and participants

This was a multicenter, prospective follow-up study conducted among HD patients at Hospital Universiti Sains Malaysia (HUSM), which is a tertiary care hospital and its associated dialysis centers in Kelantan, Malaysia. All confirmed hypertensive HD patients between 1st April 2017 to 31st December 2017 who received anti-hypertensives and have to undergo dialysis three times a week were consecutively enrolled in the study.

Operational definitions

Hypertension

According to KDOQI guidelines, pre-dialysis and postdialysis BP goals should be < 140/90 mmHg and < 130/80 mmHg, respectively.

Controlled hypertension

Patients with a mean systolic/diastolic BP of < 130/80 mmHg were considered as having controlled hypertension.

Hypervolemia, Euvolemia and hypovolemia

A multi-frequency (5–1000 kHz) portable bioimpedance spectroscopy device (Body Composition Monitor, BCM, Fresenius Medical Care, Germany) was used to assess fluid status. The BCM-calculated overhydration (OH) value was used as a fluid overload indicator. Accordingly, OH > 1.1 L was categorized as fluid overload or hypervolemia. An OH value lower than the 10th percentile (− 1.1 L) was defined as hypovolemia. An OH value of ±1.0 L was defined as euvolemia, i.e., normal hydration status [2325].

Patients with pre-dialytic hypotension (having a systolic BP less than 110 mmHg) or high BP > 200/100 mmHg were excluded from the study. A total of 220 met the eligibility criteria and were included in the study (Fig. 1). From this number, 75 hyper and hypovolemic patients were excluded. Finally, the pre-dialysis BP measurements and the effect of antihypertensive drugs on BP on 145 euvolemic patients were assessed. The study procedures were in accordance with the clinical practice guidelines for HD from National Kidney Foundation Kidney Disease Outcome Quality Initiative (NKF KDOQI) [26]. Diagnosis of cardiovascular disease and other comorbidities were based on documentation from patient’s medical record. Patients with ischemic heart disease, heart failure and left ventricular hypertrophy were considered to have cardiovascular disease. We used the criteria based on advisory committee suggestions, extensive literature review, hypothetical possible association and nephrologist’s suggestions i.e. If three consecutive BCM readings confirms the euvolemic state, then those patients are considered as euvolemic HD patients and we further proceeded them for hypertension evaluation.
Fig. 1
Fig. 1

Study Design

Data collection

Both socio-demographic and clinical data were collected from the regularly updated Advanced Dialysis Nephrology Application Network (ADNAN) at the study sites (URL: http://www.microsemi.com.my/product/advanced-dialysis-nephrologist-application-network-adnan-system) using a standardized data collection form. Height, weight and BP were measured during the physical examination. Only a single calibrated manual sphygmomanometer was used to measure BP in all of the patients. A multi-frequency (5–1000 kHz) portable bioimpedance spectroscopy device (Body Composition Monitor, BCM, Fresenius Medical Care, Germany) was used to assess fluid status.

On the dialysis day, pre-dialysis BP was taken as a mean of three consecutive measurements with 5-min intervals. BP was recorded by a senior member of the nursing staff dedicated to the study. As per KDOQI guidelines, BP goals were defined as < 140/90 and < 130/80 mmHg for pre-and post-dialysis respectively. Patients with a mean systolic/diastolic BP of > 140/90 mmHg were considered as having an uncontrolled hypertension. During the 6 months’ follow-up, the mean pre-dialysis BP readings at baseline, 1, 2, 3, 4, 5 and 6 months were recorded and the effects of antihypertensive drugs on pre-dialysis BP control were assessed.

Statistical analysis

Statistical Package for Social Sciences (SPSS version 21, Chicago, USA) was used for data analysis. Means and standard deviations were calculated for continuous variables, whereas categorical variable are presented as frequencies and percentages. Chi-squared test was used to observe significance between categorical variables. Multivariate logistic regression analysis with the Wald statistical criteria was used to obtain a final model. A p-value of < 0.05 was considered statistically significant. Relevant variables with a p-value < 0.25 in the univariate analysis were included in the multivariate analysis. We confirmed the correlations among variables entered in the multivariate analysis. The results of multivariate analysis were presented as beta, standard error, p-value, adjusted odds ratio and 95% confidence interval. The fit of the model was assessed by Hosmer Lemeshow and overall classification percentage.

