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Original Investigation |

Use of Sympathomimetic Drugs Leads to Increased Risk of Hospitalization for Arrhythmias in Patients With Congestive Heart Failure FREE

Marcel L. Bouvy, PharmD; Eibert R. Heerdink, PhD; Marie L. De Bruin, PharmD; Ron M. C. Herings, PhD; Hubert G. M. Leufkens, PhD; Arno W. Hoes, PhD
[+] Author Affiliations

From the Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht (Drs Bouvy, Heerdink, De Bruin, Herings, and Leufkens), Stevenshof Institute for Research, Leiden (Dr Bouvy), and Julius Centre for Patient-Oriented Research, Utrecht (Dr Hoes), the Netherlands.


Arch Intern Med. 2000;160(16):2477-2480. doi:10.1001/archinte.160.16.2477.
Text Size: A A A
Published online

Background  Sympathomimetic agents have a direct positive chronotropic effect on heart rate and may cause hypokalemia, even when administered by inhalation. In selected patients (eg, patients with congestive heart failure [CHF]) this can lead to arrhythmias. Despite the potential adverse effects of these agents, they are used frequently in patients with CHF, due to a high incidence of respiratory comorbidity. This study investigates the effects of sympathomimetics on the incidence of hospitalizations for arrhythmias in patients with CHF.

Methods  In a cohort of 1208 patients with a validated hospital discharge diagnosis of CHF, we identified 149 cases with a readmission for arrhythmias, and compared these in a nested matched case-control design with 149 controls from the remainder of the cohort with no hospital readmission for any cardiac cause. Conditional logistic regression was used to calculate the risk for hospitalization for arrhythmias associated with exposure to sympathomimetic agents, expressed as odds ratios.

Results  Of 149 case patients, a total of 33 (22.1%) were treated with any sympathomimetic agent, and 6 patients (4.0%) were treated with systemic sympathomimetics. The use of any sympathomimetic drug was associated with an increased risk of admission for arrhythmia (odds ratio, 4.0; 95% confidence interval, 1.0-15.1). For systemic sympathomimetic drugs, the corresponding odds ratio was 15.7 (95% confidence interval, 1.1-228.0).

Conclusions  The results of this study strongly suggest an increased risk of hospitalization for arrhythmias in patients with CHF treated with sympathomimetic drugs. Sympathomimetics should be given under close surveillance to patients with CHF.

ARRHYTHMIAS can be induced or aggravated by a variety of drugs, which include cardiotonic drugs (digoxin, sympathomimetics, and antiarrhythmics), and by drugs that lower plasma potassium levels, such as diuretics and corticosteroids. A special group comprises drugs that lengthen QT interval and can lead to induction of torsade de pointes (eg, antihistamines, antidepressants, macrolide antibiotics, cisapride, and antipsychotics).1

Sympathomimetic drugs have a direct positive chronotropic effect that can promote arrhythmia. Moreover, sympathomimetics can induce hypokalemia and further worsen arrhythmias.2,3 Studies on chronotropic and hypokalemic effects of sympathomimetics have shown small but significant effects, which can even be induced by inhalation of sympathomimetics.4,5 At the introduction of selective β2-sympathomimetics, a limited number of small-scale studies suggested that these drugs could be safely used in patients with chronic obstructive pulmonary disease (COPD).6 By now, however, evidence accumulates that arrhythmias due to systemic use of sympathomimetics do occur occasionally.7,8 Even the occurrence of arrhythmias after inhalation of sympathomimetics has incidentely been reported.9

Elderly patients and patients with congestive heart failure (CHF), renal or hepatic dysfunction, electrolyte disturbance (hypokalemia, hypomagnesemia), or a history of arrhythmias are probably more prone to the proarrhythmic effect of sympathomimetics.10 Moreover, patients with CHF often use diuretics. The hypokalemic response to diuretics could be additive to that of sympathomimetics.11,12

Cardiac arrest and arrhythmia are the major causes of death in patients with CHF.13 Despite the potential negative effects of sympathomimetics in patients with CHF, they often receive such drugs, due to a high incidence of respiratory comorbidity (in particular COPD). This study investigates the effects of sympathomimetics on the incidence of hospitalizations due to arrhythmias in patients with CHF.

