Appendix Table. List of Studies of Use of Bisphosphonates (BP) and Risk of Atrial Fibrillation

Appendix Table. List of studies of use of Bisphosphonates (BP) and risk of Atrial fibrillation (AF)

Author / Study Design / Source Population / Total n / Mean age / Drug Exposure / Adverse Event / OR/RR/HR/events
Black et al, (2007)[1] / Double-blind, placebo-controlled trial / Postmenopausal osteoporotic women / 7714 / BP :73.1 NonBP use: 73.0 / Zolendronic acid (ZA) / Serious AF / 50 patients ZA vs 20 patients treated with placebo. (1.3% versus 0.5% ; p<.001)
Cummings et al, (2007)[2] / Double-blind, placebo-controlled trial / Postmenopausal women / 6459 / 69 / Alendronate (AL) / Serious AF / 47 AL patients vs 31 patients treated with placebo. (1.5% versus 1.0% ; p<.07).
Karam et al, (2007)[3] / Double-blind, placebo-controlled trial / Patients with osteoporosis / 10068 / BP :73.5 NonBP use: 73.4 / Risedronate (RI) 5mg / Serious AF / 29 RI patients vs 24 patients treated with placebo (0.6% versus 0.5%; p<0.49)
Lyles et al, (2007)[4] / Double-blind, placebo-controlled trial / Patients with a hip fracture / 2111 / BP :74.4 NonBP use: 74.6 / Zolendronic acid (ZA) / Serious AF / 12 ZA patients vs 14 patients treated with placebo(1.1% versus 1.3%; p<0.84)
Lewiecki EM et al,(2010)[5] / Clinical Trial / Postmenopausal osteoporotic women / 8754 / BP use: 67
Non BPuse: 68.7 / Ibandronate (IB) / AF / 57 IB patients vs 18 patients treated with placebo (0.8% versus 0.9%)
Black et al, (2012)[6] / Double-blind, placebo-controlled trial / Postmenopausal osteoporotic women / 1229 / 75.5 / Zolendronic acid (ZA) / Serious AF / 12 Z6-patients vs 7 Z3P3-patients treated with placebo (Z6 2.0% versus 1.1% in ZA3P3; p.0.26)
Heckbert et al, (2008)[7] / Population based Case Control study / Women in a clinical practice setting in Washington State. / 1685 / cases: 75
controls: 71 / Alendronate / Incident AF / Ever users OR 1.86;95%CI (1.09-3.15)
Sorensen et al, (2008)[8] / Population based Case Control study / Hospital Discharge in Denmark 1999-2005 / 81640 / ≤70, 70+ / Etidronate and alendronate / AF and flutter / Current: RR: 0.95 , 95%CI (0.84-1.07)
Former: RR: 1.04 , 95%CI (0.90-1.21)
Grosso et al, (2009)[9] / Self Controlled Case Series / Female patients registered in the General Practice Research Database (GPRD) in the UK Dec 2004 -Dec 2006 / 2195 / 82 / Alendronate and Risedronate / AF and flutter / Overall IRR 1.07, 95%CI (0.94-1.21) Alendronate IRR 1.09, 95%CI (0.93–1.26) Risedronate IRR 0.99, 95%CI 0.78–1.26)
Hodgkinson et al (2011)[10] / Case Control study / Adults aged 18 years and older registered in the (GPRD) in the UK. / 271812 / 18+ / NA / AF / Current RR 0.95,95% CI (0.85 -1.07) Recent RR 1.08, 95% CI (0.96–1.21) Past RR 0.99 ,95% CI 0.88–1.11)
Abrahamsen et al, (2009)[11] / Population based Cohort study / Fractures patients from the National Hospital Discharge Register in Denmark 1996-2005 / 43033 / 74.3 / Alendronate and Risedronate / Probable AF and AF / PA :HR 1.18 95% CI (1.08-1.29) AF : HR 1.13 95% CI (1.01-1.26)
Bunch et al, (2009)[12] / Prospective databases / Angiographic database & Patients registered at Intermountain at Heart Collaborative Study from 1993 to 2008 / 9623
37485 / cases: 59.2
controls: 64.8 &
cases: 51.1
controls: 52.0 / Alendronate, Ibandronate, zoledronic,acid,zolendronic, risedronate and etidronate / AF / HR 0.90, 95% CI (0.48-1.68) & HR 0.82, 95% CI (0.66-1.01)
