DiltiazemA 52-year old man presents via EMS with a chief complaint of “racing heartbeat” for one hour. He is placed on a cardiac monitor which shows a heart rate of 185, an ECG reveals supraventricular tachycardia (SVT), and his blood pressure is 143/95 mmHg. As you ask the nurse to procure 6 mg of adenosine, the patient’s eyes grow wide.

“Please doc…” he pleads, “anything but that! Last time they gave that to me I thought I was gonna die!”

You recently read about using calcium channel blockers (CCBs) for paroxysmal SVT (PSVT), but can’t recall the last time you actually considered using them. After all, it’s been over 20 years since we switched to using adenosine first-line.

Background

PSVT is a clinical syndrome characterized by the presence of a regular and rapid tachycardia of abrupt onset and termination. It represents a subset of SVT, an umbrella term used to describe tachycardias involving tissue from the His bundle or above.1 The 3 most common types of PSVT are atrioventricular nodal reentrant tachycardia (AVNRT), atrioventricular reciprocating tachycardia (AVRT), and atrial tachycardia (AT).2 Treatment pathways for PSVT depend on hemodynamic stability and underlying rhythm. While AVNRT and AVRT will likely terminate with AV nodal blocking agents, AT is not dependent on the AV node and these agents will typically only slow ventricular response rate.2,3

Guidelines

Advanced Cardiac Life Support (ACLS) guidelines and joint guidelines released in 2015 by the American Heart Association, American College of Cardiology, and the Heart Rhythm Society (AHA/ACC/HRS) recommend both pharmacologic and non-pharmacologic therapies for the acute management of PSVT.1,4

  • Unstable patients
    • Consider adenosine if the tachycardia is regular and narrow complex
    • When vagal maneuvers or adenosine are ineffective or not feasible, perform synchronized cardioversion (class I recommendation)
  • Stable patients
    • Vagal maneuvers and/or IV adenosine (class I recommendations)
    • IV beta-blockers, diltiazem, or verapamil (class IIa recommendations)

So, what’s the problem with adenosine?

Before the introduction of adenosine in 1989, verapamil was the mainstay of treatment of stable PSVT.5 In 1992, adenosine replaced verapamil as the first-line recommended agent in the American Heart Association (AHA) Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care and has remained a first-line agent in subsequent updates. However, adenosine is associated with a high incidence of adverse effects including dyspnea, chest tightness, dizziness, headache, facial flushing, nausea and an “electric shock” sensation.5,6 Trials comparing outcomes of CCBs to adenosine have been conducted for over 30 years, yet there remains controversy regarding the relative effectiveness and safety of adenosine and verapamil for the treatment of PSVT.5

Pharmacology

CCBs can be divided into two subclasses, dihydropyridine (DHP) and non-DHP. DHP agents have high vascular selectivity and limited AV nodal activity and are not clinically useful in the treatment of PSVT. Non-DHP agents include the cardioselective phenylalkylamine verapamil and the non-selective benzothiazepine diltiazem. Both agents have been studied for use in patients with PSVT and are FDA approved for rapid conversation of PSVT to sinus rhythm.5–11 Adenosine slows conduction through the AV node through a different mechanism, binding to A1 receptors, and is also FDA approved for conversion of PSVT to sinus rhythm. 11

Adenosine Verapamil Diltiazem
Adult dose 6 mg rapid push; repeat with 12 mg if needed 3 mg initial dose in patients taking dipyridamole or carbamazepine, those with transplanted hearts, or if given by central
venous access Consider 12 mg initial bolus in patients consuming caffeine in the last 4 hours (see Bryan Hayes’ ALiEM post)
2.5 to 5 mg IV over 2 minutes, repeat with 5-10 mg IV every 15-30 minutes to a total dose of 20-30 mg as needed OR slow infusion 1 mg/min IV up to conversion of SVT or 20 mg total. 0.25 mg/kg over 2 minutes, repeat with 0.35 mg/kg IV in 15 minutes if needed OR slow infusion 2.5 mg/min IV up to conversion of SVT or 50 mg total.
Action/indication Terminates SVT, therapeutic and diagnostic in wide complex tachycardia and AT Decreases rate, terminates SVT Decreases rate, terminates SVT
Onset of action Average 21.9 to 34.2 seconds About 100-400 seconds About 180-400 seconds
Duration of action < 10 seconds Early distribution phase of 4 minutes, terminal half-life of 2-5 hours 3-4 hours
Adverse effects Dyspnea, chest tightness, dizziness, headache, facial flushing, nausea, “electric shock” sensation, transient AV block Bradycardia, hypotension, worsening heart failure in patients with pre- existing ventricular dysfunction Bradycardia, hypotension, worsening heart failure in patients with pre- existing ventricular dysfunction
Table 1: Comparative pharmacokinetic and pharmacodynamic parameters of adenosine and CCBs1–4,7–12