SETTING

Data were used from the PHARMO record linkage system, a database containing drug dispensing records from community pharmacies and linked hospital discharge records of a defined population of 300,000 residents of 6 medium-sized cities in the Netherlands.14

Medication histories and hospital data were collected from 1986 to 1992. Drugs were coded according to the Anatomical Therapeutic Chemical (ATC) classification. Hospital discharge records were coded according to the International Classification of Diseases, Ninth Revision (ICD-9).15 Clinical modification codes were used.

PATIENTS

A total of 1208 patients with a validated hospital discharge diagnosis for CHF were included in the study.16 These patients were followed up for a total of 5038 person-years (mean follow-up, 4.2 years per patient). In this cohort we identified a total of 454 readmissions for cardiac causes, including myocardial infarction, angina pectoris, arrhythmias, and CHF. We found 149 patients with a rehospitalization for arrhythmias (cases). For each case, a control was sampled randomly from the remainder of the cohort who were not readmitted for any cardiac cause and matched according to follow-up time. An index date was assigned to each control matching the hospitalization date of the case.

EXPOSURE DEFINITION

A patient was defined as exposed when there was at least 1 prescription filled for a given drug in the 3 months before hospital admission for the cases or the corresponding index date for the controls.

DATA ANALYSIS

We performed a nested case-control analysis comparing exposure in cases vs controls. Odds ratios (ORs) were calculated for exposure to sympathomimetic agents, at the time of the hospitalization due to arrhythmias (cases) or matched index date (controls). Conditional logistic regression techniques were applied to adjust for potential confounders. All statistical analyses were performed with Egret software (Egret for Windows, version 2.0, Cytel Software Corporation, Cambridge, Mass).

POTENTIAL CONFOUNDERS

This study was done in a group of patients with a high frequency of comorbidity. Arrhythmia is a common complication in patients with CHF. Left ventricular hypertrophy and local ischemia of heart tissue may contribute to arrhythmogenic effects.

Arrhythmias frequently occur in patients with COPD. An important risk factor is the occurrence of hypoxemia in patients with COPD. An increased risk for hospital admissions for arrhythmias could therefore be related to the underlying disease instead of the use of sympathomimetics. On the other hand, sympathomimetics can also aggravate the effects of hypoxemia.17

In addition, a broad range of drugs could affect the occurrence of arrhythmias by direct effect on heart rate (eg, angiotensin-converting enzyme inhibitors, β-blockers, calcium antagonists, digoxin, antiarrhythmics, and ibopamin), blood potassium levels (eg, angiotensin-converting enzyme inhibitors, corticosteroids, diuretics, and laxatives), or QT interval (eg, antihistaminic drugs, antidepressants, antipsychotics, macrolides, and cisapride).

We corrected for these potential confounders by including the presence of hospital admissions for arrhythmias, myocardial infarction, angina pectoris, asthma, and COPD in the year preceding the hospitalization for CHF and the use of aforementioned drugs in the 3 months prior to the hospital admission in the multiple regression model.

Table 1 details the general characteristics of the study population. The majority of arrhythmias were classified as atrial fibrillation (n = 98, 60%). The other frequently seen arrhythmias were ventricular tachycardia (n = 15, 9%) and fibrillation (n = 16, 10%). The characteristics of users of sympathomimetics differed in some aspects from patients not using these drugs (eg, sex, use of corticosteroids, and prior hospital admissions for COPD). The following inhalation sympaticomimetics were used: albuterol, 94% of all prescriptions; and terbutaline sulfate, 6% of all prescriptions. Systemic sympaticomimetics used were albuterol in 74% and terbutaline in 26%. There was only 1 nasal sympaticomimetic used, which was xylometazoline hydrochloride.