Results

The mean age of the study participants (n = 145) was 58.68 (± 9.86) years. The majority were females (51.7%), 41–60 years old (57.2%), of a normal body mass index (BMI) (62.1%) and on dialysis for more than 5 years (31%). Since the study was conducted in the Malaysian state of Kelantan, most patients were of Malay ethnicity (96.6%) (Table 1).
Table 1

Baseline demographics and characteristics of euvolemic hemodialysis patients (n = 145)

Variables

No. (%)

Gender

 Female

75 (51.7)

 Male

70 (48.3)

Age mean (±SD)

58.68 (± 9.857)

Age group (years)

 < 40

7 (4.8)

 41–60

83 (57.2)

 > 60

55 (37.9)

BMI mean (±SD)

23.908 (± 4.3505)

BMI classification

 Underweight

6 (4.1)

 Normal

90 (62.1)

 Overweight

42 (29)

 Obese

7 (4.8)

Education

 Uneducated

40 (27.6)

 Educated

105 (72.4)

Marital status

 Single

6 (4.1)

 Married

139 (95.9)

Ethnicity

 Malay

140 (96.6)

 Others

5 (3.4)

Smoking status

 Current Smoker

44 (30.3)

 Non-Smoker

101 (69.7)

Alcohol

 Current drinker

6 (4.1)

 Non-drinker

139 (95.9)

Drug addiction

 Current Drug Addiction

16 (11)

 No Drug Addiction

129 (89)

Employment

 Unemployed

77 (53.1)

 Employed

68 (46.9)

Years of dialysis

 1 year

43 (29.7)

 2–4 years

57 (39.3)

 > 5 years

45 (31)

Hemodialysis centers

 Private

84 (57.9)

 NGO

24 (16.6)

 Governmental

37 (25.5)

Vascular access

 Fistula

135 (93.1)

 Others

10 (6.9)

Diabetes mellitus

 No

48 (33.1)

 Yes

97 (66.9)

Cardiovascular diseases

 No

125 (86.2)

 Yes

20 (13.8)

Cerebrovascular accident

 No

131 (90.3)

 Yes

14 (9.7)

Hyperlipidemia

 No

125 (86.2)

 Yes

20 (13.8)

Gouty arthritis

 No

127 (87.6)

 Yes

18 (12.4)

Other comorbiditiesa

 No

104 (71.7)

 Yes

41 (28.3)

SD Standard deviation, BMI Body Mass Index, NGO Non-governmental organization

aOther comorbidities: Blood clots, depression, asthma, osteoarthritis, pregnancy losses/birth defects and osteoporosis

The most common comorbidities were hypertension (n = 118, 81.3%) and diabetes (n = 97, 66.9%). Calcium channel blockers (n = 43, 29.7%) was the most prescribed antihypertensive followed by beta antagonist (n = 42, 29%). Table 2 gives an account for euvolemic hemodialysis patients comorbid conditions and antihypertensive medication.
Table 2

Euvolemic hemodialysis patient’s antihypertensive medication and comorbidities (n = 145)

Patient variables

No. (%)

Antihypertensive medication

 ACE-I

12 (8.3)

 ARBs

36 (24.8)

 CCBs

43 (29.7)

 Alpha antagonist

6 (4.1)

 Beta antagonist

42 (29)

 Diuretics

41 (28.3)

Antihypertensive combination therapy

15 (10.3)

Co-morbid conditions

 Hypertension

118 (81.3)

 Diabetes mellitus

97 (66.9)

 Cardiovascular diseases

20 (13.8)

 Cerebrovascular accident

14 (9.7)

 Hyperlipidemia

20 (13.8)

 Gouty arthritis

18 (12.4)

 Other comorbiditiesa

41 (28.3)

ACE-I Angiotensin converting enzyme inhibitors, ARBs Angiotensin receptor blockers, CCBs Calcium channel blockers, aOther comorbidities: Blood clots, depression, asthma, osteoarthritis, pregnancy losses/birth defects and osteoporosis

