Cardiology

The effect of serum calcium level on the success of diltiazem treatment: A retrospective cohort study

a b s t r a c t

Introduction: Diltiazem is an antiarrhythmic drug widely used in the treatment of Atrial fibrillation with rapid ventricular response (RVR). It reveals its effect by blocking L-type calcium channels. Thus, it inhibits the extracellular calcium influx into the cytosol. The relationship between serum calcium level and the efficacy of in- travenous (IV) diltiazem used in the treatment of AFib with RVR has not been investigated in vivo. The aim of this study is to investigate the mentioned relationship.

Methods: This study was planned as a single-center retrospective study. The data of 349 patients who presented to the emergency department with AFib with RVR and treated with diltiazem were retrospectively analyzed. A patient was considered to have responded to diltiazem treatment if the existing heart rhythm returned to sinus rhythm, or the heart rate decreased below 100 beats/min, or the heart rate decreased >20% provided that it was below 120 beats/min. The ionized calcium levels were recorded. The relationship between serum cal- cium level and the success of diltiazem treatment was examined.

Results: Fifty five percent of the patients were female. The median age was 75 years. The rate of response to dil- tiazem treatment was 67.3%. The median of ionized calcium levels in the group which responded to diltiazem treatment (n = 235) was 1.14 mmol/L (IQR: 0.12), and the group which did not respond to diltiazem treatment (n = 114) was 1.11 mmol/L (IQR: 0.12) (p = 0.322). The patients were divided into three groups as low, normal, and high calcium levels according to the calcium reference levels determined by the hospital laboratory. The rate of response to diltiazem treatment was 61.4% in patients with low ionized calcium levels, 76.1% in patients with normal ionized calcium levels, and 40.0% in patients with high ionized calcium levels. The rate of response to dil- tiazem treatment was higher in patients with normal ionized calcium levels compared to patients with low or high ionized calcium levels (p = 0.004, p = 0.003).

Conclusion: The success rate of diltiazem used in the treatment of AFib with RVR was highest in physiological calcium levels. The current study may provide the clinician with awareness about the consideration of serum ion- ized calcium levels when choosing drugs in patients with AFib with RVR.

(C) 2023

  1. Introduction

Atrial fibrillation (AFib) is one of the most common cardiac dys- rhythmias in emergency departments and is one of the important areas of concern for emergency medicine physicians [1-3]. Converting symptomatic AFib with Rapid ventricular response to normal sinus rhythm or providing Rate control is very important to prevent morbidity and mortality, and diltiazem is widely used in Heart rate control [4,5].

* Corresponding author.

E-mail address: [email protected] (A. Batur).

In cardiac myocytes, voltage-dependent calcium channels have important roles in excitation-contraction coupling, electrical conduc- tion, and transcription. In pacemaker (PM) cells, the main ion responsi- ble for the phase 0 part of the action potential (AP) is calcium unlike other myocardial cells. Diltiazem is a calcium channel blocker. It lowers the intracellular calcium level by blocking L-type calcium channels, which are the main effective channels for spontaneous stimulation of sinoatrial (SA) and atrioventricular (AV) node cells, and by inhibiting calcium flow from extracellular to intracellular space [6,7]. However, data on how diltiazem affects serum and urine calcium levels are incon- sistent [8-10]. The role of serum calcium level in the success of diltiazem treatment is an issue that has not been investigated in vivo. In this study, it was aimed to investigate the relationship between blood ionized calcium level and effectiveness of diltiazem used in the acute treatment of AFib with RVR.

https://doi.org/10.1016/j.ajem.2023.06.007

0735-6757/(C) 2023

  1. Materials and methods

Approval for the study was obtained from Clinical Research Ethics Committee of the University. This study was planned as a single- center retrospective study. Patients over the age of 18 who admitted to the emergency department between January 1, 2015 and May 31, 2019 were included. Patients who had AFib with RVR on their electro- cardiograms (ECG) and treated with diltiazem were included in the study. The data were scanned through the hospital information system and printed files. Patients to be included in the study had to fulfill all following criteria.

  1. AFib with RVR must have been detected in the patient’s ECG.
  2. Standard dose of diltiazem (0.25 mg/kg) should be used in the treatment.
  3. Serum calcium level must have been measured within 30 min prior to calcium channel blocker treatment.
  4. The ECGs of the patients should have been recorded just within 5 min before the treatment and within 20 min after the treatment.
  5. Patients should not have received any rate-limiting medication (calcium channel blocker, beta-blockers, digoxin, Sodium channel blockers and potassium channel blockers) before and within 20 min of diltiazem treatment.

The current study was conducted in a tertiary hospital emergency department which had an average of 35,000 patients per year. Diagnosis codes and treatment services of all patients who had emergency service records between January 1, 2015 and May 31, 2019 were retrieved from the hospital information system. In total, 383 patients were diagnosed with AFib with RVR and given diltiazem treatment were included in the study. Thirty-four patients who did not meet the inclusion criteria were excluded from the study. In total, 349 patients met the criteria and were included in the study.

