Cardiac monitoring of high-dose verapamil in cluster headache: An international Delphi study

Introduction

Cluster headache is a highly disabling brain disorder characterized by recurrent attacks of intense unilateral headache and facial autonomic features for 30–180 minutes (1). Attacks typically strike several times a day, in most patients clustered in periods of several weeks to months alternating with attack-free periods of months to years (episodic cluster headache) (1). Up to 20% of patients may have chronic cluster headache without attack-free periods. To prevent attacks, treatment guidelines recommend verapamil in doses that usually exceed those generally used in cardiovascular disease (2,3). Adverse events of high-dose verapamil (HDV) may include cardiac arrhythmia, heart failure, and pulmonary edema (4). Consequently, patients with atrioventricular (AV) blocks, ventricular dysfunction, hypotension, or certain forms of atrial fibrillation are usually excluded (4). Evidence-based guidelines on how to prescreen and monitor cardiac safety in cluster headache patients treated with HDV are, however, lacking (2,5). In clinical practice this may cause suboptimal treatment results with HDV in some patients.

The goal of the present study was to define guidelines for safe use and electrocardiogram (EKG) monitoring of HDV in cluster headache. To this end we interviewed cardiologists who are experts in cardiac rhythm disorders and used the Delphi approach to arrive at consensus.

Methods

We randomly identified 40 cardiologists from the membership list of the Heart Rhythm Society who were invited to participate. Cardiologists were eligible if they had been first or last author of at least five publications on cardiac rhythm disorders in peer-reviewed medical journals in the last 10 years. Twenty-two (55%) responded and completed the questionnaires. (For participants, see Supplementary Table 1.)

A case vignette was presented in which a patient with cluster headache and no cardiac medical history was prescribed verapamil 240 mg/day. We used the Delphi approach (6) to arrive at consensus about the EKG protocol and which EKG findings were considered contraindications for continuation of verapamil. The first round included questions about possible EKG protocols using a five-point Likert scale. Consensus was defined as answers “strongly agree” and “agree” adding up to ≥80%. When no consensus was reached, propositions were taken to the second round. (For questions, see Supplementary Table 2.) For continuous variables, mean values with ranges and standard deviations (SD) are presented, using SPSS software, version 20, SPSS Inc, Chicago, IL, USA, for Windows.

Results

Panel members reached consensus on one of six proposals (Table 1) as 82% agreed that an EKG should be made prior to the first dose of verapamil. Half the panel recommended performing EKGs during stable doses at set times, especially with mean daily doses of ≥330 mg (range: ≥120–480 mg). EKG before dose increase was recommended by 50% while 60% advised an EKG after dose increase. In total 45% recommended EKG both before and after dose increase. Those who advised EKG monitoring after dose increase recommended doing this after an average of five days (range 1–14 days, SD 3.8). If patients were taking ≥ 480 mg verapamil per day, ambulatory EKG Holter-monitor registration was recommended by 50% of the panel members. Most panel members deemed pretreatment EKG not necessary in patients who had had no cardiac adverse events while on verapamil during a previous period of cluster headache attacks.

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Table 1.

Results of the Delphi questionnaire.

Propositions Need for EKG	Agreement by cardiologists
1. Prior to start of verapamil	82%
2. At set times during stable dose	50%
If not necessary at all doses, cut-off dose (mean)	330 mg/day
3. Prior to dose increase	50%
4. After dose increase	60%
5. Holter EKG ≥ 480 mg/day verapamil	50%
6. Before restart when previously no side effects	23%
EKG absolute contraindications
Bradycardia < 40 bpm (asymptomatic)	92% a
Third-degree AV block	86%
Second-degree AV block, Mobitz type	86%
Sinus pause > 3 seconds	69% a
Second-degree AV block, Wenckebach type	69% a
Sick-sinus syndrome	46% a
First-degree AV block but < 250 ms	31% a
Re-entrant tachycardia	23% a
Asymptomatic bradycardia < 50 bpm	8% a
EKG relative contraindications
First-degree AV block > 250 ms	92% a
New junctional rhythm	77% a
Asymptomatic bradycardia < 50 bpm	75% a
Second-degree AV block, Wenckebach type	75% a
Bradycardia < 40 bpm (asymptomatic)	50% a
New bundle branch block	31% a
Verapamil
Sustained release preferred	52%
Highest daily dose to prescribe (mean) b	550 mg (range 240–960)

Absolute contraindications for continuation of verapamil treatment included: (1) bradycardia < 40 beats per minute (bpm) (92% agreement); (2) third-degree AV block (86%); and (3) second-degree AV block Mobitz type (86%) (Table 1). A first-degree AV block (>250 ms) was regarded as a relative contraindication (92%). For bradycardia < 50 bpm and second-degree AV block Wenckebach type, near consensus as to relative contraindications was reached (75% agreement).