Overall blood pressure changes

At the baseline visit, the mean pre-dialysis systolic BP was 161.2 ± 24.9 mmHg while pre-dialysis diastolic BP was 79.21 ± 11.8 mmHg at baseline. At the end of the 6-months follow-up, the mean pre-dialysis systolic BP was 154.6 ± 18.3 mmHg giving a change in BP of − 6.6 mmHg. Similarly, pre-dialysis diastolic BP which was 79.21 ± 11.8 mmHg at baseline, dropped to 75.0 mmHg ±7.2 mmHg at the end of study; a difference of − 4.2 mmHg. The mean pulse rate was 78 ± 13.9 beats per min at baseline which decreased to 74.5 ± 10.4. The mean baseline interdialytic weight gain was 1.8 ± 0.8 kg with only 1.5 ± 0.5 kg mean interdialytic weight gain at the end of study (Table 3).
Table 3

Blood Pressure readings during the course of study (n = 145)

Variables

Baseline

Mean (±SD)

1st month

Mean

(±SD)

2nd month

Mean

(±SD)

3rd month

Mean

(±SD)

4th month

Mean

(±SD)

5th

Month

Mean

(±SD)

6th

Month

Mean

(±SD)

Pre-dialysis systolic BP

161.2 (±24.9)

159.2 (±23.3)

158.0 (±21.9)

157.1 (±21.0)

156.4 (±20.1)

155.7 (±19.5)

154.6 (±18.3)

Pre-dialysis diastolic BP

79.2 (±11.8)

78.3 (±10.7)

77.5 (±9.5)

77.2 (±9.1)

76.5 (±8.4)

75.9 (±7.8)

75.0 (±7.2)

Pre-dialysis pulse rate

78.0 (±13.9)

77.2 (±12.9)

76.6 (±12.0)

76.1 (±11.4)

75.7 (±11.2)

75.15 (±10.8)

74.5 (±10.4)

Interdialytic weight gain

1.8 (±0.8)

1.8 (±0.7)

1.6 (±0.6)

1.5 (±0.5)

1.6 (±0.6)

1.4 (±0.5)

1.3 (±0.4)

Pre-dialysis BP variations of study duration are presented in graphical form in Fig. 2. There is a linear decrease in both mean systolic and diastolic BP from baseline towards sixth month.
Fig. 2
Fig. 2

Graphical representation of pre-dialysis blood pressure variations during the six month's follow up

Overall mean blood pressure readings of all visits of study participants

At the end of 6-month patient follow-up, the mean readings of all visits were calculated. The mean pre-dialysis systolic BP of all visits was 157.4 ± 2.2 mmHg and pre-dialysis diastolic BP was 77.0 ± 1.4 mmHg. Mean pulse rate was 76.1 ± 1.2 beats/min and mean interdialytic weight gain was reported as 1.5 ± 0.1 kg at the end of study. Table 4 provides the overall mean BP readings.
Table 4

Overall mean BP readings during the course of study (n = 145)

Variables

Mean (±SD)

Pre-dialysis systolic (mean of all BP readings)

157.4 (±2.2)

Pre-dialysis diastolic (mean of all BP readings)

77.0 (±1.4)

Pre-dialysis pulse rate (mean of all readings)

76.1 (±1.2)

Interdialytic weight gain (mean of all readings)

1.5 (±0.1)

Univariate and multivariate analysis (baseline)

On baseline visit, a total of 30 (20.6%) patients were on pre-dialysis goal BP of <130/80 mmHg. Upon univariate binary logistic regression analysis, the associations observed between various independent variables and pre-dialysis controlled hypertension at baseline visit are given in (Table 5).
Table 5

Univariate and multivariate analysis of factors associated with pre-dialysis controlled hypertension at baseline (n = 145)

Variables

Patients with pre-dialysis controlled hypertension at baseline

Number (%)

Univariate analysis

OR (95% CI)

p-value

Multivariate analysis

OR (95% CI)

p-value

Yes

No

Gender

 Female

18 (24)

57 (76)

Reference

   

 Male

12 (17.1)

58 (82.9)

0.655 (0.289-1.483)

0.310

  

