1. Dual Action Drug for Treatment of Osteoporosis รศ. นพ. ศุภศิลป์ สุนท ราภา ภาควิชาออร์โธปิดิกส์ คณะ แพทยศาสตร์ มหาวิทยาลัยขอนแก่น

2. Therapeutic options for osteoporosis Stimulators of bone formation Parathyroid hormone Inhibitors of bone resorption  Bisphosphonates Alendronate Risedronate Ibandronate Zoledronate Estrogen ± progestin Selective estrogen receptor modulators (SERMs) Raloxifene Denosumab Dual action (formation & resorption) Vitamin D and metabolites ?? Vitamin K ?? Strontium ranelate Recommended for all women at risk for osteoporosis Calcium and vitamin D

3. 5-[bis(carboxymethyl)amino]-2-carboxy-4-cyano-3- thiopheneacetic acid, distrontium salt Ranelic acid (Organic moiety) + 2 Strontium atoms S CN N - OOC COO - Sr 2+ Strontium ranelate

4. | o 40 87

6. To investigate, in human cells, the mechanisms by which strontium ranelate is able to influence the activities of osteoblasts and osteoclastsTo investigate, in human cells, the mechanisms by which strontium ranelate is able to influence the activities of osteoblasts and osteoclasts Objectives

7. Osteoblasts Human primary osteoblasts were used to examine effects of strontium ranelate on replication (thymidine incorporation) differentiation (Runx2 and alkaline phosphatase) cell survival (cell counts)

8. Runx 2 ( Runt-related transcription factor 2 )formerly called Cbfa 1 ( core-binding factor subunit alpha-1 ) is transcription factor that control the expression of genes that are required for a cell to function as an osteoblast Runx 2 ( Runt-related transcription factor 2 ) formerly called Cbfa 1 ( core-binding factor subunit alpha-1 ) is transcription factor that control the expression of genes that are required for a cell to function as an osteoblast Runx 2 is considered a “master regulator” of osteoblast differentiation Runx 2 is considered a “master regulator” of osteoblast differentiation Osteoblast & Bone Formation

9. Strontium ranelate (mM Sr 2+ ) Strontium ranelate increases replication and differentiation of primary human osteoblasts *P<0.05, **P<0.01 vs. Control Alkaline phosphatase activity ** 1Control0.010.12 ALP activity as % of vehicle (corrected per mg total protein) ** Replication Control0.010.11 3 H-Thymidine incorporation (cpm as % of vehicle) 2 * Brennan T, et al. Calcified Tissue Int. 2007;80(Suppl.1):S72-S73 (P132T).

12. Osteoclasts Osteoprotegerin (OPG) and (RANKL)

13. 13 Excess RANK Ligand Can Increase Bone Resorption Leading to Osteoporosis Bone Formation Bone Resorption Activated Osteoclast CFU-GM Prefusion Osteoclast Multinucleated Osteoclast Osteoblasts RANKL RANK OPG Decreased Estrogen Leads to Increased RANK Ligand Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342. © 2009 Amgen. All rights reserved. Do not copy or distribute.

14. 14 OPG Is a Decoy Receptor That Prevents RANK Ligand Binding to RANK and Inhibits Osteoclast Formation, Function, and Survival Bone Formation Bone Resorption Inhibited Osteoclast Formation, Function, and Survival Inhibited CFU-GM Prefusion Osteoclast Osteoblasts RANKL RANK OPG Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342. © 2009 Amgen. All rights reserved. Do not copy or distribute. Estrogen Estrogen limits the expression of RANK Ligand

15. 15 RANK Ligand OPG Reduction in Estrogen Increases RANK Ligand Expression, Causing Increased Bone Resorption Adapted from the following: Boyle WJ, et al. Nature 2003;423:337–342. Eghbali-Fatourechi G, et al. J Clin Invest 2003;111:1221–1230. Increased RANK Ligand in Postmenopausal Women Leads to Excessive Bone Resorption Imbalanced Resorption and Formation Leads to Decreased Bone Mass Osteoblasts Decreased Estrogen increases RANK Ligand expression Decreased Estrogen

