Cardiac safety in cluster headache patients using the very highdose of verapamil (‡720 mg/day) M. Lanteri-Minet • F. Silhol • V. Piano •A. Donnet Received: 3 September 2010 / Accepted: 29 December 2010Ó The Author(s) 2011. This article is published with open access at Use of high doses of verapamil in preventive patients presented a delayed-onset cardiac adverse event treatment of cluster headache (CH) is limited by cardiac (delay C2 years). Our work confirms the need for sys- toxicity. We systematically assess the cardiac safety of the tematic EKG monitoring in CH patients treated with very high dose of verapamil (verapamil VHD) in CH verapamil. Such cardiac safety assessment must be con- patients. Our work was a study performed in two French tinued even for patients using VHD without any adverse headache centers (Marseilles–Nice) from 12/2005 to 12/2008. CH patients treated with verapamil VHD(C720 mg) were considered with a systematic electrocar- diogram (EKG) monitoring. Among 200 CH patients, 29 (14.8%) used verapamil VHD (877 ± 227 mg/day). Inci-dence of EKG changes was 38% (11/29). Seven (24%)patients presented bradycardia considered as nonserious adverse event (NSAE) and four (14%) patients presentedarrhythmia (heart block) considered as serious adverse event According to quality criteria developed by the American (SAE). Patients with EKG changes (1,003 ± 295 mg/day) Academy of Neurology [], verapamil received a grade C were taking higher doses than those without EKG changes rating in a recent meta-analysis of trials of pharmacotherapy (800 ± 143 mg/day), but doses were similar in patients for cluster headache (CH) []. In spite of this low evidence with SAE (990 ± 316 mg/day) and those with NSAE level, verapamil is generally considered to be the mainstay (1,011 ± 309 mg/day). Around three-quarters (8/11) of of CH preventive therapy as in the European guidelines The starting daily dose of verapamil in CH should be the360 mg effective in two randomized clinical trials The daily dose could be increased up to 720 mg and some De´partement d’Evaluation et traitement de la Douleur Me´decinepalliative, Poˆle Neurosciences Cliniques du CHU de Nice, CH patients may even need unusual very high daily dose Hoˆpital Pasteur Avenue de la Voie Romaine, 06002 Nice Cedex, from 720 to 1,200 mg []. Considering such a clinical practice, the dose of verapamil used for CH is approxi- mately twice the dose required by cardiovascular diseases This difference could be explained by the fact that the INSERM Unite´ 829, Faculte´ de Chirurgie dentaire, cardiovascular effects are related to blood level, whereas the preventive CH effect takes place across the blood–brainbarrier where the efflux transporter P-glycoprotein restricts F. SilholService de Cardiologie, CHU Timone, Rue St Pierre, net brain uptake of verapamil by immediately transporting it out of the brain Considering the use of high doses, thecardiac safety of verapamil therapy was specifically studied in one series that included 108 CH patients treated Service de Neurologie, Poˆle Neurosciences cliniques,CHU Timone, Rue St Pierre, 13005 Marseille, France by verapamil with systematic electrocardiogram (EKG) assessment ]. In this series, verapamil was started at (720 mg: 16; 840 mg: 2; 960 mg: 7; 1,200 mg: 1; 240 mg/day and then increased until the CH was sup- 1,440 mg: 3). Concomitant treatments for CH (acute and pressed, or to a maximum daily dose of 960 mg (mean daily dose 584 ± 257 mg) and incidence of arrhythmia was 19%and bradycardia 36% []. We developed a similar approach to assess the cardiac safety of verapamil therapy in CH witha focus on very high daily dose equal or higher than EKG changes concerned 11 (38%) patients: bradycardia (heart rate \60 bpm) in 7 patients, first-degree heart block(PR interval [0.2 s) in 2 patients, second-degree heartblock in 1 patient and third degree heart block in 1 patient.
Patients with EKG changes used a mean verapamil dailydose of 1,003 ± 295 mg, whereas patients without EKG The notes were assessed for patients with episodic CH or changes used a mean verapamil dose of 800 ± 143 mg.
chronic CH attending two headache specialty centers EKG changes have been considered as cardiac serious (Marseilles and Nice) belonging to the French Observatory adverse event (SAE) in the four (14%) patients with heart of Migraine and Headaches ] from December 2005 to block inducing verapamil discontinuation in two patients December 2008. Patients had a diagnosis of CH according and a dose reduction in one patient. EKG changes have to the criteria of the second edition of the International been considered as cardiac nonserious adverse event Classification of Headache Disorders [When the (NSAE) in seven (24%) patients with bradycardia, but verapamil was used, the starting dose was 360 mg with an verapamil dose was decreased in one patient.
increase by 120 mg every 2 weeks with a check EKG, until Cardiac SAE concerned 4 men with mean age the CH was suppressed or adverse events intervened.
