Targ Oncol DOI 10.1007/s11523-016-0417-x
Cardiovascular risk profile of patients with peripheral arterial occlusive disease during nilotinib therapy E. Bondon-Guitton 1 & S. Combret 2 & M. C. Pérault-Pochat 3 & M. Stève-Dumont 4 & H. Bagheri 1 & F. Huguet 5 & F. Despas 6 & A. Pathak 6 & J. L. Montastruc 1
# Springer International Publishing Switzerland 2016
Abstract Background Over the past few years, data have suggested that severe peripheral arterial occlusive disease (PAOD) is associated with nilotinib exposure. However, the characteristics of this adverse drug reaction are poorly described since its frequency is low. As far as we know, no study using a spontaneous adverse drug reactions reporting system was performed to describe the characteristics of cases of PAOD related to nilotinib. Objective We performed a study to describe the cardiovascular risk profile of cases of PAOD in patients treated with nilotinib spontaneously reported to the French Pharmacovigilance Database (FPVD). Patients/Methods We selected all cases of Bvascular disorders,^ as the System Organ Class in MedDRA®, in which nilotinib was Bsuspected^ and recorded in the French Pharmacovigilance Database between 2007 and 21 October 2014. We then identified cases of PAOD with a Low Level
Term and through a detailed summary of the clinical description. Results We identified 25 cases of POAD. Most of the patients were older than 60 years (84 %) or had another cardiovascular risk factor such as hypercholesterolemia, arterial hypertension, overweight/obesity, smoking, or diabetes mellitus (72 %). Females (13 cases) and males (12 cases) were equally represented, but the presence of cardiovascular risk factors was more frequent in females than in males. The mean time from initiation of nilotinib to PAOD onset was 24 months and was significantly longer in patients aged less than 60 years compared with those aged over 60 years (33.8 ± 24.6 months vs. 22.6 ± 17.5 months, p = 0.002). Pre-existing cardiovascular risk factors, especially diabetes mellitus, also seem to accelerate its occurrence. Conclusions The FPVD is a useful tool in describing the cardiovascular risk profile of patients with PAOD during nilotinib exposure. Physicians have to be particularly vigilant
* E. Bondon-Guitton [email protected]
Pharmacologie Clinique et Vigilances, Centre Hospitalier Universitaire, Poitiers, France
Centre Régional de Pharmacovigilance, Hôpital de Cimiez, Nice, France
Service d’Hématologie, Institut Universitaire du Cancer, Toulouse, France
Service de Pharmacologie Médicale et Clinique, CHU Toulouse, Faculté de Médecine de l’Université de Toulouse, Toulouse, France
Service de Pharmacologie Médicale et Clinique, Centre Midi-Pyrénées de Pharmacovigilance, Pharmacoépidémiologie et Informations sur le Médicament, Pharmacopôle Midi-Pyrénées, CHU Toulouse, Faculté de Médecine de l’Université de Toulouse, Toulouse, France Centre Régional de Pharmacovigilance de Bourgogne, Centre Hospitalier Universitaire, Dijon, France
in patients older than 60 years of age; in patients younger than 60 years of age, long-term surveillance has to be maintained. Key Points
We described the characteristics of 25 cases of peripheral arterial occlusive disease during nilotnib therapy using the French spontaneous adverse drug reactions reporting system. Most patients were older than 60 years. Males and females were equally represented. The mean time from initiation of nilotinib to onset of PAOD in patients aged less than 60 years, at around 34 months, and was longer than in patients aged over 60 years.
1 Introduction Nilotinib is a BCR-ABL tyrosine kinase inhibitor approved in 2007 and 2010 in France for second- and first-line use, respectively, in the management of chronic myeloid leukemia. In 2011, Aichberger and colleagues  described an association between nilotinib therapy and adverse vascular events, particularly peripheral arterial occlusive disease (PAOD). Subsequently, several reports of PAOD with nilotinib were published [2–7] and a case series using mainly data from clinical trials described the frequencies of cardiovascular risk factors in 11 patients . Here we present an original approach of this issue using national pharmacovigilance data to describe the cardiovascular risk profile of cases of PAOD spontaneously reported and related to nilotinib exposure.
2 Methods The French Pharmacovigilance Database (FPVD) was established in 1985 to record spontaneous reporting of adverse drug reactions (ADRs) . For each report, information about the patient (gender, age, past medical history, previous treatment), ADRs (delay in occurrence), and drug exposure are recorded in the FPVD. A detailed summary of the clinical description is added to each pharmacovigilance case report. ADRs are coded according to the Medical Dictionary for Drug Regulatory Activities (MedDRA®) . For each drug, a causality assessment is performed, using the validated method of the French Pharmacovigilance System . This algorithm relies on the evaluation of three main groups of criteria: (i) chronology, i.e., time to event onset, drug dechallenge, and rechallenge, (ii) semiology, i.e., alternative non-drugrelated explanation, clinical signs suggestive of the drug causation, favoring factor, and specific laboratory test, and (iii) bibliography. If causality was found between the
drug and occurrence of the ADR, the drug was defined as Bsuspected.^ We first selected all cases of Bvascular disorders,^ as the System Organ Class in MedDRA®, in which nilotinib was Bsuspected^ and recorded in the FPVD between 2007, the year at which nilotinib was first available in France, and 21 October 2014. We next selected the cases with the following Low Level Terms: Bperipheral arterial occlusive disease,^ Bperipheral obliterative arteriopathy,^ Barterial stenosis,^ Barteriopathic disease,^ Barteritis obliterans,^ Barteriosclerosis obliterans,^ Bischaemia peripheral,^ Bclaudication,^ and Bnecrosis ischaemic.^ Finally we identified cases of PAOD after reading the detailed summary of the clinical description. For each notification of PAOD, we collected data on the patient (gender, age, previous BCR/ABL inhibitors, cardiovascular risk factors), drugs (date of initiation, dose changes), and ADRs (date of occurrence, seriousness, outcome, symptomatic treatment). We calculated means and standard deviations for age. We used the Wilcoxon-Mann Whitney test to compare means.