16. Protaxos Increases Osteoprotegerin and Decreases RANKL Expressions by Osteoblasts ** P<0.01 vs. Control Primary Human Fœtal Osteoblasts RANKL expression (mRNA % of control) 0 40 80 120 160 Control0.010.11 SR (mM Sr 2+ ) ** OPG Expression (mRNA % of control) ** SR (mM Sr 2+ ) 0 50 100 150 200 Control0.010.11

17. Preplanned analysis Primary analysis International, double-blind, placebo-controlled studies (12 countries) 2g/day of Strontium ranelate given orally All patients received Ca/vitamin D supplement Strontium ranelate M0M12M36M24M48M60 M0M12M36M24M48M60 FIRST (Run-in) (2 weeks-6 months) SOTI Vertebral fractures n=1649 TROPOS Non-vertebral fractures n=5091 (months) Placebo Antifracture efficacy program of Strontium ranelate in postmenopausal osteoporosis

18. Strontium ranelate 2 g/day Strontium ranelate 2 g/day vs placebo All patients received calcium and vitamin D supplementation Efficacy on vertebral fracture(s) Primary end points Efficacy on non-vertebral fracture(s) Efficacy on clinical vertebral fracture(s) Efficacy on vertebral fracture(s) Secondary end points BMD - Bone markers - Tolerability - Quality of lifeBMD - Bone markers - Tolerability SOTI Spinal Osteoporosis Therapeutic Intervention n=1649 TROPOS TReatment Of Peripheral OSteoporosis n=5091 From Meunier PJ, et al. N Engl J Med. 2004;350(5):459-468 From Reginster JY, et al. J Clin Endocrinol Metab. 2005;90(5):2816-2822 Antifracture efficacy program of Strontium ranelate in postmenopausal osteoporosis

19. SOTI Inclusion Criteria  Age at least 50 years old  Postmenopausal for at least five years  Had at least one fracture confirmed by spinal radiography (after minimal trauma)  Lumbar-spine BMD < 0.840 g/cm 2 (measured with Hologic instruments)

20. SOTI: Baseline characteristics Age (years) 69.4  7.2 69.2  7.3 Duration of menopause (years) 22.1  8.8 21.6  8.7 87.5%86.3% Patients with at least one prevalent vertebral fracture 2.2  2.0 2.2  2.2 Number of vertebral fracture(s) / patient - 3.5  1.3 - 3.6  1.2 Lumbar BMD T-score Femoral neck BMD T-score - 2.8  0.8 Strontium ranelate (n=719)Placebo(n=723) Meunier PJ, et al. N Engl J Med. 2004;350(5):459-468 Expressed as mean  standard deviation unless otherwise stated

21. Strontium ranelate reduces vertebral fracture risk from the first year and over 4 years Meunier PJ, et al. Osteoporos Int. 2009;20(10):1663-1673 Meunier PJ, et al. N Engl J Med. 2004;350(5):459-468 ITT population Placebo Strontium ranelate n=1442, RR=0.51 95% CI [0.36; 0.74] ARR=3.8% Patients (%) 0-1 year  RR: - 49%  RR: - 41% 0-3 years n=1442, RR=0.59 95% CI [0.48; 0.73] ARR=11.9% SOTI 0 5 10 15 20 25 30 35 40 10.2 6.4 P<0.001 32.8 20.9 NNT=9  RR: - 33% 0-4 years n=1445, RR=0.67 95% CI [0.55; 0.81] ARR=10% P<0.001 37.1 27.1

22. Strontium ranelate reduces clinical vertebral fracture risk from the first year and over 4 years Meunier PJ, et al. Osteoporos Int. 2009;20(10):1663-1673 Meunier PJ, et al. N Engl J Med. 2004;350(5):459-468  RR: - 38%  RR: - 52% n=1442, RR=0.48 95% CI [0.29; 0.80] ARR=3.3% n=1442, RR=0.62 95% CI [0.47; 0.83] ARR=6.1% P=0.003P<0.001 Patients (%) SOTI  RR: - 36% n=1445, RR=0.64 95% CI [0.49; 0.83] ARR=5.9% P<0.01 6.4 3.1 17.4 11.3 21.0 15.1 Placebo Strontium ranelate ITT population

