Κολπική μαρμαρυγή και διφωσφονικά. Ενας ακόμη μύθος!

Δρ, Αχιλ. Ε. Γεωργιάδης, ρευματολόγος
Διευθυντής κέντρου μυοσκελετικών παθήσεων,
Γυναικολογικό Νοσοκομείο ΛΗΤΩ, Αθήνα
axikos@hotmail.com

Πριν μερικά χρόνια στην μελέτη Horizon που έγινε για την τεκμηρίωση της δράσης του Ζολεδρονικού οξέος στην αύξηση της οστικής μάζας και στην μείωση των καταγμάτων παρατηρήθηκε μια σημαντική αύξηση των επεισοδίων καρδιακών αρρυθμιών. Το εύρημα αυτό προκάλεσε εντύπωση διότι δεν βρέθηκε κανένας παράγοντας που να μπορούσε να το προκαλέσει στους συγκεκριμένους ασθενείς.
Σήμερα παρουσιάζουμε 3 πρόσφατες εργασίες που δείχνουν ότι τα διφωσφονικά συμπεριλαμβανομένου και του Ζολεδρονικού οξέος δεν προκαλούν καρδιακές αρρυθμίες οποιουδήποτε τύπου.
Η πρώτη αφορά μια αναζήτηση από την Division of Cardiac and Vascular Sciences, St. George's University of London, London, UK. jcamm@sgul.ac.uk,  στο PubMed από το 1991 έως το 2009 για προκλινικές ή κλινικές μελέτες που αφορούσε την σχέση όλων των διφωσφονικών με καρδιακές επιπλοκές. Τα αποτελέσματα έδειξαν ότι εκτός από την συγκεκριμένη μελετη που αναφέραμε, καμμιά άλλη τόσο του Ζολεδρονικού οξέος, όσο και της Αλενδρονάτης και της Ριζεδρονάτης δεν παρουσίασε αύξηση των καρδιακών αρρυθμιών στους ασθενείς που ελάμβαναν τα φάρμακα.
Η δεύτερη αποτελεί μελέτη από University of California, San Diego, La Jolla, CA, USA, ebarrettconnor@ucsd.edu. και αφορά μια μεταανάλυση όλων των διπλών τυφλών μελετών που έκανε η Merck τα τελευταία χρόνια για την Αλενδρονάτη. Τα αποτελέσματα έδειξαν ότι δεν υπάρχει κάποια σχέση μεταξύ Αλενδρονάτης και καρδιακών αρρυθμιών για οπoiοαδήποτε δόση και για οποιαδήποτε διάρκεια θεραπείας.
Τέλος η τρίτη από το Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehangno, Jongno-Gu, Seoul, 110-799, South Korea  και βασίστηκε σε στοιχεία των υπηρεσιών υγείας της Κορέας. Τα αποτελέσματα έδειξαν ότι η συχνότητα της κολπικής μαρμαρυγής στους ασθενείς που ελάμβαναν διφωσφονικά (120.319 ασθενείς) ήταν 0,52%, ενώ στους ασθενείς (9863 ασθενείς) που ελάμβαναν κάποιο άλλο αντιοστεοπορωτικό φάρμακο ήταν 0,67%. Η περαιτέρω ανάλυση των στοιχείων έδειξε ότι ίσως η Αλενδρονάτη να αποτελεί και προστατευτικό παράγοντα για την εκδήλωση κολπικής μαρμαρυγής.
Το τελικό συμπέρασμα από αυτές τις μελέτες είναι ότι τα διφωσφονικά δεν προκαλούν καρδιακές αρρυθμίες οποιουδήποτε τύπου και το μόνο θετικό της αρχικής μελέτης ήταν ότι μας ανάγκασε να ψάξουμε για την σχετική ανεπιθύμητη ενέργεια και να την αποκλείσουμε.

Για να κρίνουν οι αναγνώστες μας και μόνοι τους παραθέτουμε ολόκληρα τα abstracts των σχετικών μελετών που προαναφέραμε.

John Camm A., Review of the cardiovascular safety of zoledronic acid and other bisphosphonates for the treatment of osteoporosis. Clin Ther. 2010 Mar;32(3):426-36.

Division of Cardiac and Vascular Sciences, St. George's University of London, London, UK. jcamm@sgul.ac.uk