Age

  ≤ 40

1 (14.3)

6 (85.7)

Reference

   

 41-60

15 (18.1)

68 (81.9)

1.324 (0.148-11.821)

0.802

  

  > 60

14 (25.5)

41 (74.5)

2.049 (0.227-18.531)

0.523

  

BMI

 Underweight

3 (50)

3 (50)

Reference

 

Reference

 

 Normal

17 (18.9)

73 (81.1)

0.233 (0.043-1.256)

0.090

0.597 (0.080-4.470)

0.615

 Overweight

7 (16.7)

35 (83.3)

0.200 (0.033-1.203)

0.079

0.378 (0.036-3.951)

0.417

 Obese

3 (42.9)

4 (57.1)

0.750 (0.084-6.710)

0.797

1.737 (0.109-1.851)

0.268

Smoking status

 Current Smoker

8 (18.2)

36 (81.8)

Reference

   

 Non-Smoker

22 (21.8)

79 (78.2)

1.253 (0.509-3.083)

0.623

  

Drug addiction

 Current drug addiction

5 (31.3)

11 (68.8)

Reference

   

 No drug addiction

25 (19.4)

104 (80.6)

0.529 (0.169-1.660)

0.275

  

Hemodialysis centers

 Private

16 (19)

68 (81)

Reference

 

Reference

 

 NGO

3 (12.5)

21 (87.5)

0.607 (0.161-2.288)

0.461

0.448 (0.109-1.851)

0.268

 Governmental

11 (29.7)

26 (70.3)

1.798 (0.738-4.382)

0.197

0.959 (0.299-3.077)

0.944

Vascular access

 Fistula

28 (20.7)

107 (79.3)

Reference

   

 Others

2 (20)

8 (80)

0.955 (0.192-4.753)

0.956

  

Diabetes mellitus

 No

10 (20.8)

38 (79.2)

Reference

   

 Yes

20 (20.6)

77 (79.4)

0.987 (0.421-2.316)

0.976

  

Cardiovascular diseases

 No

26 (20.8)

99 (79.2)

Reference

   

 Yes

4 (20)

16 (80)

0.952 (0.293-3.091)

0.935

  

Cerebrovascular accident

 No

27 (20.6)

104 (79.4)

Reference

   

 Yes

3 (21.4)

11 (78.6)

1.051 (0.274-4.032)

0.943

  

Hyperlipidemia

 No

30 (24)

95 (76)

Non-computable

   

 Yes

20 (100)

 

  

Gouty arthritis

 No

29 (22.8)

98 (77.2)

Reference

 

Reference

 

 Yes

1 (5.6)

17 (94.4)

0.199 (0.25-1.558)

0.124

0.304 (0.033-2.770)

0.291

Others comorbiditiesa

 No

18 (17.3)

86 (82.7)

Reference

 

Reference

 

 Yes

12 (29.3)

29 (70.7)

1.977 (0.851-4.593)

0.113

2.307 (0.851-6.260)

0.101

ACE-I

 No

30 (22.6)

103 (77.4)

Non-Computable

   

 Yes

12 (100)

 

  

ARB

 No

20 (18.3)

89 (81.7)

Reference

 

Reference

 

 Yes

10 (27.8)

26 (72.2)

1.712 (0.713-4.109)

0.229

3.436 (0.965-12.238)

0.061

CCB

 No

13 (12.7)

89 (87.3)

Reference

 

Reference

 

 Yes

17 (39.5)

26 (60.5)

4.476 (1.925-10.411)

0.001

7.530 (2.413-23.498)

0.001

Alpha antagonist

 No

27 (19.4)

112 (80.6)

Reference

 

Reference

 

 Yes

3 (50)

3 (50)

4.148 (0.793-21.698)

0.092

4.049 (0.510-32.120)

0.186

Beta antagonist

 No

19 (18.4)

84 (81.6)

Reference

   

 Yes

11 (26.2)

31 (73.8)

1.569 (0.671-3.667)

0.299

  

Diuretics

 No

23 (22.1)

81 (77.9)

Reference

   

 Yes

7 (17.1)

34 (82.9)

0.725 (0.284-1.849)