23. A. shows absolute changes from base-line values in bone-specific alkaline phosphatase B. shows absolute changes from base-line values in C- telopeptide cross-links

24. C. shows differences over time in biochemical markers between Sr vs. placebo

26. Mean+SEM, n=210 sCTXb-ALP ng/mLpmol/L Switch to placebo Months Switch to placebo SOTI Data on file Change in bone markers after treatment stop

27. TROPOS Inclusion Criteria 1) Femoral neck bone mineral density (BMD) 0.600 g/cm 2 or less (measured with Hologic instruments), corresponding to a T-score < -2.5 2) 74 yr or older 70-74 yr but with one additional fracture risk factor (i.e. history of osteoporotic fracture after menopause, residence in a retirement home, frequent falls, or a maternal history of osteoporotic fractures of the hip, spine, or wrist).

28. TROPOS: Baseline characteristics Age (years) 76.7  5.0 76.8  5.0 Time since menopause (years) 28.4  7.3 28.5  7.5 39.3%37.8% Patients with at least one prevalent non-vertebral fracture 1.5  0.9 1.6  0.9 Number of vertebral fracture(s) / patient - 3.1  0.6 Femoral neck BMD T-score Lumbar BMD T-score - 2.8  1.6 Strontium ranelate (n=2479)Placebo(n=2453) Expressed as mean  standard deviation unless otherwise stated Reginster JY, et al. J Clin Endoc Metab. 2005;90(5):2816-2822

29. Strontium ranelate reduces non-vertebral, major non- vertebral and hip fractures over 3 years ITT population  RR: - 19%  RR: - 16% n=4932, RR=0.84 95% CI [0.702; 0.995] ARR=1.7% n=4932, RR=0.81 95% CI [0.66; 0.98] ARR=1.7% P<0.05 Patients (%) TROPOS  RR: - 36% n=1977, RR=0. 64 95% CI [0.412; 0.997] ARR=2.1% P<0.05 12.9 11.2 10.4 8.7 6.4 4.3 Placebo Strontium ranelate Hip, wrist, pelvis and sacrum, ribs-sternum, clavicle, or humerus Patients aged 74 years or more and with femoral neck BMD T-score ≤ − 2.4 SD Reginster JY, et al. J Clin Endoc Metab. 2005;90(5):2816-2822

30. Strontium ranelate increases lumbar spine bone mineral density Relative change from baseline Placebo Strontium ranelate Strontium ranelate Mean change (%) - 4 12 16 0 4 8 061218243036 + 14.4% *** - 4 0 4 8 12 16 061218243036 Mean change (%) + 14.7% *** SOTI TROPOS Meunier PJ, et al. N Engl J Med. 2004;350(5):459-468 Reginster JY, et al. J Clin Endocrinol Metab. 2005;90(5):2816-2822 Months ***P<0.001, hierarchical step-down procedure

31. Strontium ranelate increases femoral neck bone mineral density

33. Preplanned analysis Primary analysis International, double-blind, placebo-controlled studies (12 countries) 2g/day of Strontium ranelate given orally All patients received Ca/vitamin D supplement Strontium ranelate M0M12M36M24M48M60 M0M12M36M24M48M60 FIRST (Run-in) (2 weeks-6 months) SOTI Vertebral fractures n=1649 TROPOS Non-vertebral fractures n=5091 (months) Placebo Antifracture efficacy program of Strontium ranelate in postmenopausal osteoporosis

34. 0 Vertebral fractures Non-vertebral fractures 5 10 15 20 25 30 Patients (%)  RR: - 24%  RR: - 15% 24.9 20.8 P<0.001 20.9 18.6 P=0.032 n=4935, RR=0.85 95% CI [0.73; 0.99] ARR=2.3% n=3646, RR=0.76 95% CI [0.65; 0.88] ARR=4.1% Placebo Strontium ranelate TROPOS Reginster JY, et al. Arthritis Rheum. 2008;58(6):1687-1695ITT population Strontium ranelate decreases vertebral and non-vertebral fractures over 5 years

