Ivan Buitrago, MD

In Reply: We appreciate the interest and comments of Dr. Alraies. We would like to clarify that the patient’s baseline electrocardiogram before the nuclear stress test was normal. Second-degree atrioventricular (AV) block (Mobitz type I) was evident only during adenosine infusion before ventricular asystole. The patient was on two AV nodal blockers (labetalol and clonidine) but had no underlying conduction disease. There is no contraindication to continuing these agents before pharmacologic stress testing. In addition, the patient’s electrolyte levels were within normal ranges before testing.

We agree that the valuable teaching point for clinicians is to appreciate the contraindication to and consequences of the use of dipyridamole-containing oral medications and either adenosine or regadenoson during pharmacologic stress testing. As Dr. Alraies points out, most cardiologists may be familiar with this interaction, but a large proportion of stress tests are ordered by emergency room physicians, internists, and hospitalists who are not. Still, the overall incidence of side effects with pharmacologic stress testing is very low and comparable to that with exercise testing, with safety enhanced by following the American Society of Nuclear Cardiology (ASNC) guidelines for performing stress myocardial perfusion imaging.¹ Avoidance of this interaction may be enhanced through education, but also by using checklists and building notifications into the electronic medical record when ordering pharmacologic stress testing. Of note, according to the ASNC guidelines, the use of intravenous dipyridamole as a stress agent is a safe alternative for pharmacologic stress testing in patients taking oral dipyridamole-containing medications.

In Reply: We appreciate the interest and comments of Dr. Alraies. We would like to clarify that the patient’s baseline electrocardiogram before the nuclear stress test was normal. Second-degree atrioventricular (AV) block (Mobitz type I) was evident only during adenosine infusion before ventricular asystole. The patient was on two AV nodal blockers (labetalol and clonidine) but had no underlying conduction disease. There is no contraindication to continuing these agents before pharmacologic stress testing. In addition, the patient’s electrolyte levels were within normal ranges before testing.

We agree that the valuable teaching point for clinicians is to appreciate the contraindication to and consequences of the use of dipyridamole-containing oral medications and either adenosine or regadenoson during pharmacologic stress testing. As Dr. Alraies points out, most cardiologists may be familiar with this interaction, but a large proportion of stress tests are ordered by emergency room physicians, internists, and hospitalists who are not. Still, the overall incidence of side effects with pharmacologic stress testing is very low and comparable to that with exercise testing, with safety enhanced by following the American Society of Nuclear Cardiology (ASNC) guidelines for performing stress myocardial perfusion imaging.¹ Avoidance of this interaction may be enhanced through education, but also by using checklists and building notifications into the electronic medical record when ordering pharmacologic stress testing. Of note, according to the ASNC guidelines, the use of intravenous dipyridamole as a stress agent is a safe alternative for pharmacologic stress testing in patients taking oral dipyridamole-containing medications.

In Reply: We appreciate the interest and comments of Dr. Alraies. We would like to clarify that the patient’s baseline electrocardiogram before the nuclear stress test was normal. Second-degree atrioventricular (AV) block (Mobitz type I) was evident only during adenosine infusion before ventricular asystole. The patient was on two AV nodal blockers (labetalol and clonidine) but had no underlying conduction disease. There is no contraindication to continuing these agents before pharmacologic stress testing. In addition, the patient’s electrolyte levels were within normal ranges before testing.

We agree that the valuable teaching point for clinicians is to appreciate the contraindication to and consequences of the use of dipyridamole-containing oral medications and either adenosine or regadenoson during pharmacologic stress testing. As Dr. Alraies points out, most cardiologists may be familiar with this interaction, but a large proportion of stress tests are ordered by emergency room physicians, internists, and hospitalists who are not. Still, the overall incidence of side effects with pharmacologic stress testing is very low and comparable to that with exercise testing, with safety enhanced by following the American Society of Nuclear Cardiology (ASNC) guidelines for performing stress myocardial perfusion imaging.¹ Avoidance of this interaction may be enhanced through education, but also by using checklists and building notifications into the electronic medical record when ordering pharmacologic stress testing. Of note, according to the ASNC guidelines, the use of intravenous dipyridamole as a stress agent is a safe alternative for pharmacologic stress testing in patients taking oral dipyridamole-containing medications.

A 60-year-old woman was referred for pharmacologic nuclear stress testing before treatment for breast cancer. She had hypertension, diabetes mellitus, coronary artery disease, and a remote history of stroke, and she was taking clonidine (Catapres), labetalol (Normodyne, Trandate), furosemide (Lasix), hydralazine, valsartan (Diovan), insulin, and the aspirin-dipyridamole combination Aggrenox. Her vital signs and electrocardiogram before the stress test were normal.

The stress test was started with a standard protocol of adenosine (Adenoscan) infused intravenously over 4 minutes. For the first 2 minutes, she was stable and had no symptoms, but then sinus pauses and second-degree atrioventricular block type 2 developed, after which her heart stopped beating (Figure 1). The infusion was immediately stopped, but she became unresponsive and remained pulseless.