Comparison

Two meta-analyses have compared the efficacy and safety of CCBs to adenosine in patients with PSVT.5,6 Each analysis evaluated 8 clinical trials, 7 of which were used in both. Holdgate and Foo’s meta-analysis included one study performed in infants that the later meta-analysis by Delaney et al. did not include. Delaney et al. also included a later trial by Lim et al. comparing adenosine to CCBs by slow infusion.11 Both meta-analyses used verapamil as the comparative CCB with Delaney et al. excluding the patients in Lim et al. who received diltiazem.

Holdgate & Foo (2006)6 Delaney et al. (2011)5
Included population 8 trials, 577 patients 8 trials, 692 patients
Conversion rate Adenosine: 92% Verapamil: 89% p=0.15 Adenosine: 91% Verapamil: 90% p=0.51
Time to conversion Longer with verapamil, significant heterogeneity (see table 1 for average results) Longer with verapamil, significant heterogeneity (see table 1 for average results)
Relapse rate Adenosine: 10.2% Verapamil: 1.9% p=0.09 Not reported
Minor adverse events Adenosine: 36.9-97.7% Verapamil: 0-16.3% p<0.001 Adenosine: 16.7-76% Verapamil: 0-9.9% p=0.006
Hypotension Adenosine: 0% Verapamil: 1.8% p=0.06 Adenosine: 0.6% Verapamil: 3.7% p=0.016
Table 2: Characteristics and outcomes of meta-analysis comparing adenosine and CCBs in the treatment of PSVT

Both meta-analyses support:

  • Equivalence in efficacy
  • Greater time to conversion with verapamil
  • A small increased risk of hypotension with verapamil
  • Higher risk of minor adverse effects with adenosine
    • Reported examples: Dyspnea, chest tightness, dizziness, headache, facial flushing, nausea, “feeling funny”, “electric shock” sensation, and “bad feeling”.

It is important to note that in most trials, patients with a systolic blood pressure (SBP) <90 mmHg and those with cardiac failure or evidence of shock were excluded. Additionally, although verapamil was the only CCB evaluated in the meta-analyses, diltiazem carries an FDA approval for the conversion of PSVT and several small trials have shown equivalence between diltiazem and verapamil.10,11

As CCBs have been associated with an increased risk of hypotension, administration by slow infusion has been proposed as a method of converting SVT while minimizing hypotensive effects. Only one trial has evaluated the comparative efficacy of this administration technique. Lim et al. randomized  206 patients to adenosine (n=104) or CCBs (verapamil n = 48, diltiazem n = 54) by slow infusion.

Adenosine Verapamil Diltiazem
Dose 6 mg IV bolus, followed by 12 mg if needed 1 mg/min IV up to conversion of SVT or 20 mg total 2.5 mg/min IV up to conversion of SVT or 50 mg total
Baseline SBP / DBP (mmHg) 114.8 ± 27.9 / 78.7 ± 20.9 117.7 ± 26.1 / 75 ± 14.9 117.1 ± 28.2 / 78.1 ± 18.7
Change in SBP / DBP post-conversion (mmHg) 2.6 / -1.7 -13.0 / -8.1 -7.0 / -9.4
Time to conversion 1.48 min 6.5 min 6.76 min
Average dose required (mg) by % of patients converted Not stated 25% – 3.81 50% – 5 75% – 7.69 25% – 9.38 50% – 12.5 75% – 18.13
Conversion rate 86.5% 98% 98.1%
Table 3. Study by Lim et al. comparing adenosine to CCBs by slow infusion11

One patient in the CCB group and no patients in the adenosine group developed hypotension. CCBs were more likely to convert SVT (RR = 1.13, 95% CI 1.04–1.23) compared to adenosine, and no difference was noted between verapamil and diltiazem. This trial is limited by its single center nature, lower rates of conversion with adenosine than in historical trials, and lack of comparison to IV bolus CCBs. Nevertheless, the AHA/ACC/HRS guidelines list slow infusion of CCBs as an acceptable administration method.1

Case Resolution

After determining the patient has no other cardiac history and is hemodynamically stable, you decide to administer diltiazem. As your infusion pumps are not programmed to administer diltiazem by slow infusion, you feel safer administering a 0.25 mg/kg bolus. Five minutes after the bolus, the patient converts to sinus tachycardia while maintaining his blood pressure. On his way out, he thanks you for not making him “feel lousy”.