Vestergaard et al, (2010)[13] / Population based Retrospective cohort / Bisphosphonates users from Denmark between 1996-2006 / 414245 / 70.5 / Raloxifine, Etidronate, Alendronate / AF and flutter / Raloxifene OR 0.98, 95%CI (0.72-1.33) Etidronate OR 1.04, 95%CI (0.98-1.10)*
Alendronate OR 1.05, 95%CI (0.96-1.15)**adjusted by COPD
Huang et al, (2010)[14] / Population based Retrospective cohort / Osteoporotic women in Taiwan registered on the National Health Insurance / 27257 / BP useAL:73.93
BPuseRA: 73.64 / Alendronate and raloxifene / AF / Alendronate HR 1.06 , 95%CI (0.85-1.32)
Wilkinson et al, (2010)[15] / Retrospective cohort study / Cancer patients / 20571 / 65+ / Intravenous BP / AF / HR 1.30, 95%CI (1.18-1.43)
Pazianas et al, (2011)[16] / Retrospective cohort study / Women exposed to bisphosphonates comprised in three independent databases during 2002-2005. / 144548 / Range 50-89 / Alendronate and Risedronate / AF / Overall HR 0.93, 95%CI (0.88-0.99) HR 0.92, 95%CI (0.84-1.00)
HR 0.94, 95%CI (0.78-1.13)
HR 0.64, 95%CI (0.28-1.46)
Lu PY et al, (2011)[17] / Population based
Retrospective cohort / Osteoporotic women during 2002-2006. / 6343 / AL 10mg: 74.78 AL 70mg: 75.23 / Alendronate Raloxifene / AF / AL 10mg HR 1.66, 95%CI (1.12-2.46)
Erichsen et al, (2011)[18] / Population based
cohort study / Cancer patients during 2000-2008 in Denmark / 11887 / 65.5 / Intravenous Zolendronic andPamidronate / AF / HR 1.7, 95% CI (1.2-2.4)
Rhee et al, (2012)[19] / Population based
Retrospective cohort / Osteoporotic women in Taiwan registered Korean Health Insurance between 2005 -2006 / 120319 / BP use :72.95
BPuseOS: 72.64 / Alendronate, Risedronate, Pamidronate, Etidronate. / AF / HR 0.52, 95%CI (0.29-0.91)
Kim et al, (2010)[20] / Meta-analysis / 3 Cohort studies+3 Case control+1 Self Controlled Case series / 266761 / ≈ 70.5 / Alendronate,Etidronate,Ibandronate,Risedronate and Zoledronic acid / AF / Overall OR 1.04, 95%CI% (0.92-1.16)
Loke et al, (2009)[21] / Meta-analysis / 4Randomized controlled trials (RCTs) +2 Case-control studies. / RCT = 26,352
OS= 83,325 / RCT ≈ 72 / Alendronate,Risedronate and Zoledronic acid / Serious AF / OR 1.47, 95%CI (1.01-2.14)
Bhuriya R et , (2010)[22] / Meta-analysis / 4Randomized controlled trials (RCTs) + 3 Population based case control studies / 26,126 / ≈ 72.3 / Alendronate, Risedronate and Zoledronic acid / Serious AF / RR 1.525, 95% CI (1.166 to 1.997; p=0.002)
Mak et al, (2009)[23] / Meta-analysis / 4 RCTs +2 reports of RCTs+3 observational studies (OB) / RCT =40,104
OB=126,233 / RCT ≈ 69.7
OS≈ 74.3 / zoledronate, ibandronate, alendronate, risedronate, etidronate, pamidronate clodronate / AF and
Serious AF / Overall RCT: OR 1.184, 95% CI (0.84-1.66) RCT: OR 1.590, 95% CI (0.61-3.75) OB: OR 1.251 , 95%CI (0.98-1.73)
Barrett-Connor et al, (2012)[24] / Meta-analysis / Placebo Controlled Clinical Trials / 17291 / OS≈ 63 / Alendronate / AF and Serious AF / Overall RR 1.16 , 95%CI (0.87-1.55) Serious RR1.25,95% CI( 0.82, 1.93; p = 0.33)
Sharma A et al (2013)[25] / Meta-analysis / 6 observational studies (OB) + 6 RCT / OB= 149856
RCT= 41375 / OB≈ 64.8
RCT≈ 71.83 / OB:Alendronate, clorodronate, etidronate, ibandronate, risedronate, pamidronate, zolendronate
RCT:Zolendronic acid, alendronate, risedronate and ibandronate. / AF / OB : OR1.27 95% CI (1.16-1.39)
RCT: OR 1.40 95%CI (1.02-1.93)