Cardiopulmonary resuscitation was started, aminophylline 100 mg was given intravenously, and she regained a pulse and blood pressure within a few minutes. She was then transferred to the emergency room, where she returned to her baseline clinical and neurologic status without symptoms.

AN UNRECOGNIZED DRUG INTERACTION

Asystole occurred in this patient because of the interaction of intravenous adenosine with the dipyridamole in the medication Aggrenox. Although adenosine, given during pharmacologic stress testing, is known to interact with various medications, the potential for this interaction may be overlooked if the culprit is present in a combination drug. Aggrenox is commonly given for secondary stroke prevention and should be discontinued before pharmacologic nuclear stress testing.

Pharmacologic stress testing involves two commonly used stress agents, adenosine and regadenoson (Lexiscan), which cause coronary vasodilation through their action on A2A receptors in the heart. Coronary vasodilation results in flow heterogeneity in the region of a stenotic artery, which can be detected with nuclear perfusion agents. In addition, adenosine has a short-lived effect on the A1 receptors that block atrioventricular conduction.¹

Dipyridamole (Persantine) is contraindicated when either adenosine or regadenoson is used. Dipyridamole enhances the effect of exogenous and endogenous adenosine by inhibiting its uptake by cardiac cells, thus enhancing the action of these coronary vasodilators.² Atrioventricular block is common during adenosine stress testing but is transient because adenosine has a short half-life (< 10 seconds), and complete heart block or asystole, as seen in this patient, is rare. Giving intravenous adenosine or regadenoson to patients on dipyridamole may have a marked effect on adenosine receptors, so that profound bradycardia and even asystole leading to cardiac collapse may occur. No data are available on the specific interaction of dipyridamole and regadenoson.

Even though the pharmacodynamics of the interaction between dipyridamole and adenosine are known,³ few reports are available detailing serious adverse events. The contraindication to pharmacologic stress testing in patients taking dipyridamole is noted in the American Society of Nuclear Cardiology Guidelines for stress protocols,⁴ which advise discontinuing dipyridamole-containing drugs at least 48 hours before the use of adenosine or regadenoson. Similarly, the American Heart Association guidelines⁵ for the management of supraventricular tachycardia recommend an initial dose of 3 mg of adenosine rather than 6 mg in patients who have been taking dipyridamole.

The dose of aminophylline for reversing the adverse effects of adenosine or regadenoson is 50 to 250 mg intravenously over 30 to 60 seconds. But since these adverse effects are short-lived once the infusion is stopped, aminophylline is usually given only if the adverse effects are severe, as in this patient.

Pharmacologic nuclear stress testing with adenosine receptor agonists (eg, adenosine or regadenoson) is contraindicated in patients taking dipyridamole or the combination pill Aggrenox because of the potential for profound bradyarrhythmias or asystole.

A 60-year-old woman was referred for pharmacologic nuclear stress testing before treatment for breast cancer. She had hypertension, diabetes mellitus, coronary artery disease, and a remote history of stroke, and she was taking clonidine (Catapres), labetalol (Normodyne, Trandate), furosemide (Lasix), hydralazine, valsartan (Diovan), insulin, and the aspirin-dipyridamole combination Aggrenox. Her vital signs and electrocardiogram before the stress test were normal.

The stress test was started with a standard protocol of adenosine (Adenoscan) infused intravenously over 4 minutes. For the first 2 minutes, she was stable and had no symptoms, but then sinus pauses and second-degree atrioventricular block type 2 developed, after which her heart stopped beating (Figure 1). The infusion was immediately stopped, but she became unresponsive and remained pulseless.

Cardiopulmonary resuscitation was started, aminophylline 100 mg was given intravenously, and she regained a pulse and blood pressure within a few minutes. She was then transferred to the emergency room, where she returned to her baseline clinical and neurologic status without symptoms.

AN UNRECOGNIZED DRUG INTERACTION

Asystole occurred in this patient because of the interaction of intravenous adenosine with the dipyridamole in the medication Aggrenox. Although adenosine, given during pharmacologic stress testing, is known to interact with various medications, the potential for this interaction may be overlooked if the culprit is present in a combination drug. Aggrenox is commonly given for secondary stroke prevention and should be discontinued before pharmacologic nuclear stress testing.

Pharmacologic stress testing involves two commonly used stress agents, adenosine and regadenoson (Lexiscan), which cause coronary vasodilation through their action on A2A receptors in the heart. Coronary vasodilation results in flow heterogeneity in the region of a stenotic artery, which can be detected with nuclear perfusion agents. In addition, adenosine has a short-lived effect on the A1 receptors that block atrioventricular conduction.¹

Dipyridamole (Persantine) is contraindicated when either adenosine or regadenoson is used. Dipyridamole enhances the effect of exogenous and endogenous adenosine by inhibiting its uptake by cardiac cells, thus enhancing the action of these coronary vasodilators.² Atrioventricular block is common during adenosine stress testing but is transient because adenosine has a short half-life (< 10 seconds), and complete heart block or asystole, as seen in this patient, is rare. Giving intravenous adenosine or regadenoson to patients on dipyridamole may have a marked effect on adenosine receptors, so that profound bradycardia and even asystole leading to cardiac collapse may occur. No data are available on the specific interaction of dipyridamole and regadenoson.