In the study investigating the pharmacodynamics and pharmacoki- netics of Intravenous diltiazem used in the treatment of atrial fibrilla- tion, three objective findings were determined as response to diltiazem treatment [11]. The findings listed below were accepted as ob- jective findings indicating response to diltiazem treatment.

  1. The existing heart rhythm returned to sinus rhythm
  2. The heart rate decreased below 100 beats/min
  3. The heart rate decreased >20% provided that it was below 120 beats/ min [11-13].

The ionized calcium levels were measured at Medical Biochemistry Laboratories with devices branded “Radiometer”, model named “ABL 90 Flex” and “ABL 800 Flex”. In these devices, the measurement of ion- ized calcium concentration is made according to the potentiometric measurement principle, in which an electrode chain potential recorded in the voltmeter is correlated with the calcium concentration via the Nernst equation. Normal reference levels for ionized calcium was deter- mined as between 1.13 mmol/L and 1.32 mmol/L.

IBM SPSS Statistic version 23 software was used in statistical analysis. The conformity to the normal distribution was examined by histogram, probability graphs and analytical methods (Kolmogorov Smirnov test). Descriptives was given as median and interquartile range for non-normally distributed variables. The frequencies of the nominal variables were analyzed with crosstabs. Differences in frequen- cies between groups were compared using the chi-square, Fisher’s Exact Test (in cases where the expected values in cells did not satisfy the chi-square assumption) and the Fisher-Freeman Halton Exact Test (for

tests (p < 0.008). Cases with a P value <0.05 were considered statistically significant.

  1. Results

Fifty five percent (n = 192) of the patients were female and 45% (n = 157) were male. The median age was 75 years (IQR: 18; min 33, max 98).

The characteristics of subgroups determined by ionized calcium level is shown in Table 1. There is no significant difference between subgroups in terms of characteristics. There was at least one existing chronic disease in 338 (96.8%) of 349 patients.

The median of ionized calcium levels in the group which responded to diltiazem treatment (n = 235) was 1.14 mmol/L (IQR: 0.12), and the group which did not respond to diltiazem treatment (n = 114) was

1.11 mmol/L (IQR: 0.12). The difference between ionized calcium levels among two groups was not statistically significant (p = 0.322, Mann Whitney U test), (Table 2).

In patients who responded to the treatment, ionized calcium levels were analyzed for each Treatment response criterion (p = 0.064, Kruskal Wallis test; Table 3). Treatment response criterion were returning the existing heart rhythm to sinus rhythm, decreasing the heart rate below 100 beats/min, or decreasing the heart rate more than 20% provided that it was below 120 beats/min.

The patients were divided into three groups as low, normal, and high calcium levels according to the calcium reference levels determined by the hospital laboratory. All groups were evaluated for their response to diltiazem treatment. The rate of response to the treatment was 61.4% (n = 105) in low ionized calcium level group, 76.4% (n = 124) in normal ionized calcium level group, and 40.0% (6) in high ionized calcium level group.

There was no statistically significant difference between the rate of response to diltiazem treatment in patients with low and high ionized calcium levels (p = 0.105, Pearson chi-square; Table 4). On the other hand, the rate of response to diltiazem treatment in patients with normal ionized calcium levels was higher than in patients with low

Table 1

Characteristics of subgroups determined by ionized calcium level.

Ionized calcium

Characteristics Low Normal High p value Gender (n, %)

Male

76 (44.4)

75 (46)

6 (40)

0.887*

Female

95 (55.6)

88 (54)

9 (60)

Age (median, IQR) 76 (19) 75 (18) 73 (18) 0.504+

Hypertension (n, %)

110 (64.3)

106 (65)

9 (60)

0.926*

Diabetes Mellitus (n, %)

42 (24.6)

40 (24.5)

6 (40)

0.403*

CAD (n, %)

63 (36.8)

63 (38.7)

4 (26.7)

0.648*

CHF (n, %)

53 (31)

57 (35)

6 (40)

0.632*

COPD (n, %)

50 (29.2)

54 (33.1)

4 (26.7)

0.696*

Malignancy (n, %)

40 (23.4)

36 (22.1)

7 (46.7)

0.100*

CKD (n, %)

34 (19.9)

37 (22.7)

5 (33.3)

0.475*

CAD: Coronary Artery Disease, CHF: Congestive Heart Failure, COPD: Chronic Obstructive Pulmonary Disease, CKD: Chronic Kidney Disease.

* Kruskal Wallis test + Pearson chi-square.

