Amlodipine-Induced Pedal Edema and Its Relation to Other Variables in Patients at a Tertiary Level Hospital of Kathmandu, Nepal

Abstract

Background: Vasodilatory edema is a frequently encountered side effect among hypertensive patients using antihypertensive drugs. This dose-dependent adverse effect is seen more commonly with amlodipine, so low-dose combination therapy is often used and preferred in practice. Pedal edema following use of amlodipine is scarcely studied in Nepalese population so far. Objectives: To find out the prevalence of amlodipine-associated pedal edema and its relation with other variables among patients presenting to a tertiary care center of Kathmandu, Nepal. Methods: A prospective cross-sectional study was conducted among hypertensive patients using amlodipine in combination with or without other antihypertensive medications under regular follow-up in an outpatient department of internal medicine of Shree Birendra Hospital, Kathmandu, Nepal, during the 7-month period from September 2017 to March 2018. The prevalence of pedal edema and its relation with amlodipine dose, duration, and other factors were studied using χ² test and logistic regression using SPSS version 22. Results: A total of 505 patients were observed during the study period, with the mean age of the population being 61.5 ± 13.4 years. Among the cases studied, edema was present in 79 (15.6%) cases. Use of amlodipine longer than 5 years was 21.65 (confidence interval [CI] = 9.575-48.970, P ˂ .001) times more likely to exhibit pedal edema; similarly, there was 2.149 (CI = 1.209-3.820, P = .009) times higher risk of having pedal edema in hypertensive individuals with other comorbidities. Increasing the dose of amlodipine has increased the likelihood of having pedal edema, but it is not statistically significant (odds ratio = 2.804, CI = 0.423-18.584, P = .285). Conclusion and Relevance: Significant number of hypertensive patients using amlodipine developed pedal edema. Likelihood of vasodilatory edema increases with the presence of comorbidities, higher dose, along with longer duration of amlodipine use.

Background

Vasodilatory edema is a frequently encountered side effect among hypertensive patients using antihypertensive drugs. Amlodipine and nifedipine are common drugs associated with vasodilatory edema. When used as monotherapy, calcium channel blockers (CCBs) are associated with a substantial risk of peripheral edema, including pedal edema, which is the most common reason for its discontinuation.¹ This is a dose-dependent adverse effect, so low-dose combination therapy is a preferred choice over high-dose monotherapy. It is less common with newer generation CCBs.² Reported rates of peripheral edema are dose-dependent, ranging from 5% to 70% with a high dose.³ Only 5% of pedal edema was seen with a 5 mg dose, 25% with a 10 mg dose, whereas >75% was seen with 20 mg of daily dose.⁴ Ankle edema is developed mostly in women, elderly patients, those with heart failure, upright position, and those in humid environments.⁵ CCB-related edema is caused by preferential arteriolar or precapillary dilation without commensurate dilation in the venous or postcapillary circulation.^3,6 The addition of an angiotensin converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) to a dihydropyridine (DHP) calcium antagonist significantly reduces vasodilatory edema, while the addition of diuretics is of little help.²

Shree Birendra hospital is a tertiary level, central hospital of Nepalese Army located in Chhauni, Kathmandu, which is a referral center for soldiers and their families. There is a huge number of hypertensive patients who are under treatment. With this study, we aim to know the prevalence of pedal edema as an adverse effect of the commonly prescribed CCB (amlodipine) and association of pedal edema with other variables.

Methods

This was a prospective, cross-sectional study conducted among hypertensive patients under amlodipine with or without other antihypertensive medications under regular follow-up of the Internal Medicine Department of a tertiary level army hospital (Shree Birendra Hospital) in Kathmandu over a period of 7 months from September 2017 to March 2018. With the help of semistructured questionnaire, demographic variables, comorbidities, significant adverse event (edema), amlodipine dose, and duration were recorded (see the Data Collection Questionnaire in supplementary material of the article). At every visit, proper blood pressure monitoring was done among all hypertensive cases to check the optimum blood pressure. The study proposal was approved by institutional ethical review committee of the Nepalese Army Institute of Health Sciences following which the study was conducted. Informed verbal consent was taken before enrolling the individuals in the study.

The primary objective of this study was to determine the prevalence of amlodipine-associated pedal edema in patients of a tertiary care hospital of Kathmandu valley.