Table Graphic Jump LocationTable 1. Characteristics of Patients With Congestive Heart Failure According to the Use of Sympathomimetic Agents*

Of the 149 cases and controls 33 (22%) and 17 (11%) were treated with any sympathomimetic agent, yielding a crude OR of 2.2 (95% confidence interval [CI], 1.2-4.3). We adjusted for a number of possible confounders, notably, sex, age, prior hospitalizations for arrhythmia, asthma, COPD, myocardial infarction, and angina pectoris. In addition, we adjusted for the use of a broad range of drugs that may have direct proarrhythmic effects, give rise to hyperkalemia or hypokalemia, or are markers for a history of rhythm disturbances, such as digoxin, calcium channel inhibitors, β-blockers, oral anticoagulants, antiarrhythmics, angiotensin-converting enzyme inhibitors, corticosteroids, laxatives, diuretics, nitrates, neuroleptics, H1-antihistamines, antidepressants, and ibopamin. Adjusted ORs were 4.0 (95% CI, 1.0-15.1) for the use of any sympathomimetic drug and 15.7 (95% CI, 1.1-228.0) for the use of systemic sympathomimetic drugs (Table 2). Separate ORs for inhalation and nasal sympathomimetics and theophylline were not significantly associated with hospitalization for arrhythmia.

Table Graphic Jump LocationTable 2. Association Between Use of Sympathomimetic Agents and Risk of Hospitalization for Arrhythmia

Our results strongly suggest an increased risk (OR, 4.0; 95% CI, 1.0-15.1) for hospitalization for arrhythmias in patients with CHF using sympathomimetic drugs. This risk was much higher (OR, 15.7; 95% CI, 1.1-228) in patients using systemic sympathomimetics than in patients using inhalation sympathomimetics (OR, 2.4; 95% CI, 0.5-13.1). Possibly due to the relatively small number of patients, the risk found for the inhalation group was not statistically significant, but data suggest that use of sympathomimetics by inhalation also leads to an increase in the risk of arrhythmia.

Surprisingly, we did not find an increased risk for arrhythmias in patients taking theophylline. This is difficult to explain, since the hypokalemic and heart rate effects of theophylline are well known. Perhaps, physicians are familiar with these effects and only prescribe theophylline for low-risk patients. Moreover, theophylline is usually prescribed as a maintenance dose. Sympathomimetics are probably more often used "on demand." Patients with acute dyspnea due to CHF could overuse these bronchodilators, while they are already more susceptible to develop arrhythmias.

In this study there were no patients using long-acting sympathomimetics. Studies suggest that these drugs have systemic effects comparable to those of short-acting sympathomimetics.18 More research on their effects in patients with CHF is warranted.

We did not have direct data on the severity of CHF. However, we tried to compensate for this by correcting for a variety of comedications and previous hospitalizations that we see as "proxies" for the severity of CHF. After adjustment for possible confounders such as sex, age, prior hospitalizations for arrhythmia, asthma, COPD, myocardial infarction, angina pectoris, and the use of a broad range of comedications, the OR remained statistically significant. These findings remain suggestive of a causal relation between use of sympathomimetics and arrhythmias. We were not able to control for caffeine use, which could also be a confounder.

This study was conducted in a selected group of seriously ill patients. Use of β2-sympathomimetics is generally safe in patients with asthma or COPD.19 However, patients with severe cardiac comorbidity are probably more prone to their systemic effects.

Sudden death—often due to arrhythmias—is the major cause for mortality in patients with CHF.