35. Patients (%)  RR: - 15%  RR: - 18% P=0.032P=0.025 n=4935, RR=0.85 95% CI [0.73; 0.99] ARR=2.3% n=4935, RR=0.82 95% CI [0.69; 0.98] ARR=2.1% Placebo Strontium ranelate Hip, wrist, pelvis/sacrum, ribs/sternum, clavicle, and humerus TROPOS Reginster JY, et al. Arthritis Rheum. 2008;58(6):1687-1695ITT population Strontium ranelate decreases non-vertebral and major non-vertebral fractures over 5 years

37. Reginster JY, et al. Arthritis Rheum. 2008;58(6):1687-1695 Reginster JY, et al. Calcif Tissue Int. 2007;80(Suppl.1):S47 (Abstract P036-T) Patients (%)  RR: - 45%  RR: - 43% P=0.036P=0.049 TROPOS n=1128, RR=0.57 95% CI [0.33; 0.97] ARR=3% n=1128, RR=0.55 95% CI [0.30; 0.99] ARR=2.3% Placebo Strontium ranelate ITT population Patients aged 74 years or more and with femoral neck and lumbar spine BMD T- score ≤ − 2.4 SD Strontium ranelate protects against hip fractures over 3 and 5 years

38. Strontium ranelate increases BMD over 5 years ***P<0.001 Placebo Strontium ranelate + 20.2% *** Relative changes from baseline (%) Relative changes from baseline (%) + 11.3% Placebo *** Femoral neck BMDLumbar spine BMD Strontium ranelate Reginster JY, et al. Arthritis Rheum. 2008;58(6):1687-1695 TROPOS

39. Strontium ranelate increases total hip BMD over 5 yearsPlacebo Strontium ranelate Relative changes from baseline (%) + 14.1% ***P<0.001Reginster JY, et al. Arthritis Rheum. 2008;58(6):1687-1695 *** TROPOS

40. EFFICACY IN THE LONG TERM Over 4 years (SOTI) Over 5 years (TROPOS) Over 8 years Over 10 years

41. 04 Strontium ranelate 358 years Fracture incidence Vertebral & Non-vertebral Anti-fracture efficacy Strontium ranelate vs. Placebo Placebo SOTI TROPOS Assessment of anti-fracture efficacy of Strontium ranelate over 8 years

42. Main Clinical Risk Factors (mean values) Patients treated with Strontium ranelate over 8 years (n=879) Age (years) 73.979.1 25.9 BMI (kg/m²) - 2.41- 2.06 Femoral Neck BMD T-score (NHANES) 19.8%21.5% 10-year fracture probability (mean of all individual probabilities) Baseline visit (M0)Baseline extension visit (M60) SOTI TROPOS Reginster JY, et al. Bone. 2009;45(6):1059-1064 Baseline characteristics and fracture probability of patients treated with Strontium ranelate over 8 years

43. Cumulative incidence 0-3 years* 11.5% Cumulative incidence 5-8 years* 13.7% Fractures incidence (%) *First new fractures on the period ns 23 34 789766731 312923 789766731 SOTI TROPOS Placebo 0-3 years; Incidence of vertebral fractures: 20% Reginster JY, et al. Bone. 2009;45(6):1059-1064 Efficacy of Strontium ranelate against vertebral fractures is sustained over 8 years

44. * Cumulative incidence 0-3 years* 9.6% Cumulative incidence 5-8 years* 12.0% Fractures incidence (%) 271429 726699685 34 17 25 726645554 ns TROPOS *First new fractures on the period Reginster JY, et al. Bone. 2009;45(6):1059-1064 Placebo 0-3 years; Incidence of vertebral fractures: 12.9% Efficacy of Strontium ranelate against non-vertebral fractures is sustained over 8 years