40.2 ± 14.5 years (range 21–52 years) and using a mean Ordinary release formulation or controlled release formu- very high verapamil daily dose of 990 ± 315 mg. One patient had a high blood pressure history and regarding Study considered CH patients using verapamil with a tobacco use, two were present smokers, one was past very high daily dose defined as C720 mg. The following smoker and one patient had never smoked. Cardiac SAE data were collected for each patient: sex, age, tobacco use concerned patients using verapamil without concomitant and cardiovascular history, diagnosis (episodic or chronic medications expect sumatriptan or zolmitriptan as acute CH), duration of verapamil use, very high dose of verap- treatment. Cardiac SAE were delayed onset in three amil achieved, duration of use of such a very high dose patients (72, 71 and 24 months after the very high dose was of verapamil, concomitant medications, clinical adverse achieved). Cardiac SAE were asymptomatic in two patients events related to verapamil (constipation, lethargy, hypo- and symptomatic in two patients with lethargy, and dysp- tension, lower edema, dyspnea, impotence, gingival nea for one patient and lethargy for the other.
hyperplasia). EKG assessment before verapamil introduc- Cardiac NSAE concerned seven men with mean age tion was compared with EKG assessment done at the very 40.7 ± 10 years (range 28–52 years) and using a mean very high verapamil daily dose of 1,011 ± 309 mg. Nopatient had cardiovascular history and regarding tobaccouse, six were present smokers and one had never smoked.
Cardiac NSAE concerned one patient without any con-comitant treatment, three patients without concomitant treatment except acute treatment (sumatriptan and oxygen)and three patients with prophylactic concomitant treatment Among 200 CH identified seen during the study period, (topiramate and/or indomethacin). Cardiac NSAE was 29 (14.8%) used verapamil with a daily dose C720 mg.
delayed onset in five patients (60, 36, 27, 24 and 24 months Very high verapamil dose CH patients were 28 men and after the very high dose was achieved). Cardiac NSAE 1 woman with a mean age 43.2 ± 10 years (range were asympomatic in four patients and associated lethargy 21–55 years). Twenty one were present smokers, six were past smokers and two had never smoked. Three had a highblood pressure and one a coronary heart disease. Ninesuffered of episodic CH and 20 of chronic CH. Mean duration of verapamil therapy was 46 ± 36 months andmean duration of very high dose use was 36 ± 32 months.
Considering the frequent use of high daily doses, cardiac Mean very high dose of verapamil was 877 ± 227 mg/day safety assessment with systematic EKG monitoring is Table 1 Cardiac safety of the very high verapamil CH patients Sex, age (years), tobacco use (TU), cardiovascular history (CVH) with high blood pressure (HBP) and coronary arteries disease (CAD), type ofCH (E: episodic CH–C: chronic CH), duration of verapamil use (vD) in months, duration of supra-maximum dose of verapamil (vSMD) inmonths, supra-maximum dose of verapamil achieved (SM) in mg/day, acute concomitant treatments (ACT/scC: subcutaneous sumatriptan–oZ:oral –O2: oxygen), prophylactic concomitant treatments (PCT/I: indomethacin–G: gabapentin–L: lithium–T: topiramate), electrocardiogram(EKG) changes, serious adverse event (SAE), change in verapamil dose (vC), clinical adverse events (CAE/C: constipation–D: dyspnea–E:edema of lower limbs–G: gingival hyperplasia–I: impotence–L: lethargy) Patients with serious cardiac adverse event are in bold and patient with nonserious cardiac adverse event are in italics essential in the management of CH patients treated by patients needing daily dose reduction, second- and third- verapamil This is all the more essential as the very high degree heart block in two others patients needing verapamil daily dose (C720 mg) is used. The use of the very high discontinuation. In a previous study on 108 CH patients daily dose is not infrequent and our study showed that it using a mean daily dose of 584 ± 264 mg, incidence of corresponds to 14.8% of CH patients managed in two arrhythmia (mostly first-degree heart block and junctional centers representative of French headache tertiary centers.