The collected data were entered in SPSS version 22 and analyzed. Chi-square test was used to see an association between important factors associated with edema with the help of P value based on a 95% confidence interval (CI) and 5% standard error. A logistic regression analysis was performed to see the likelihood of having pedal edema. Pedal edema was taken as a dependent variable, while age, gender, comorbidities, dose of amlodipine, type of amlodipine, duration of amlodipine, and concurrent use of ACEI/ARBs were considered independent variables.

Results

A total of 505 patients were observed during the study period. Mean age was 61.5 ± 13.4 years. There were 277 (54.9%) males, while 228 (45.1%) were females (see Table 1). Among the enrolled cases, 299 (59.2%) patients were solely hypertensive and devoid of any comorbidities while the remaining had some forms of comorbidities. Diabetes mellitus was the most common comorbidity associated with hypertension, comprising 116 (23%) of the cases. Other comorbidities included chronic obstructive pulmonary diseases, thyroid disorders, coronary artery diseases, cerebrovascular diseases, and dyslipidemia in descending order (Table 2). Amlodipine with or without other antihypertensives was used by 498 (96.8%) patients, while S-amlodipine was used instead of amlodipine in the remaining 16 patients. In 49.3% (249/505), only amlodipine was used as an antihypertensive, while in the remaining, various combinations of agents based on achievement of optimum blood pressure were used. Among all the cases, ankle edema was present in 79 (15.6%) patients (Figure 1).

Table 1.

Relation of Age, Gender, Comorbidities, ARBs/ACEI Use, Type of Amlodipine, Dose, and Duration of Pedal Edema.

Variables	Edema		Total	P
	Yes, n (%)	No, n (%)
Age (Years)				.062
60 or less	29 (5.7)	205 (40.6)	234
More than 60	50 (9.9)	221 (43.8)	271
Gender				.681
Male	45 (8.9)	232 (45.9)	277
Female	34 (6.7)	194 (38.4)	228
Comorbidities				.001
Yes	46 (9.1)	160 (31.7)	206
No	33 (6.5)	266 (52.7)	299
Drug				.728
Amlodipine	76 (15.5)	413 (81.8)	489
S-Amlodipine	3 (0.6)	13 (2.6)	16
ARBs/ACEI				.514
Yes	35 (6.9)	172 (34.1)	207
No	44 (8.7)	254 (50.3)	298
Dose of amlodipine (mg)				.019
5 or less	68 (13.5)	399 (79)	467
More than 5	11 (2.2)	27 (5.3)	38
Duration (years)				<.001
5 or less	12 (2.4)	327 (64.8)	339
More than 5	67 (13.3)	99 (19.6)	166

Abbreviations: ARB, angiotensin II receptor blocker; ACEI, angiotensin converting enzyme inhibitor.

Table 2.

Comorbidities Among Hypertensive Cases Under Medications.

Comorbidities (Other Than Hypertension)	Frequency	Percentage
None	299	59.2
Diabetes mellitus (DM)	106	21.0
Chronic obstructive airway diseases	23	4.6
Cerebrovascular accidents	17	3.4
Coronary artery diseases (CAD)	17	3.4
Hyperthyroidism	16	3.2
Dyslipidemia	15	3.0
DM + thyroid disorder	6	1.2
DM + CAD	4	.8
Chronic kidney disease	2	.4
Total	505	100.0

Figure 1.

Pedal edema among study population.

Pedal edema is significantly associated with the presence of comorbidities (P = .001) and dose of amlodipine (P = .019), while age, gender, type of amlodipine, and concurrent use of ACEIs/ARBs were not associated (P > .05; Table 1).

A logistic regression was performed to ascertain the effects of age, comorbidities, dose, and duration of amlodipine use on the likelihood that participants will develop pedal edema. The model explained 38.6% (Nagelkerke R²) of the variance in pedal edema and correctly classified 84.6% of cases. Use of amlodipine longer than 5 years had 21.65 (CI = 9.575-48.970, P < .001) times more likelihood to exhibit pedal edema than its use for 5 years or less. Having comorbidities other than hypertension had 2.149 (CI = 1.209-3.820, P = .009) times higher risk of having pedal edema. Increasing the dose of amlodipine (more than 5 mg) was associated with an increased likelihood of having pedal edema, but it is statistically not significant (odds ratio = 2.804, CI = 0.423-18.584, P = .285). Age of the patients and other factors have no significant relation to likelihood of developing pedal edema.