45. Vertebral fracture incidence Non-vertebral fracture incidence 0358 11.5%13.7% ns 11.9%9.6% Maintenance of efficacy over 8 years Strontium ranelate (n=879) SOTI TROPOS time (years) Reginster JY, et al. Bone. 2009;45(6):1059-1064 Strontium ranelate has the longest antifracture efficacy over time (8 years)

46. ***P<0.001 Mean relative change (%) Years Lumbar BMD Mean relative change (%) Femoral neck BMD *** Years Reginster JY, et al. Bone. 2009;45(6):1059-1064 Strontium ranelate increases BMD over 8 years

47. Completers Mean treatment exposure (months) Mean compliance (%) 69% 87.6 ± 11.4 87.9 ± 12.9 Strontium ranelate over 8 years (n=879) Reginster JY, et al. Bone. 2009;45(6):1059-1064 Patients have a good compliance over 8 years to Strontium ranelate

49. Strontium ranelate 01324 Placebo Long term anti-fracture efficacy of strontium ranelate 01324 10 Extention study SOTI TROPOS 5 5 Strontium ranelate 0105 Fracture incidence Vertebral & Non-vertebral

50. Main baseline characteristics of patients treated for 10 years with strontium ranelate Age (years) 72.0 (5.5) 75.0 (6.4) years Any prevalent osteoporotic fracture Lumbar BMD T-score* Femoral Neck BMD T-score* 10-year extension n=233SOTI-TROPOSn=655168.2%63.5% -3.3 (1.4) -3.0 (1.6) -3.0 (0.57) -3.1 (0.67) The patients who received the treatment for 10 years are representative of the whole SOTI and TROPOS population *Slosman reference Reginster JY et al. Osteoporos Int. 2011;22(Suppl.1):S110-S111 (Abstract OC32)

51. 0-5 years period5-10 years period NS Cumulative incidence (%) P=0.016 18.5% 20.6% 28.2% Placebo*Strontium ranelate  RR: - 35% Vertebral fracture incidence over 10 years Cumulative incidence (%) Patients treated over 10 years with Strontium ranelate n=216 n=458 *Placebo from TROPOS matched using FRAX Reginster JY et al. Osteoporos Int. 2011;22(Suppl.1):S110-S111 (Abstract OC32)

52. NS P=0.023 12.9% 13.7% 20.2%  RR: - 38% Non vertebral fracture incidence over 10 years Patients treated over 10 years with Strontium ranelate 0-5 years period5-10 years periodPlacebo*Strontium ranelate n=233 n=458 *Placebo from TROPOS matched using FRAX Cumulative incidence (%) Reginster JY et al. Osteoporos Int. 2011;22(Suppl.1):S110-S111 (Abstract OC32)

53. Relative change in BMD over 10 years with strontium ranelate Mean relative change (%) years Lumbar BMD * * * * * * * * * + 34.5% * * P<0.05 versus previous year Reginster JY et al. Osteoporos Int. 2011;22(Suppl.1):S110-S111 (Abstract OC32)

54. Long-term safety of strontium ranelate Reginster JY et al. Osteoporos Int. 2011;22(Suppl 1):S110-S111 (OC32)

55. ADDITIONAL BENEFITS Tolerability Compliance Back pain Quality of life

56. Strontium ranelate has a Good Tolerability Profile over 5 years Symptoms (% patients) Nausea7.14.6 7.05.0 Diarrhoea 3.32.7 Headache 2.32.0Dermatitis Eczema 1.81.4 Strontium ranelate (n=) (n=3352)Placebo (n=) (n=3317) Annual incidence of VTE 0.90.6 Phase III program Significant differences between groups Post Marketing experience: 1/73 000 patient-year case of hypersensitive reaction (DRESS) DRESS= Drug Rash Eosinophilia and Systemic Symptoms

57. 7.0*7.2* Strontium ranelate (n=2408) Alendronate (n=20084) versus untreated osteoporotic population RR**=1.09 [0.60-2.01] P=0.773 RR**=0.92 [0.63-1.33] P=0.646 * Annual incidence for 1000 patients-years ** Relative risk adjusted on age and main risk factors for VTE Bréart G et al. Osteoporos Int. 2010 (In press) Strontium ranelate and alendronate do not increase the incidence of VTE in osteoporotic patients (GPRD)