References

1. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356 (18):1809-1822. doi:356/18/1809 [pii]10.1056/NEJMoa067312

2. Cummings SR, Schwartz AV, Black DM (2007) Alendronate and atrial fibrillation. N Engl J Med 356 (18):1895-1896. doi:356/18/1895 [pii]10.1056/NEJMc076132

3. Karam R, Camm J, McClung M (2007) Yearly zoledronic acid in postmenopausal osteoporosis. N Engl J Med 357 (7):712-713; author reply 714-715

4. Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S (2007) Zoledronic Acid in Reducing Clinical Fracture and Mortality after Hip Fracture. N Engl J Med 357:nihpa40967. doi:10.1056/NEJMe074941

5. Lewiecki EM, Cooper C, Thompson E, Hartl F, Mehta D, Papapoulos SE (2010) Ibandronate does not increase risk of atrial fibrillation in analysis of pivotal clinical trials. Int J Clin Pract 64 (6):821-826. doi:10.1111/j.1742-1241.2010.02335.x

6. Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, Cummings SR, Hue TF, Lippuner K, Lakatos P, Leung PC, Man Z, Martinez RL, Tan M, Ruzycky ME, Su G, Eastell R (2012) The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 27 (2):243-254. doi:10.1002/jbmr.1494

7. Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM (2008) Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 168 (8):826-831. doi:168/8/826 [pii]10.1001/archinte.168.8.826

8. Sorensen HT, Christensen S, Mehnert F, Pedersen L, Chapurlat RD, Cummings SR, Baron JA (2008) Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study. BMJ 336 (7648):813-816. doi:bmj.39507.551644.BE [pii]10.1136/bmj.39507.551644.BE

9. Grosso A, Douglas I, Hingorani A, MacAllister R, Smeeth L (2009) Oral bisphosphonates and risk of atrial fibrillation and flutter in women: a self-controlled case-series safety analysis. PLoS One 4 (3):e4720. doi:10.1371/journal.pone.0004720

10. Hodgkinson JA, Taylor CJ, Hobbs FD (2011) Predictors of incident atrial fibrillation and influence of medications: a retrospective case-control study. Br J Gen Pract 61 (587):e353-361. doi:10.3399/bjgp11X578034

11. Abrahamsen B, Eiken P, Brixen K (2009) Atrial fibrillation in fracture patients treated with oral bisphosphonates. J Intern Med 265 (5):581-592. doi:JIM2065 [pii]10.1111/j.1365-2796.2008.02065.x

12. Bunch TJ, Anderson JL, May HT, Muhlestein JB, Horne BD, Crandall BG, Weiss JP, Lappe DL, Osborn JS, Day JD (2009) Relation of bisphosphonate therapies and risk of developing atrial fibrillation. Am J Cardiol 103 (6):824-828. doi:S0002-9149(08)02092-4 [pii]10.1016/j.amjcard.2008.11.037