0.501

  

Other combination of antihypertensives

 No

27 (20.8)

103 (79.2)

Reference

   

 Yes

3 (20)

12 (80)

0.954 (0.251-3.621)

0.944

  

Type of therapy

 Mono-therapy

15 (19)

64 (81)

Reference

   

 Multi-therapy

15 (22.7)

51 (77.3)

1.255 (0.561-2.806)

0.580

  

Statins

 No

8 (20)

32 (80)

Reference

   

 Yes

22 (21)

83 (79)

1.060 (0.428-2.624)

0.899

  

Phosphate binders

 No

5 (27.8)

13 (72.2)

Reference

   

 Yes

25 (19.7)

102 (80.3)

0.637 (0.208-1.954)

0.431

  

Analysis: Univariate and Multivariate binary logistic regression analysis. All variables with p-value < 0.25 will be included in the multivariate analysis. OR Odds ratio, CI confidence interval, BMI Body mass index, NGO Non-governmental organization, aOther comorbidities: Blood clots, depression, asthma, osteoarthritis, pregnancy losses/birth defects and osteoporosis. ACE-I Angiotensin converting enzyme inhibitors, ARB Angiotensin receptor blocker, CCB Calcium channel blocker

In the multivariate logistic regression analysis, the only variable which was statistically significant associated with pre-dialysis controlled hypertension was the use of CCBs (OR = 7.530, p-value = 0.001) (Table 5).

Univariate and multivariate analysis (upon study completion)

Upon final visit, a total of 42 (28.9%) patients were on pre-dialysis goal BP of <130/80 mmHg. Upon univariate binary logistic regression analysis, the associations observed between various independent variables and pre-dialysis controlled hypertension at final visit are given in Table 6.
Table 6

Univariate and multivariate analysis of factors associated with pre-dialysis controlled hypertension upon study completion (n = 145)

Variables

Patients with pre-dialysis controlled hypertension on final visit

Number (%)

Univariate analysis

OR (95% CI)

p-value

Multivariate analysis

OR (95% CI)

p-value

Yes

No

Gender

 Female

20 (26.7)

55 (73.3)

Reference

   

 Male

22 (31.4)

48 (68.6)

1.260 (0.614-2.586)

0.528

  

Age

  ≤ 40

3 (42.9)

4 (57.1)

Reference

   

 41-60

22 (26.5)

61 (73.5)

0.481 (0.100-2.321)

0.362

  

  > 60

17 (30.9)

38 (69.1)

0.596 (0.120-2.962)

0.527

  

BMI

 Underweight

3 (50)

3 (50)

Reference

 

Reference

 

 Normal

22 (24.4)

68 (75.6)

0.324 (0.061-1.720)

0.186

0.809 (0.123-5.330)

0.826

 Overweight

13 (31)

29 (69)

0.448 (0.080-2.526)

0.363

0.705 (0.084-5.927)

0.747

 Obese

4 (57.1)

3 (42.9)

1.333 (0.149-11.929)

0.797

4.775 (0.352-64.836)

4.775

Smoking status

 Current Smoker

12 (27.3)

32 (72.7)

Reference

   

 Non-Smoker

30 (29.7)

71 (70.3)

1.127 (0.512-2.480)

0.767

  

Drug addiction

 Current drug addiction

8 (50)

8 (50)

Reference

 

Reference

 

 No drug addiction

34 (26.4)

95 (73.6)

0.358 (0.125-1.028)

0.056

0.492 (0.129-1.870)

0.298

Hemodialysis centers

 Private

20 (23.8)

64 (76.2)

Reference

 

Reference

 

 NGO

7 (29.2)

17 (70.8)

1.318 (0.478-3.630)

0.594

1.130 (0.302-4.224)

0.856

 Governmental

15 (40.5)

22 (59.5)

2.182 (0.955-4.985)

0.064

1.909 (0.601-6.062)

0.273

Vascular access

 Fistula

38 (28.1)

97 (71.9)

Reference

   

 Others

4 (40)

6 (60)

1.702 (0.455-6.368)

0.430

  

Diabetes mellitus

 No

18 (37.5)

30 (62.5)

Reference

 

Reference

 