This study was not designed to reveal the incidence of sudden death outside the hospital. The effects of sympathomimetics could therefore even be more deleterious. In this light, it seems important to avoid every possible factor that could lead to arrhythmias in these patients. Due to the high rate of comorbidity, the complete avoidance of sympathomimetics is often not possible. However, the necessity of the use of sympathomimetics should be evaluated critically. The beneficial effects of bronchodilators in patients with heart failure and shortness of breath should be clearly documented by pulmonary function test before these drugs are prescribed. Oral sympathomimetics should be avoided in all patients. When patients have problems with inhalation, extra attention should be given to inhalation instruction. Potassium levels should be measured regularly and the clinician should be alert for the occurrence of arrhythmias.

Accepted for publication March 8, 2000.

Corresponding author: Marcel L. Bouvy, PharmD, Universiteit Utrecht, Pharmacoepidemiology and Pharmacotherapy, PO Box 80082, 3508 TB Utrecht, the Netherlands (e-mail: m.bouvy@pharm.uu.nl).

Doig  JC Drug-induced cardiac arrhythmias: incidence, prevention and management. Drug Saf. 1997;17265- 275
Link to Article
Haffner  CAKendall  MJ Metabolic effects of β2-agonists. J Clin Pharm Ther. 1992;17155- 164
Link to Article
Lipworth  BJ Risks versus benefits of inhaled β2-agonists in the management of asthma. Drug Saf. 1992;754- 70
Link to Article
Udezue  ED'Souza  LMahajan  M Hypokalemia after normal doses of neubulized albuterol (salbutamol). Am J Emerg Med. 1995;13168- 171
Link to Article
Wong  CSPavord  IDWilliams  JBritton  JRTattersfield  AE Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma [see comments]. Lancet. 1990;3361396- 1399
Link to Article
Crawford  SMMiles  DW Salbutamol and cardiac arrhythmias. Curr Med Res Opin. 1981;7410- 415
Banner  ASunderrajan  EAgarwal  MAddington  W Arrhythmogenic effects of orally administered bronchodilators. Arch Intern Med. 1979;139434- 437
Link to Article
Mettauer  BRouleau  JLBurgess  JH Detrimental arrhythmogenic and sustained beneficial hemodynamic effects of oral salbutamol in patients with chronic congestive heart failure. Am Heart J. 1985;109840- 847
Link to Article
Breeden  CCSafirstein  BH Albuterol and spacer-induced atrial fibrillation. Chest. 1990;98762- 763
Link to Article
Cazzola  MImperatore  FSalzillo  A  et al.  Cardiac effects of formoterol and salmeterol in patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia [see comments]. Chest. 1998;114411- 415
Link to Article
Newnham  DMMcDevitt  DGLipworth  BJ The effects of frusemide and triamterene on the hypokalaemic and electrocardiographic responses to inhaled terbutaline. Br J Clin Pharmacol. 1991;32630- 632
Link to Article
Struthers  ADWhitesmith  RReid  JL Prior thiazide diuretic treatment increases adrenaline-induced hypokalaemia. Lancet. 1983;11358- 1361
Link to Article
Goldberger  JJ Treatment and prevention of sudden cardiac death: effect of recent clinical trials. Arch Intern Med. 1999;1591281- 1287
Link to Article
Herings  RMBakker  AStricker  BHNap  G Pharmaco-morbidity linkage: a feasibility study comparing morbidity in two pharmacy based exposure cohorts. J Epidemiol Community Health. 1992;46136- 140
Link to Article
World Health Organization, International Classification of Diseases, Ninth Revision (ICD-9).  Geneva, Switzerland World Health Organization1977;
Heerdink  ERLeufkens  HGHerings  RMOttervanger  JPStricker  BHBakker  A NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med. 1998;1581108- 1112
Link to Article
Crane  JBurgess  CDGraham  ANMaling  TJ Hypokalaemic and electrocardiographic effects of aminophylline and salbutamol in obstructive airways disease. N Z Med J. 1987;100309- 311
Bennett  JASmyth  ETPavord  IDWilding  PJTattersfield  AE Systemic effects of salbutamol and salmeterol in patients with asthma. Thorax. 1994;49771- 774
Link to Article
Martelli  NARaimondi  ACLazzari  JO Asthma, cardiac arrhythmias, and albuterol aerosol. Chest. 1986;89192- 194
Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Characteristics of Patients With Congestive Heart Failure According to the Use of Sympathomimetic Agents*
Table Graphic Jump LocationTable 2. Association Between Use of Sympathomimetic Agents and Risk of Hospitalization for Arrhythmia