3 Results As at 21 October 2014 in the FPVD, we found 172 cases of ADRs spontaneously reported where nilotinib was Bsuspected,^ including 29 cases of Bvascular disorders.^ Of these 29 cases, 25 were identified as PAOD. Most patients were older than 60 years (84 %). Among them, there were as many males as females (Fig. 1). Cardiovascular risk factors, i.e., hypercholesterolemia (nine cases), arterial hypertension (eight cases), overweight/obesity (seven cases), smoking (five cases), or diabetes mellitus (three cases), were identified in most females (9/10) and half of the males (6/11). Most patients had two or more cardiovascular risk factors (n = 22, 88 %) and the most frequent combination of cardiovascular risk factors was being male plus age more than 60 years (n = 11, 44 %). Around half of patients with PAOD had previously been treated with another BCR-ABL inhibitor (14/25): imatinib alone (nine), imatinib followed by dasatinib (three), or dasatinib alone (two), but only imatinib and dasatinib were Bsuspected^ in one case. Other drugs were Bsuspected^ in three cases: omacetaxine mepesuccinate, levothyroxine, dabigatran, bisoprolol, furosemide, ramipril, and atorvastatin. Among the four patients aged less than 60 years, we found a woman with no pre-existing cardiovascular risk factors. Before developing PAOD, she had been treated with imatinib for 72 months and then with nilotinib for 49.4 months. The mean delay between initiation of nilotinib and occurrence of PAOD was 24.4 ± 18.7 months in all patients and significantly longer in patients aged less than 60 years compared with patients over 60 years of age (33.8 ± 24.6 months vs. 22.6 ± 17.5 months, p = 0.002). Independent of gender and
Targ Oncol Fig. 1 Flow chart depicting the characteristics of the 25 patients with peripheral arterial occlusive disease (PAOD) during nilotinib therapy
age, delays seemed to be longer in patients without any cardiovascular risk factor than in patients with at least one cardiovascular risk factor (Fig. 2). The shortest delays, 3.8 and Fig. 2 Time between nilotinib initiation and peripheral arterial occlusive disease (PAOD) onset according to gender, age group, and cardiovascular risk factors (arterial hypertension, hypercholesterolemia, overweight/obesity, smoking, or diabetes)
5.3 months, were found in two males, 75 years old and 68 years old, respectively, both with a past medical history of diabetes mellitus and arterial hypertension.
4 Discussion Rare ADRs or those occurring a long time after drug initiation are unlikely to be identified during clinical trials because of the low number of patients or the short follow-up. Analysis of spontaneous reports is the sole method of identifying the early signs of rare ADRs . The largest published series using mainly data from clinical trial includes 11 cases of PAOD in patients receiving nilotinib . Although under-reporting is a usual and well-known limitation of all pharmacovigilance surveys, use of national pharmacovigilance data allowed us to describe 25 cases of PAOD associated with nilotinib therapy. The frequency of nilotinib-associated PAOD in a series of reports ranged between 1.2 % and 33.3 % . We cannot estimate frequency in our study since we do not know the number of patients treated with nilotinib in France. We showed that most patients with PAOD during nilotinib therapy were older than 60 years, and there were as many females as males. Within the general population, age but also male gender are the most important risk factors identified for PAOD [13, 14]. Physicians have to consider women as at-risk patients for PAOD to the same extent as men. We cannot exclude that previous therapy with imatinib predisposed patients to development of PAOD. Imatinib, as nilotinib, is a BCR-ABL, PDGFR, and KIT kinase inhibitor . Furthermore, Tefferi and Letendre  reported a case without any pre-existing cardiovascular risk factors but previously treatment with imatinib over 4 years. Our study showed that the mean time to PAOD onset during nilotinib therapy was 24 months and longer in some patients, particularly those younger than 60 years old. PAOD also occurred a long time after initiation of nilotinib in some published cases but only one was younger than 60 years old [1–4, 6, 7]. Our study shows the need to maintain long-term surveillance in patients aged less than 60 years. The FPVD was a useful tool for describing the cardiovascular risk profile of patients with PAOD during nilotinib exposure. Physicians have to be particularly vigilant in patients older than 60 years of age. The frequency was lower in patients younger than 60 years of age, but long-term surveillance has to be maintained with them. Our study underlines the need to maintain active pharmacovigilance through spontaneous reporting of ADR by physicians. Acknowledgments Dr Laurence Legros (CHU Nice), Pr Antoine Thyss (Centre Antoine Lacassagne, Nice), Dr Emmanuel Petit (Clinique Oxford, Cannes), the National Research Agency (Paris). Compliance with Ethical Standards
Funding This work was supported by the National Research Agency (ANR: Agence Nationale de la Recherche) for the Binvestissement d’avenir^ (ANR-11-PHUC-001). The funding allowed the development of the CAPTOR program (Cancer Pharmacology of Toulouse-Oncopole and Region) and performance of the present study. Conflicts of Interest EB-G, SC, MCP-P, MS-D, HB, FH, FD, AP and JLM declare no conflicts of interest.
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