 Yes

24 (24.7)

73 (75.3)

0.548 (0.260-1.154)

0.113

0.415 (0.156-1.105)

0.078

Cardiovascular diseases

 No

26 (20.8)

99 (79.2)

Reference

   

 Yes

4 (20)

16 (80)

0.793 (0.269-2.340)

0.674

  

Cerebrovascular accident

 No

37 (29.6)

88 (70.4)

Reference

   

 Yes

5 (25)

15 (75)

0.643 (0.170-2.434)

0.516

  

Hyperlipidemia

 No

41 (32.8)

84 (67.2)

Reference

   

 Yes

7 (35.0)

13 (65)

0.830 (0.730-2.903)

0.830

  

Gouty arthritis

 No

39 (30.7)

88 (69.3)

Reference

 

Reference

 

 Yes

3 (16.7)

15 (83.3)

0.451 (0.124-1.649)

0.229

1.312 (0.213-8.094))

0.770

Others comorbiditiesa

 No

26 (25)

78 (75)

Reference

 

Reference

 

 Yes

16 (39)

25 (61)

1.920 (0.890-4.141)

0.096

1.865 (0.690-5.041)

0.219

ACE-I

 No

39 (29.3)

94 (70.7)

Reference

   

 Yes

3 (25)

9 (75)

0.803 (0.206-3.127)

0.752

  

ARB

 No

31 (28.4)

78 (71.6)

Reference

   

 Yes

11 (30.6)

25 (69.4)

1.107 (0.487-2.519)

0.808

  

CCB

 No

17 (16.7)

85 (83.3)

Reference

 

Reference

 

 Yes

25 (58.1)

18 (41.9)

6.296 (2.843-13.943)

< 0.001

8.988 (3.140-25.728)

< 0.001

Alpha antagonist

 No

40 (28.8)

99 (71.2)

Reference

   

 Yes

2 (33.3)

4 (66.7)

1.237 (0.218-7.027)

0.810

  

Beta antagonist

 No

28 (27.2)

75 (72.8)

Reference

   

 Yes

14 (33.3)

28 (66.7)

1.339 (0.617-2.906)

0.460

  

Diuretics

 No

34 (32.7)

70 (67.3)

Reference

 

Reference

 

 Yes

8 (19.5)

33 (80.5)

0.499 (0.208-1.196)

0.119

0.349 (0.108-1.132)

0.080

Other combination of antihypertensives

 No

36 (27.7)

94 (72.3)

Reference

   

 Yes

6 (40)

9 (60)

1.741 (0.578-5.241)

0.324

  

Type of therapy

 Mono-therapy

24 (30.4)

55 (69.6)

Reference

   

 Multi-therapy

18 (27.3)

48 (72.7)

0.859 (0.417-1.772)

0.681

  

Statins

 No

12 (30)

28 (70)

Reference

   

 Yes

30 (28.6)

75 (71.4)

0.933 (0.420-2.073)

0.865

  

Phosphate binders

 No

5 (27.8)

13 (72.2)

Reference

   

 Yes

37 (29.1)

90 (70.9)

1.069 (0.356-3.212)

0.906

  

Analysis: Univariate and Multivariate binary logistic regression analysis. All variables with p-value < 0.25 will be included in the multivariate analysis. OR Odds ratio, CI confidence interval, BMI Body mass index, NGO Non-governmental organization, aOther comorbidities: Blood clots, depression, asthma, osteoarthritis, pregnancy losses/birth defects and osteoporosis. ACE-I Angiotensin converting enzyme inhibitors, ARB Angiotensin receptor blocker, CCB Calcium channel blocker

In the multivariate logistic regression analysis, the only variable which had statistically significant association with pre-dialysis controlled hypertension was prescription of CCBs (OR = 8.988, p-value = < 0.001). Those patients who were receiving CCBs had significantly high rate of hypertension control than those who were not receiving it (Table 6).

Discussion

Although the use of ACE inhibitors and ARBs are associated with reduction of BP in HD patients [8] limited literature is available on the evaluation of factors associated with pre-dialysis controlled hypertension among euvolemic hemodialysis patients. This is seen even though the prevalence of uncontrolled hypertension in HD patients as defined based on the recommendations by KDOQI of achieving a pre-HD systolic BP < 140 mmHg and a post-HD systolic BP < 130 mmHg, [5] is reported to be high (80–90%) [27].