Abstract
BACKGROUND: In 2 large, randomized, placebocontrolled trials, yearly 5-mg infusions of the bisphosphonate zoledronic acid were associated with increased bone mineral density and reduced fracture incidence in patients with osteoporosis, previous fracture, or both. Objective: This review evaluated the cardiovascular risks of bisphosphonates (with a focus on zoledronic acid) for the treatment of osteoporosis and put these potential risks into perspective, summarizing available evidence from randomized clinical trials.
METHODS: A search of PubMed (1991-September 2009) for preclinical and clinical trials was conducted using the following search terms: arrhythmia, atrial fibrillation, bisphosphonate, osteoporosis, cardiovascular adverse events, bone mineral density, fracture incidence, stroke, alendronate, etidronate, ibandronate, risedronate, and zoledronic acid. New analyses using unpublished data from the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) and Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Recurrent Fracture Trial (HORIZON-RFT) were also performed to evaluate the cardiovascular risk of zoledronic acid using stepwise Cox proportional hazards regression and risk modeling. After selection of risk factors for the model, treatment-by-factor interactions were evaluated at the 0.10 level of significance.
RESULTS: Atrial fibrillation (AF) serious adverse events (SAEs) were observed among more patients receiving zoledronic acid (1.3%) than placebo (0.5%) over 36 months in HORIZON-PFT (P 0.001), but the overall incidence of AF events was not significantly different between groups. The timing of AF SAEs did not correspond with drug administration or the pharmacokineti profile of the drug. Nearly all women with sick sinus syndrome had predisposing conditions. An electrocardiography study after the third yearly infusion found no differences between those who received zoledronic acid versus placebo. Cardiovascular deaths, stroke, and other nonarrhythmia cardiovascular adverse events (AEs) were not significantly different between groups,
but arrhythmia was more common in the zoledronic acid group than in the placebo group (6.9% vs 5.3%; P = 0.003). In analyses of pooled data from HORIZON-PFT and HORIZON-RFT to determine risk factors associated with the likelihood of experiencing AF, atrial flutter, or stroke, the only treatment-by-factor interaction was age (hazard ratio = 0.963; P or =85 years, AF AEs occurred in 5.9% of the placebo group and 5.3% of the zoledronic acid group. Preclinical and other clinical trials of zoledronic acid for the treatment of osteoporosis or other indications did not identify an effect on AF AEs. A reanalysis of risedronate controlled clinical trials found no difference in the incidence of AF among active-treatment or placebo groups. In alendronate trials, AF SAEs occurred in 1.5% of the alendronate group and 1.0% of the placebo group (P = 0.07); the overall incidence of AF AEs was similar.
CONCLUSION: Despite the greater incidence of AF SAEs among zoledronic acid recipients versus placebo recipients in one study (not observed in other trials of this agent), clinical data for zoledronic acid, risedronate, and alendronate indicate no significant differences from placebo in overall incidence of AF AEs.

Barrett-Connor E, Swern AS, Hustad CM, Bone HG, Liberman UA, Papapoulos S, Wang H, de Papp A, Santora AC. Alendronate and atrial fibrillation: a meta-analysis of randomized placebo-controlled clinical trials.Osteoporos Int. 2011 Mar 3.

University of California, San Diego, La Jolla, CA, USA, ebarrettconnor@ucsd.edu.

Abstract
In this meta-analysis of all Merck-conducted, placebo-controlled clinical trials of alendronate, the occurrence of AF was uncommon, with most studies reporting two or fewer events. Across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious AF was observed.
INTRODUCTION: To explore the incidence of atrial fibrillation (AF) and other cardiovascular endpoints in clinical trials of alendronate.
METHODS: All double-blind, placebo-controlled studies of alendronate 5, 10, or 20 mg daily, 35 mg once-weekly, 35 mg twice-weekly, and 70 mg once-weekly of at least 3 months duration conducted by Merck were included in this meta-analysis. The primary method of analysis was exact Poisson regression. Estimated relative risk (RR) of alendronate versus placebo and the associated 95% confidence interval was derived from a model that included number of episodes with factors for treatment group and study and an offset parameter for number of person-years on study.
RESULTS: Of 41 studies considered, 32 met all criteria for inclusion in the analysis (participants-9,518 alendronate, 7,773 placebo). Estimated RR for all AF events was 1.16 (95% CI = 0.87, 1.55; p = 0.33). Most trials had two or fewer AF events. The RR of AF classified as a serious adverse event was 1.25 (95% CI = 0.82, 1.93; p = 0.33), but became 0.97 (95% CI = 0.51, 1.85) when the clinical fracture cohort of the Fracture Intervention Trial was excluded, indicating that results were driven by events in that study. Estimated RRs for other cardiovascular endpoints were less than 1.
CONCLUSIONS: The incidence of atrial fibrillation was low in Merck clinical trials of alendronate and was not significantly increased in any single trial nor in the meta-analysis. Based on this analysis, alendronate use does not appear to be associated with an increased risk of atrial fibrillation

Rhee CW, Lee J, Oh S, Choi NK, Park BJ. Use of bisphosphonate and risk of atrial fibrillation in older women with osteoporosis. Osteoporos Int. 2011 Mar 24.

Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehangno, Jongno-Gu, Seoul, 110-799, South Korea.

Abstract
Concerns have been raised among clinicians and patients whether or not bisphosphonates increase the risk of atrial fibrillation. In this large cohort study, increased risk of atrial fibrillation was not found to be associated with bisphosphonate. In fact, bisphosphonate even showed a protective effect against cardiac arrhythmia compared to other osteoporosis medications.
INTRODUCTION: Increased risk of atrial fibrillation among bisphosphonate users has been reported; however, the results from these studies are controversial. The purpose of this study was to evaluate the risk of atrial fibrillation associated with bisphosphonate use in older women.
METHODS: We used the Korean Health Insurance Review and Assessment Service claims database from May 1, 2005 to June 30, 2006. Retrospective cohort analysis was conducted on women 65 years or older with newly diagnosed cases of osteoporosis (ICD 10 code: M80, M81) who had not previously taken any medications for osteoporosis. Bisphosphonate-exposed and non-exposed patients were followed until they were either diagnosed with atrial fibrillation (ICD 10 code: I48) or until the end of the study. The Cox proportional hazards model was used to calculate hazard ratios and the 95% confidence intervals.
RESULTS: Atrial fibrillation was reported in 626 of the 120,319 patients (0.52%) treated with bisphosphonates and 66 of 9,863 patients (0.67%) treated with other osteoporosis medications. Overall hazard ratio for developing atrial fibrillation in the bisphosphonate-treated group was 0.52 (95% CIs, 0.29-0.91). In patients with a medication possession ratio greater than 0.7, the hazard ratio was lower (HR 0.41, 95% CIs 0.23-0.75). In the subgroup analysis, alendronate showed a statistically significant protective effect against the risk of atrial fibrillation with a hazard ratio of 0.75 (95% CI, 0.58-0.97).
CONCLUSION: Among older Korean women with osteoporosis, bisphosphonate was found to have a protective effect against atrial fibrillation.