Discussion

CCBs are commonly prescribed antihypertensive drug for both new-onset hypertension and for long-term control of hypertension. DHPs are a common choice of antihypertensive drug both as monotherapy or combination therapy among clinicians. Some DHP calcium antagonists like nifedipine and amlodipine have more propensity to cause vasodilatory edema.⁷ Amlodipine is the most popular CCB in the United States and is part of the World Health Organization’s essential medicine list, but pedal edema is its major drawback.^8-10 Pedal edema is believed to be due to a level of derangement in normal vasoconstrictor reflex as well as itself being a part of its highly complicated nature, a consistent pharmacological effect whose detailed underlying mechanism is still not fully understood.¹¹ Though there is no sizeable generalized study showing a national prescription pattern of Nepal, diffuse studies done in both rural and town settings have shown CCBs as being the most commonly prescribed and effective drug class.^12-14

Vasodilatory edema was observed in 15.6% cases in our study. Similarly, one meta-analysis revealed 12.3% patients on DHPs developed peripheral edema, while it was present in 3.1% of hypertensive patients using non-DHPs.¹⁵ Another clinical trial comparing occurrences of pedal edema on using racemic amlodipine and S-amlodipine found the occurrence more with racemic variant than S-amlodipine as 46.5% and 31.4% as a total of individual drug users.¹⁶ Among the patients studied, they were using 5, 7.5, or 10 mg of amlodipine daily. Compared with 5 mg or less group, edema was found to be significantly associated (P = .019) with more than 5 mg dose group. Previous studies have illustrated the dose relationship with the incidence of edema. The incidence of peripheral edema among hypertensive patients under CCB varies in the literature due to its dose-dependent nature and among different CCB.^3,4,11 While some studies suggest adverse effects being more pronounced in female patients, some studies showed no significant differences between male patients and female patients.¹⁶ This study is adherent to the latter in not showing a significant association between gender of the patients, P > .05. Some studies done previously suggest combination therapy with ACEI/ARB and concurrent use of ARB or ACEI to be beneficial in reducing adverse effects including peripheral vascular edema in patients even to the level of half of the dose prescribed (especially with mild hypertension).^5,11,17,18

The underlying mechanism is suggestive to be related to the ability of ACEI/ARB to oppose the circulatory changes by CCBs causing edema.¹⁷ But, in the present study, the concurrent use of ACEI/ARBs, type of amlodipine used (S isomer), age, and gender of the patient did not have association (P > .05) with vasodilatory edema. In contrast, previous studies have shown the association between the incidence of vasodilatory edema among elderly patients.⁵ Pedal edema is found to be more common with CCB monotherapy; so it is advisable to use combination therapy with either ARB or ACEI.¹ This not only reduces pedal edema but also the combination therapy is more effective than monotherapy with CCB to maintain optimum blood pressure in hypertensive patients.¹⁹ This study also showed an increased incidence of pedal edema in those who have been using amlodipine for more than 5 years in comparison to those who have been using it for a lesser period of time (P < .001). Studies done in past have shown an increased duration of CCB use with increased incidence of pedal edema with incidences usually plateauing from sixth month onward.² These findings may not be generalizable throughout Nepal due to its small sample size, but to conclude the association further, a large sampled, controlled, and national-level study is needed. Although pedal edema is perceived as a less severe side effect of this drug, it has proven troublesome to many patients with a withdrawal rate of 5% to 9.3%.^15,20 Health professionals should carefully monitor the patients while administering CCBs like amlodipine. The early detection, discontinuation of offending drug, and prescription of alternative hypertensive agent can improve a patient’s condition.

Conclusion and Relevance

This study concludes that a significant number of the patient under antihypertensive medication developed dose-dependent pedal edema. Vasodilatory edema in this study was associated with the presence of other comorbidities, amlodipine dose, and duration, while age, gender, type of amlodipine, and concurrent use of ACEIs/ARBs were not associated. With comorbidities, longer duration, and a higher dose of amlodipine, likelihood of pedal edema goes up. This article adds the prevalence of pedal edema in hypertensive individuals under amlodipine and relation between pedal edema and other variables.