Even though the pharmacodynamics of the interaction between dipyridamole and adenosine are known,³ few reports are available detailing serious adverse events. The contraindication to pharmacologic stress testing in patients taking dipyridamole is noted in the American Society of Nuclear Cardiology Guidelines for stress protocols,⁴ which advise discontinuing dipyridamole-containing drugs at least 48 hours before the use of adenosine or regadenoson. Similarly, the American Heart Association guidelines⁵ for the management of supraventricular tachycardia recommend an initial dose of 3 mg of adenosine rather than 6 mg in patients who have been taking dipyridamole.

The dose of aminophylline for reversing the adverse effects of adenosine or regadenoson is 50 to 250 mg intravenously over 30 to 60 seconds. But since these adverse effects are short-lived once the infusion is stopped, aminophylline is usually given only if the adverse effects are severe, as in this patient.

Pharmacologic nuclear stress testing with adenosine receptor agonists (eg, adenosine or regadenoson) is contraindicated in patients taking dipyridamole or the combination pill Aggrenox because of the potential for profound bradyarrhythmias or asystole.

A 60-year-old woman was referred for pharmacologic nuclear stress testing before treatment for breast cancer. She had hypertension, diabetes mellitus, coronary artery disease, and a remote history of stroke, and she was taking clonidine (Catapres), labetalol (Normodyne, Trandate), furosemide (Lasix), hydralazine, valsartan (Diovan), insulin, and the aspirin-dipyridamole combination Aggrenox. Her vital signs and electrocardiogram before the stress test were normal.

The stress test was started with a standard protocol of adenosine (Adenoscan) infused intravenously over 4 minutes. For the first 2 minutes, she was stable and had no symptoms, but then sinus pauses and second-degree atrioventricular block type 2 developed, after which her heart stopped beating (Figure 1). The infusion was immediately stopped, but she became unresponsive and remained pulseless.

Cardiopulmonary resuscitation was started, aminophylline 100 mg was given intravenously, and she regained a pulse and blood pressure within a few minutes. She was then transferred to the emergency room, where she returned to her baseline clinical and neurologic status without symptoms.

AN UNRECOGNIZED DRUG INTERACTION

Asystole occurred in this patient because of the interaction of intravenous adenosine with the dipyridamole in the medication Aggrenox. Although adenosine, given during pharmacologic stress testing, is known to interact with various medications, the potential for this interaction may be overlooked if the culprit is present in a combination drug. Aggrenox is commonly given for secondary stroke prevention and should be discontinued before pharmacologic nuclear stress testing.

Pharmacologic stress testing involves two commonly used stress agents, adenosine and regadenoson (Lexiscan), which cause coronary vasodilation through their action on A2A receptors in the heart. Coronary vasodilation results in flow heterogeneity in the region of a stenotic artery, which can be detected with nuclear perfusion agents. In addition, adenosine has a short-lived effect on the A1 receptors that block atrioventricular conduction.¹

Dipyridamole (Persantine) is contraindicated when either adenosine or regadenoson is used. Dipyridamole enhances the effect of exogenous and endogenous adenosine by inhibiting its uptake by cardiac cells, thus enhancing the action of these coronary vasodilators.² Atrioventricular block is common during adenosine stress testing but is transient because adenosine has a short half-life (< 10 seconds), and complete heart block or asystole, as seen in this patient, is rare. Giving intravenous adenosine or regadenoson to patients on dipyridamole may have a marked effect on adenosine receptors, so that profound bradycardia and even asystole leading to cardiac collapse may occur. No data are available on the specific interaction of dipyridamole and regadenoson.

Even though the pharmacodynamics of the interaction between dipyridamole and adenosine are known,³ few reports are available detailing serious adverse events. The contraindication to pharmacologic stress testing in patients taking dipyridamole is noted in the American Society of Nuclear Cardiology Guidelines for stress protocols,⁴ which advise discontinuing dipyridamole-containing drugs at least 48 hours before the use of adenosine or regadenoson. Similarly, the American Heart Association guidelines⁵ for the management of supraventricular tachycardia recommend an initial dose of 3 mg of adenosine rather than 6 mg in patients who have been taking dipyridamole.

The dose of aminophylline for reversing the adverse effects of adenosine or regadenoson is 50 to 250 mg intravenously over 30 to 60 seconds. But since these adverse effects are short-lived once the infusion is stopped, aminophylline is usually given only if the adverse effects are severe, as in this patient.

Pharmacologic nuclear stress testing with adenosine receptor agonists (eg, adenosine or regadenoson) is contraindicated in patients taking dipyridamole or the combination pill Aggrenox because of the potential for profound bradyarrhythmias or asystole.