Table 2

The respond of diltiazem treatment and ionized calcium levels.

frequency comparisons >2 x 2 without the chi-square assumption). The relationships of the nominal and continuous variables were

Response to the

Treatment

No Response to the p

Treatment

evaluated with the eta coefficient. The Kruskal Wallis test was used for comparisons of more than two groups. The analysis was continued with the Mann Whitney U Test for the significant variables. The signifi- cance of the p value was checked by Bonferroni correction in post hoc

n Median (mmol/L) n Median (mmol/dL)

Ionized Calcium 235 1.14 (IQR: 0.12) 114 1.11 (IQR: 0.12) 0.322?

IQR: Interquartile Range.

* Mann Whitney U test.

Table 3

The median ionized calcium levels among each treatment response criterion.

Sinus Rhythm

HR decreased to below 100 beats/min

HR decreased by 20% and below 120 beats/min

Unsuccessful Treatment

p

n

24

99

112

114

Ionized calcium Median (IQR) mmol/L

1.12 (0.13)

1.15 (0.11)

1.12 (0.13)

1.11 (0.12)

0.064?

HR: Heart Rate, IQR: Interquartile Range.

* Kruskal Wallis test.

and high ionized calcium levels (p = 0.004, p = 0.003, Pearson chi-square; Table 4).

  1. Discussion

Diltiazem is a calcium channel blocker which is a commonly used drug in the treatment of AFib with RVR. Although its mechanism of action is via calcium channels, its relationship with serum calcium level has not been investigated in vivo.

Consistent with the literature, in the current study, it was deter- mined that the patients treated for AFib with RVR were elderly patients with a high incidence of chronic disease [4,14,15]. Dysrhythmias and changes in serum calcium levels are common problems in this group of patients, both due to chronic disease and drugs used in the treatment of these diseases [14-17]. It would be useful to know whether there is a relationship between serum calcium level and the efficacy of calcium channel blocker treatment. If there is a relationship found, this could be useful for physicians in choosing the appropriate rate limiting treat- ment. Indeed, in the current study, it was found that Blood calcium level was related to diltiazem efficacy and diltiazem efficacy was found to be significantly higher in patients with physiologic serum calcium levels.

An in vitro study was conducted with verapamil, another non-

dihydropyridine calcium channel blocker, by Lang et al. The blood calcium level was gradually increased in the study performed in dogs with pacemaker and atropine administered under anesthesia. At differ- ent calcium levels the effects of verapamil on the AV node were investi- gated. The effects of verapamil to prolong the AV node conduction time and refractory period were antagonized when the plasma calcium con- centration was gradually increased to 5 mmol/L. However, at calcium concentrations above 5 mmol/L, the ability of calcium to antagonize the effects of verapamil gradually decreased. The effect of calcium had a bell-shaped dose-response curve that was optimal at 5 mmol/L. This dose-response curve shows that the antagonism between calcium and calcium channel blockers may vary, depending on whether patients have mild or severe hypercalcemia [18]. In the subgroup analyzes of the current study, the response to diltiazem treatment was affected by the blood ionized calcium level, similar to the in vitro study by Lang et al. Unlike the current study, Lang et al. investigated the calcium level antagonizing the efficacy of verapamil. In the current study, it was aimed to determine whether there is a relationship between the

calcium level and the success of diltiazem treatment. In the current study, the rate of response to the diltiazem treatment was higher in pa- tients with normal ionized calcium levels than in patients with low or high ionized calcium levels. The patients with high ionized calcium levels had the lowest rate of response to the treatment. This result was not surprising as diltiazem competitively blocks L-type calcium channels with ionized calcium in the extracellular space. However, it was found that the rate of response to the treatment decreased in hypo- calcemia as well. Hypocalcemia is a cause of QT prolongation through prolongation of the plateau phase of the cardiac action potential. Hypo- calcemia allows calcium ion channels to remain open longer, allowing late calcium entry and formation of early post-depolarizations [19,20]. If the depolarization threshold is reached, new action potentials are in- duced, tachycardia and re-entry are initiated. The fact that the ion chan- nels remain open for a longer period of time in patients with low blood calcium levels may have played a role in the decrease in the effective- ness of diltiazem.

In conclusion, the efficacy of diltiazem in the treatment of AFib with RVR was highest in patients with physiologic calcium levels. It should be kept in mind that the response to diltiazem treatment may change in the presence of hypocalcemia or hypercalcemia. This result may guide the clinician in determining the antiarrhythmic agent of choice in the treatment of AFib with RVR. However, comprehensive studies on the subject will be decisive for the decision-making process of clinicians.

  1. Limitations

Among the patients included in the study, the number of patients with high blood ionized calcium levels was low. In addition, electrolyte disturbances in the patients were mild. These study results do not in- clude data on the efficacy of the drug in patients with more severe hy- pocalcemia or hypercalcemia.

Presentations

None.

Financial support

None.

Table 4

Levels of ionized calcium and the rates of response to diltiazem treatment.