Take Home Points

  • CCBs by IV bolus or slow infusion are equally efficacious to adenosine in hemodynamically stable patients with SVT.
    • CAUTION with CCBs: CCBs were excluded from the above studies if there was evidence of shock, hypotension, and heart failure. CCBs should be avoided in these cases.
  • Adenosine is associated with minor adverse effects such as dyspnea, chest tightness, dizziness, headache, facial flushing, nausea, “feeling funny”, “electric shock” sensation, and “bad feeling”.
  • Hypotension is more likely with CCBs but has low absolute rates in hemodynamically stable patients.
  • CCBs have a slightly longer time to conversion.
  • As always when deciding about medication choices, if possible and where appropriate, discuss the pros/cons with the patient.

Is anyone using CCB’s for these stable cases of SVT? I would love to hear your experiences.

1.
Page R, Joglar J, Caldwell M, et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2016;67(13):e27-e115. [PubMed]
2.
Helton M. Diagnosis and Management of Common Types of Supraventricular Tachycardia. Am Fam Physician. 2015;92(9):793-800. [PubMed]
3.
Colucci R, Silver M, Shubrook J. Common types of supraventricular tachycardia: diagnosis and management. Am Fam Physician. 2010;82(8):942-952. [PubMed]
4.
Link M, Berkow L, Kudenchuk P, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132(18 Suppl 2):S444-64. [PubMed]
5.
Delaney B, Loy J, Kelly A. The relative efficacy of adenosine versus verapamil for the treatment of stable paroxysmal supraventricular tachycardia in adults: a meta-analysis. Eur J Emerg Med. 2011;18(3):148-152. [PubMed]
6.
Holdgate A, Foo A. Adenosine versus intravenous calcium channel antagonists for the treatment of supraventricular tachycardia in adults. Cochrane Database Syst Rev. 2006;(4):CD005154. [PubMed]
7.
Adenosine Package Insert. West-Ward Pharmaceuticals. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b827e3f8-dd63-4e54-90f4-0eded943de9f. Published October 2011. [Source]
8.
Diltiazem Package Insert. Hospira, Inc. https://www.hospira.com/en/images/EN-1220_tcm81-5500.pdf. Published June 2006.
9.
Verapamil Package Insert. Hospira Inc. https://www.hospira.com/en/images/EN-2504_tcm81-5741.pdf. Published April 2011.
10.
Lim S, Anantharaman V, Teo W. Slow-infusion of calcium channel blockers in the emergency management of supraventricular tachycardia. Resuscitation. 2002;52(2):167-174. [PubMed]
11.
Lim S, Anantharaman V, Teo W, Chan Y. Slow infusion of calcium channel blockers compared with intravenous adenosine in the emergency treatment of supraventricular tachycardia. Resuscitation. 2009;80(5):523-528. [PubMed]
12.
Cabalag M, Taylor D, Knott J, Buntine P, Smit D, Meyer A. Recent caffeine ingestion reduces adenosine efficacy in the treatment of paroxysmal supraventricular tachycardia. Acad Emerg Med. 2010;17(1):44-49. [PubMed]
Stephen Rappaport, PharmD, BCPS

Stephen Rappaport, PharmD, BCPS

Pharmacy Resident II - Critical Care
University of Vermont Medical Center
Stephen Rappaport, PharmD, BCPS

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Meghan Groth, PharmD, BCPS

Meghan Groth, PharmD, BCPS

Emergency Medicine Pharmacy Clinician University of Vermont Medical Center Contributor for Emergency Medicine PharmD Blog
Meghan Groth, PharmD, BCPS

@@EMPharmGirl

Just a pharmacist interested in Emergency Medicine, teaching, and #FOAMed | Pharmacocontrarian | Also, like, a very stable genius
Meghan Groth, PharmD, BCPS

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