13. Vestergaard P, Schwartz K, Pinholt EM, Rejnmark L, Mosekilde L (2010) Risk of atrial fibrillation associated with use of bisphosphonates and other drugs against osteoporosis: a cohort study. Calcified tissue international 86 (5):335-342. doi:10.1007/s00223-010-9349-0

14. Huang WF, Tsai YW, Wen YW, Hsiao FY, Kuo KN, Tsai CR (2010) Osteoporosis treatment and atrial fibrillation: alendronate versus raloxifene. Menopause 17 (1):57-63. doi:10.1097/gme.0b013e3181b34749

15. Wilkinson GS, Baillargeon J, Kuo YF, Freeman JL, Goodwin JS (2010) Atrial fibrillation and stroke associated with intravenous bisphosphonate therapy in older patients with cancer. J Clin Oncol 28 (33):4898-4905. doi:10.1200/JCO.2010.28.7524

16. Pazianas M, Cooper C, Wang Y, Lange JL, Russell RG (2011) Atrial fibrillation and the use of oral bisphosphonates. Therapeutics and clinical risk management 7:131-144. doi:10.2147/TCRM.S17899

17. Lu PY, Hsieh CF, Tsai YW, Huang WF (2011) Alendronate and raloxifene use related to cardiovascular diseases: differentiation by different dosing regimens of alendronate. Clinical therapeutics 33 (9):1173-1179. doi:10.1016/j.clinthera.2011.07.012

18. Erichsen R, Christiansen CF, Froslev T, Jacobsen J, Sorensen HT (2011) Intravenous bisphosphonate therapy and atrial fibrillation/flutter risk in cancer patients: a nationwide cohort study. Br J Cancer 105 (7):881-883. doi:10.1038/bjc.2011.338

19. Rhee CW, Lee J, Oh S, Choi NK, Park BJ (2012) Use of bisphosphonate and risk of atrial fibrillation in older women with osteoporosis. Osteoporos Int 23 (1):247-254. doi:10.1007/s00198-011-1608-z

20. Kim SY, Kim MJ, Cadarette SM, Solomon DH (2010) Bisphosphonates and risk of atrial fibrillation: a meta-analysis. Arthritis Res Ther 12 (1):R30. doi:ar2938 [pii]10.1186/ar2938

21. Loke YK, Jeevanantham V, Singh S (2009) Bisphosphonates and atrial fibrillation: systematic review and meta-analysis. Drug safety : an international journal of medical toxicology and drug experience 32 (3):219-228. doi:10.2165/00002018-200932030-00004

22. Bhuriya R, Singh M, Molnar J, Arora R, Khosla S (2010) Bisphosphonate use in women and the risk of atrial fibrillation: a systematic review and meta-analysis. Int J Cardiol 142 (3):213-217. doi:10.1016/j.ijcard.2009.11.041

23. Mak A, Cheung MW, Ho RC, Cheak AA, Lau CS (2009) Bisphosphonates and atrial fibrillation: Bayesian meta-analyses of randomized controlled trials and observational studies. BMC Musculoskelet Disord 10:113. doi:1471-2474-10-113 [pii]10.1186/1471-2474-10-113

24. Barrett-Connor E, Swern AS, Hustad CM, Bone HG, Liberman UA, Papapoulos S, Wang H, de Papp A, Santora AC (2012) Alendronate and atrial fibrillation: a meta-analysis of randomized placebo-controlled clinical trials. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 23 (1):233-245. doi:10.1007/s00198-011-1546-9

25. Sharma A, Chatterjee S, Arbab-Zadeh A, Goyal S, Lichstein E, Ghosh J, Aikat S (2013) Risk of serious atrial fibrillation and stroke with use of bisphosphonates: Evidence from a meta-analysis. Chest. doi:10.1378/chest.13-0675

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