rhythm) was 19% and bradycardia 36% In this study, In this group patients treated with the very high daily dose patients with arrhythmia (567 ± 290 mg/day) were not of verapamil (877 ± 227 mg), systematic EKG monitoring taking higher doses than those without arrhythmia demonstrated that incidence of cardiac adverse events is (586 ± mg/day) []. By contrast, we found that patients 38%, with more than one-third of cases, the occurrence of with EKG changes (1,003 ± 295 mg/day) were taking an adverse event was considered as serious. Cardiac SAE higher doses than those without EKG changes (800 ± were arrhythmias induced by reduction of transmission in 143 mg/day), but doses were similar in patients with car- the atrioventricular node: first-degree heart block in two diac SAE (990 ± 316 mg/day) and those with cardiac NSAE (1,011 ± 309 mg/day). In our study, cardiac distribution and reproduction in any medium, provided the original adverse events were not related to the patients’ age, car- diovascular history, CH type and concomitant drugs usedfor acute and/or prophylactic treatment of CH. All thesedata are congruent with those previously reported and could be related to an interindividual variability in thepharmacology of verapamil supported by a genetic com- 1. Edlund W, Gronseth G, So Y, Franklin G (2004) Clinical practice ponent This hypothesis was developed in the cardio- guideline process manual. American Academy of Neurology, St.
logic field and data collected in the INVEST suggests variability in the large-conductance and voltage-dependant 2. Francis GJ, Becker WJ, Pringshiem TM (2010) Acute and pre- ventive pharmacologic treatment of cluster headache. Neurology potassium channel beta 1 subunit gene, KCNMB1, is associated with the antihypertensive response to verapamil 3. May A, Leone M, Afra J et al (2006) EFNS guidelines on the and also with cardiovascular adverse events in patients treatment of cluster headache and other trigeminal-autonomic having hypertension with coronary arteries disease cephalalgias. Eur J Neurol 13:1066–1077 4. Bussone G, Leone M, Peccarisi C et al (1990) Double blind Our study also suggests an important intra-individual var- comparison of lithium and verapamil in cluster headache pro- iability in the risk of cardiac adverse events. Such an intra- individual variability could explain the delayed onset of 5. Leone M, D’Amico D, Frediani F, Moschiano F, Grazzi L, At- cardiac adverse events which is probably the more striking tanasio A (2000) Verapamil in the prophylaxis of episodic clusterheadache: a double-blind study versus placebo. Neurology data collected in our study. Late-onset arrhythmia was previously described in two CH patient treated with 6. Gabai IJ, Speirings ELH (1989) Prophylactic treatment of cluster verapamil Around three-quarters (8/11) of our patients headache with verapamil. Headache 29:167–168 presented cardiac adverse events with a delayed onset, this 7. Tflelt-Hansen P, Tfelt-Hansen J (2008) Verapamil for cluster headache. Clinical pharmacology and possible mode of action.
proportion being similar to bradycardia (5/7) and arrhyth- mia (3/4). In all these late-onset adverse events cases, the 8. Luurtsema G, Molthoff CF, Windhorst AD et al (2003) (R)- and time between the adverse event occurrence date and that (S)[11C]verapamil as PET-tracers for measuring P-glycioprotein corresponding to the very high daily dose verapamil use function: in vitro and in vivo evaluation. Nucl Med Biol30:747–751 was equal or higher than 2 years. This confirms the need of 9. Cohen AS, Matharu MS, Goadsby PJ (2007) Electrocardio- regular and systematic EKG monitoring as EKG abnor- graphic abnormalities in patients with cluster headache on malities can develop insidiously with rising subthreshold verapamil therapy. Neurology 69:668–675 PR intervals, or suddenly after long time of normal EKGs.
10. Lanteri-Minet M, Autret A, Baudesson G et al (2005) French survey network on headaches and facial pains. In: Olesen J (ed) This systematic assessment is all the more important than The classification and diagnosis of headache disorders. Oxford cardiac adverse events can occur without any other clinical adverse event as in four of our eight cases with late-onset 11. Headache Classification Subcommittee of the International Headache Society (2004) The international classification ofheadache disorders, 2nd edn. Cephalalgia 24(Suppl 1):1–160 12. Beitelsheess AL, Gong Y, Wang D et al (2007) KCNMB1 The authors report no conflicts of interest.
genotype influences response to verapamil SR and adverse out-comes in the International VErapamil SR/Trandolapril Study This article is distributed under the terms of the (INVSET). Pharmacogenetic Genomics 17:719–729 Creative Commons Attribution License which permits any use,


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