Seventeen respondents recommended a mean maximal daily dose of 550 mg (range 240–960 mg). There was no preference for sustained- or regular-release formulations (Table 1).

Cardiologists from Europe and the United States (US) did not differ with respect to their answers.

Discussion

We used the Delphi approach to define recommendations from cardiologists specializing in rhythm disorders for safe use and EKG monitoring of HDV in cluster headache. The panel members agreed on performing a pretreatment EKG in patients using verapamil for the first time. Pretreatment EKG was deemed not necessary in patients who did not have cardiac adverse events during a previous period of cluster headache treated with verapamil. No consensus was reached on EKG monitoring during verapamil treatment and dose adjustments. For verapamil doses of ≥480 mg/ day, half the panel advised ambulatory EKG Holter-monitor registration. Consensus about absolute and relative contraindications for continuing HDV largely followed US Food and Drug Administration (FDA) recommendations. There was no preference among the panel members for either sustained- or regular-released formulations of verapamil.

Although cardiac arrhythmias and bradycardia have been reported in up to 40% of patients using HDV (7,8), published recommendations on EKG monitoring are remarkably limited, highly variable, and based solely on expert opinions (2,5,9,10). The protocols range from: (i) starting with 240 mg verapamil daily after pretreatment EKG and increasing the dose with 80 mg every two weeks, each time preceded by an EKG, until attacks have subsided, or side effects have become too serious, or a maximum dose of 960 mg/day is reached (11) to (ii) starting with a pretreatment EKG (without specified starting dose and titration scheme) followed by (a) repeated EKGs before and 10 days after each dose increase (3); (b) repeated EKGs only at doses above 480 mg/day (12); or (c) repeated EKGs with each dose increase (without specifying whether this is before or after dose increase) and every three months when on a stable dose (13).

The recommendations of the panel members were similarly divergent. They reached consensus only about performing a pretreatment EKG and near consensus that pretreatment EKG was not necessary in patients who had not experienced cardiac adverse events during a previous cluster period treated with verapamil. No consensus was reached on EKG monitoring during treatment and around dose adjustments. Most panel members, however, did recommend repeated EKG five days after each verapamil dose increase, in line with the time it takes to reach steady-state plasma levels after increasing the dose (4). Interestingly, half the panel members recommended Holter EKG for doses ≥480 mg/day, which is not mentioned in any cluster headache treatment review or guideline.

The FDA considers second- and third-degree AV block, sick-sinus syndrome without pacemaker, and atrial flutter/fibrillation with accessory bypass tract hard contraindications for use of verapamil. Panel members felt that a second-degree AV block Wenckebach type is only a relative contraindication and did not reach consensus about whether sick-sinus syndrome and atrial flutter/fibrillation were absolute contraindications.

Verapamil is available in regular or extended release formulations with different time-to-peak-concentrations and half-life times (4). The three available efficacy studies on verapamil in cluster headache were conducted with either sustained (9), regular release (14) or not specified (10). Most cluster headache guidelines do not specify the formulation. The panel did not favor any particular formulation.

The highest recommended daily doses of verapamil ranged from 240 to 960 mg (mean 550 mg), which is consistent with the doses used in the efficacy studies (on average 354–360 mg/day in episodic cluster headache (9,13) and 574 mg/day in chronic cluster (9)). In review articles and guidelines, doses up to 1200 mg are sometimes advised (11,13).

Recommendations

Based on the results of our study, we recommend performing a pretreatment EKG before initiating verapamil therapy but this is not necessary in patients who did not experience adverse events during previous treatment with verapamil. No consensus-based recommendations on EKG monitoring during verapamil treatment and around dose increases can be given, although, based on the literature EKG prior and after every dose increase would be a logical recommendation. It goes without saying that individual patient characteristics always have to be taken into account. Future studies should compare different EKG regimens prospectively.

Clinical implications

Experts agreed on performing pretreatment electrocardiogram (EKG) when prescribing verapamil.