References

Doig  JC Drug-induced cardiac arrhythmias: incidence, prevention and management. Drug Saf. 1997;17265- 275
Link to Article
Haffner  CAKendall  MJ Metabolic effects of β2-agonists. J Clin Pharm Ther. 1992;17155- 164
Link to Article
Lipworth  BJ Risks versus benefits of inhaled β2-agonists in the management of asthma. Drug Saf. 1992;754- 70
Link to Article
Udezue  ED'Souza  LMahajan  M Hypokalemia after normal doses of neubulized albuterol (salbutamol). Am J Emerg Med. 1995;13168- 171
Link to Article
Wong  CSPavord  IDWilliams  JBritton  JRTattersfield  AE Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma [see comments]. Lancet. 1990;3361396- 1399
Link to Article
Crawford  SMMiles  DW Salbutamol and cardiac arrhythmias. Curr Med Res Opin. 1981;7410- 415
Banner  ASunderrajan  EAgarwal  MAddington  W Arrhythmogenic effects of orally administered bronchodilators. Arch Intern Med. 1979;139434- 437
Link to Article
Mettauer  BRouleau  JLBurgess  JH Detrimental arrhythmogenic and sustained beneficial hemodynamic effects of oral salbutamol in patients with chronic congestive heart failure. Am Heart J. 1985;109840- 847
Link to Article
Breeden  CCSafirstein  BH Albuterol and spacer-induced atrial fibrillation. Chest. 1990;98762- 763
Link to Article
Cazzola  MImperatore  FSalzillo  A  et al.  Cardiac effects of formoterol and salmeterol in patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia [see comments]. Chest. 1998;114411- 415
Link to Article
Newnham  DMMcDevitt  DGLipworth  BJ The effects of frusemide and triamterene on the hypokalaemic and electrocardiographic responses to inhaled terbutaline. Br J Clin Pharmacol. 1991;32630- 632
Link to Article
Struthers  ADWhitesmith  RReid  JL Prior thiazide diuretic treatment increases adrenaline-induced hypokalaemia. Lancet. 1983;11358- 1361
Link to Article
Goldberger  JJ Treatment and prevention of sudden cardiac death: effect of recent clinical trials. Arch Intern Med. 1999;1591281- 1287
Link to Article
Herings  RMBakker  AStricker  BHNap  G Pharmaco-morbidity linkage: a feasibility study comparing morbidity in two pharmacy based exposure cohorts. J Epidemiol Community Health. 1992;46136- 140
Link to Article
World Health Organization, International Classification of Diseases, Ninth Revision (ICD-9).  Geneva, Switzerland World Health Organization1977;
Heerdink  ERLeufkens  HGHerings  RMOttervanger  JPStricker  BHBakker  A NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med. 1998;1581108- 1112
Link to Article
Crane  JBurgess  CDGraham  ANMaling  TJ Hypokalaemic and electrocardiographic effects of aminophylline and salbutamol in obstructive airways disease. N Z Med J. 1987;100309- 311
Bennett  JASmyth  ETPavord  IDWilding  PJTattersfield  AE Systemic effects of salbutamol and salmeterol in patients with asthma. Thorax. 1994;49771- 774
Link to Article
Martelli  NARaimondi  ACLazzari  JO Asthma, cardiac arrhythmias, and albuterol aerosol. Chest. 1986;89192- 194
Link to Article

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