Ionized calcium [Median (IQR)]

Response to the Treatment

No Response to the Treatment

p compared to low and normal

p compared to low and high

p compared to normal and high

n

%

n

%

n

Low

[1.05 mmol/L (0.10)]

105

61.4

66

38.6

171

Normal

[1.17 mmol/L (0.06)]

124

76.1

39

23.9

163 0.004? 0.105? 0.003?

High

[1.41 mmol/L (0.19)]

6

40.0

9

60.0

15

Total

235

68.9

114

31.1

349

IQR: Interquartile Range.

* Pearson chi-square.

CRediT authorship contribution statement

Ali Batur: Writing – original draft, Validation, Methodology, Investi- gation, Formal analysis, Data curation. Safa Huseyin Kucuk: Writing – original draft, Visualization, Validation, Investigation, Formal analysis, Conceptualization. Nalan Metin Aksu: Writing – review & editing, Supervision, Methodology, Conceptualization. Meltem Akkas: Writing – review & editing, Supervision, Resources, Project administration, Methodology, Conceptualization.

Declaration of Competing Interest

All authors report no conflict of interest.

References

  1. McDonald AJ, et al. Increasing US emergency department visit rates and subsequent hospital admissions for atrial fibrillation from 1993 to 2004. Ann Emerg Med. 2008; 51(1):58-65.
  2. Patel NJ, et al. Contemporary trends of hospitalization for atrial fibrillation in the United States, 2000 through 2010: implications for healthcare planning. Circulation. 2014;129(23):2371-9.
  3. Chugh SS, et al. Epidemiology and natural history of atrial fibrillation: clinical impli- cations. J Am Coll Cardiol. 2001;37(2):371-8.
  4. January CT, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiol- ogy/American Heart Association task force on practice guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):2246-80.
  5. Hindricks G, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio- Thoracic Surgery (EACTS) the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European heart rhythm association (EHRA) of the ESC. Eur Heart J. 2021;42(5):373-498.
  6. Chaffman M, Brogden RN. Diltiazem. Drugs. 1985;29(5):387-454.
  7. van Breemen C, Hwang O, Meisheri KD. The mechanism of inhibitory action of dilti- azem on vascular smooth muscle contractility. J Pharmacol Exp Ther. 1981;218(2): 459-63.
  8. Seely EW, et al. The calcium channel blocker diltiazem lowers serum parathyroid hormone levels in vivo and in vitro. J Clin Endocrinol Metabol. 1989;68(6):1007-12.
  9. Townsend R, et al. Effects of calcium channel blockade on calcium homeostasis in mild to moderate Essential hypertension. Am J Med Sci. 1990;300(3):133-7.
  10. Villiger L, et al. Diltiazem stimulates parathyroid hormone secretion in vivo whereas felodipine does not. J Clin Endocrinol Metabol. 1993;76(4):890-4.
  11. Dias V, Weir S, Ellenbogen K. Pharmacokinetics and pharmacodynamics of intrave- nous diltiazem in patients with atrial fibrillation or atrial flutter. Circulation. 1992; 86(5):1421-8.
  12. Demircan C, et al. Comparison of the effectiveness of intravenous diltiazem and met- oprolol in the management of rapid ventricular rate in atrial fibrillation. Emerg Med

J. 2005;22(6):411-4.

  1. Al-Khatib SM, Lapointe NA, Chatterjee R, et al. Treatment of atrial fibrillation. Rockville (MD): Agency for Healthcare Research and Quality (US); June 2013..
  2. Gowen BH, et al. Mechanisms of chronic metabolic stress in arrhythmias. Antioxi- dants. 2020;9(10):1012.
  3. Hatch F, Lancaster MK, Jones SA. Aging is a primary risk factor for cardiac arrhyth- mias: disruption of intracellular Ca2+ regulation as a key suspect. Expert Rev Cardiovasc Ther. 2011;9(8):1059-67.
  4. Kelly A, Levine MA. Hypocalcemia in the critically ill patient. J Intensive Care Med. 2013;28(3):166-77.
  5. Mousseaux C, et al. Epidemiology, clinical features, and management of severe hypercalcemia in critically ill patients. Ann Intensive Care. 2019;9(1):1-10.
  6. Lang J, et al. Effect of gradual rise in plasma calcium concentration on the impair- ment of atrioventricular nodal conduction due to verapamil. J Cardiovasc Pharmacol. 1986;8(1):6-13.
  7. Shantsila E, Watson T, Lip GY. Drug-induced QT-interval prolongation and proarrhythmic risk in the treatment of Atrial arrhythmias. Europace. 2007.;9 (suppl_4) p. iv37-iv44.
  8. Bradley TJ, Metzger DL, Sanatani S. Long on QT and low on calcium. Cardiol Young. 2004;14(6):667-70.

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