The probability of combining two or more medications to achieve good targeted BP can be reduced in certain ethnic groups who are relatively more responsive to certain classes of antihypertensive drugs used for lowering BP. The fixed-dose combination therapy of certain drugs such as a CCB and ACE inhibitors are known to confer some beneficial complementary physiologic action, lower side-effect profiles, improve tolerability, compliance, and salutary effect on target organs at a relatively lower cost. To date, different types of fixed-dose combination therapies for lowering BP are available and are commonly employed for clinical use [28].

In our study, the observed positive association between prescription of CCB and predialysis controlled hypertension is similar to the findings of a randomized controlled trial on nitrendipine [10]. Similarly, the findings of another retrospective study in HD patients suggest that the use of CCBs are associated with a lower risk of mortality [29] indicating the benefits of administering CCB in HD patients. In contrast, London et al in a small clinical trial reported that a CCB named nitrendipine failed to reduce left ventricular hypertrophy as compared to the use of an ACE inhibitor (perindopril) despite having effectively lowered BP to similar levels [30]. Nevertheless, since CCBs are not removed by HD, no additional post-dialysis dosing is required. Moreover, a once daily dosing of most CCBs make them attractive for use in HD patients [31] which warrants our further investigation.

The results from an observational study by Kestenbaum et al demonstrated that CCBs contribute to a 21% lower risk of all-cause mortality and 26% cardiovascular specific mortality [11]. In addition, CCBs exhibit a variety of other potential therapeutic properties in HD patients. Vascular smooth muscle relaxation, better BP control and attenuation of heart rate as well as contractility are among the specifically important parameters for HD patients who have high incidence of hypertension and left ventricular hypertrophy [32, 33] are all purported mechanisms of action of CCBs which are useful.

A multicenter prospective study [34] conducted in Japan found that the use of benidipine, a dihydropyridine derivative calcium antagonist, alone or when added to ACE inhibitors reduced BP less than 150/90 mmHg in almost 100% patients within a month which is similar to the findings in our study. It has been reported that treatment of a group of patients with calcium antagonists do not affect urinary protein excretion, although proteinuria is significantly reduced in patients treated with ACE inhibitor. However, it was noted that although CCBs do not affect proteinuria in the treated patients, they could slow down the progression of renal insufficiency while decreasing the BP significantly [32]. Similarly, Zucchelli et al. [35] in their prospective, randomized controlled trial showed the influence of captopril (an ACE inhibitor) and nifedipine (a CCB) on BP, renal insufficiency progression and proteinuria for three consecutive years found that both treatments exhibited similar effects on the progression rate of renal failure with similar reduction in BP seen with no significant reduction in proteinuria. In addition to these results, the Systolic Hypertension in Europe (Syst-Eur) Trial (1999) demonstrated that dihydropyridine-based antihypertensive treatment is particularly beneficial in older diabetic patients with isolated systolic hypertension [36]. Taken together, the results from the current study indicates the good potential of CCBs.

In agreement to our findings, another multicenter trial [37] also indicated a rapid reduction in BP when patients were treated with CCBs. These results further support our point of view that CCBs should be incorporated into the therapy of elderly hypertensive patients with chronic renal insufficiency with careful monitoring of BP. Similarly, CCBs have been found to be effective in cases of renal failure where patients tend to exhibit significant resistance to antihypertensive medications [38]. Moreover, studies in several animal models of progressive renal failure have shown that in addition to their antihypertensive effects, CCBs have other established advantages where like other vasodilating agents, they neither cause sodium and water retention nor hyperkalemia as usually seen with ACE inhibitors administrations [39]. However, at the moment it may not be evidently claimed that the results obtained from the referred animal models could be extrapolated to humans [40].

In addition to the above, CCBs are safe and have effective roles in treating or mitigating various complications pertaining to cardiovascular disorders and renal diseases in diabetic patients. For instance, the findings of a placebo-controlled double-blind trial revealed that antihypertensive treatment employing a dihydropyridine CCB indicated some beneficial effects in older diabetic patients as compared to the non-diabetic patients which reject the hypothesis that the use of long- acting CCBs is harmful in older diabetic patients [35].

There was similar reported cardiovascular benefit in patients who receive nitrendipine alone as opposed to the use of either enalapril or hydrochlorothiazide (or both nitrendipine and either enalapril or hydrochlorothiazide) [41]. It has been reported in many outcome trials that the relative benefit of antihypertensive therapy has been similar, but there is a wide difference in the absolute benefit according to the number of outcomes observed in the control group [42]. In a randomized trial [43], it has been reported that patients receiving fosinopril experienced a significantly lower number of acute myocardial infarction or stroke or angina pectoris (14 of 189 patients, vs. 27 of 191 treated with amlodipine). However, this was an open randomized controlled trial and the adverse effects were recorded by asking patients whether they had been hospitalized or had any other discomfort.

In keeping with our findings, the Hypertension Optimal Treatment Trial [15] revealed that BP control can be achieved (target diastolic BP, 80 mmHg rather than 90 mmHg) with the use of felodipine as the first-line agent, and resulted in lower rates of all cardiovascular events in 1501 study participants with diabetes (relative risk, 0.49; 95% confidence interval, 0.29 to 0.81; p = 0.005) but not in the overall study participants of 18,790 patients (relative risk, 0.93; 95% confidence interval, 0.78 to 1.12; p = 0.50). Similarly, the effects of 5 to 20 mg/day of manidipine, a dihydropyridine-type CCB on seventy- one renal impairment hypertensive patients on their BPs and renal functions were investigated for more than 48 weeks [37]. In our study BP was well controlled in 25 (58.1%) patients out of 43 patients thus highlighting the potential benefits of CCBs in euvolemic hypertensive HD patients. Therefore, careful selection of antihypertensive drugs in these special group of patients are recommended.

Conclusion

Our study revealed a positive association between pre- dialysis controlled hypertension among euvolemic hypertensive patients and prescription of CCBs. However, the results of the current study should be interpreted with the major limitations of limited sample size and lack of information about patients’ adherence with antihypertensive medications and life style interventions. A large multi-center prospective study is recommended to confirm the present findings.

Study limitations

The findings of the present study need to be interpreted with caution since it is limited to only 6 months follow up. Nevertheless, a multicenter study with a large sample size and longer follow-up time is needed to confirm the findings of the current study. Furthermore, some other factors that affect blood pressure control such as salt intake, exercise, etc. were not assessed in this study. As the study was carried out in Kelantan, Malaysia, where Malays are the predominant inhabitants. Malaysia is multiethnic country with the three predominate ethnicities i.e. Malays, Chinese and Indians. The results of this study therefore cannot be extended to the whole population of the country.

Declarations

Acknowledgments

We are grateful to the Institute of Postgraduate Studies (IPS) of Universiti Sains Malaysia (USM) for the fellowship support [Ref. no. P-FD0011/15(R)].

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Availability of data and materials

All data generated or analyzed during this study are included in this current article. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

All authors (AK, AHK, ASA, SASS, SM, NA, IK) made substantial contributions to the conception and design of this study. AK and AHK made substantial contributions to the acquisition and analysis of the data. AK drafted the manuscript and ASA, SASS, SM, NA and IK were involved in critical revision for important intellectual content. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Our study was approved by the Human Resource Ethics Committee of Hospital Universiti Sains Malaysia (USM/JEPeM/16020058) which complies with the Declaration of Helsinki. All patients were asked to read and then sign the written consent forms before study participation. All methods were performed in accordance with the relevant guidelines and regulations.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests. Cover page including all authors affilliations.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Discipline of Clinical Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia
(2)
Chronic Kidney Disease Resource Centre, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia
(3)
Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320, Pakistan
(4)
Health Care Biotechnology Department, Atta ur Rahman School of Applied Biosciences, National University of Sciences & Technology, Islamabad, 44000, Pakistan
(5)
Faculty of Pharmacy and Health Sciences, University of Balochistan, Quetta, 87300, Pakistan

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Copyright

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