58. 3.2*5.6* Non Osteoporotic Population (n=115009) Untreated Osteoporotic population (n=11546) RR**=1.38 [1.03-1.86] P=0.030 * Annual incidence for 1000 patients-years ** Relative risk adjusted on age and main risk factors for VTE Bréart G et al. Osteoporos Int. 2010 (In press) Increase in incidence of VTE in osteoporotic patients as compared to non osteoporotic population (GPRD)

59. Meunier PJ, et al. N Engl J Med. 2004;350(5):459-468 Reginster JY, et al. J of Clin Endoc Metab. 2005;90(5):2816-2822 Mean Compliance  SD (%) TROPOSSOTI Placebo Strontium ranelate Placebo 86  16 85  17 81  27 83  26 Patients have a good compliance over 5 years to Strontium ranelate

60. 13,069 postmenopausal osteoporotic women (unselected population) treated with Strontium ranelate 68.9 years, 42 % with one prevalent vertebral fracture Persistence After 12 months: 80% After 24 months: 70% Incidence of VTE below the incidence of the pooled population of phase III studies No case of severe hypersensitivity reaction Compliance for Strontium ranelate in the current medical practice Bréart G, et al. Osteoporos Int. 2010;21(S1):S166 (Abstract P416)

61. Effect on vertebral fracture risk Effect on non-vertebral fracture risk Osteoporosis Established osteoporosis (a) Osteoporosis Established osteoporosis (a) Strontium ranelate+ Risedronate Alendronate Ibandronate Zoledronic acid HRT Raloxifene Teriparatide and PTH + + (including hip b ) + (including hip b ) + (including hip ) + + + + NA + + + NA + + + + + + + NA NA NA + ++ NA NA NA + + (b) Adapted from: J. Kanis et al. Osteoporos Int. 2008;19(4):399-428 (a) women with a prior vertebral fracture, (b) In subsets of patients European guidance for diagnosis and management of osteoporosis in postmenopausal women

62. March 2012Positive benefit-risk balance of Strontium ranelate confirmed by European Medicines Agency July 2012Creation of the PRAC (Pharmacovigilance Risk Assessment Committee) November 2012Submission of the 13th annual PSUR incorporating new data from clinical studies in male osteoporosis and osteoarthritis Numerical imbalance in myocardial infarction (MI) in a small number of patients (3 patients with MI vs 1 in MALEO, and 5 vs 1 in SEKOIA) Request for supplementary information concerning the cardiac safety of Strontium ranelate including all available data Context

63. Post-menopausal osteoporotic women Strontium ranelatePlacebo N=3803 (11269.6 PY)N=3769 (11250.1 PY) SMQ Myocardial Infarction (Standard MedDRA Queries) n (%)64 (1.7)40 (1.1) Per 1000 PY5.73.6 OR [95% CI]1.60 [1.07; 2.38] Fatal Myocard. Infarct. n (%)10 (0.3) SMQ Ischaemic Heart Disease n (%)325 (8.5)299 (7.9) Per 1000 PY28.826.6 OR [95% CI]1.08 [0.92; 1.28] SMQ Embolic & thrombotic arterial events n (%)143 (3.8)132 (3.5) Per 1000 PY12.711.7 OR [95% CI] 1.18 [0.85;1.37] Cardiovascular death n (%) 80 (2.1)81 (2.1) Per 1000 PY 7.17.2 OR [95% CI] 0.98 [0.71;1.34] Sudden death n (%) 18 (0.5)30 (0.8) Per 1000 PY 1.62.7 OR [95% CI] 0.59 [0.33; 1.06] MI or CV death n (%)132 (3.5)108 (2.9) Per 1000 PY11.79.6 OR [95% CI]1.22 [0.94;1.58] Total mortality n (%)146 (3.8)142 (3.8) Per 1000 PY13.012.6 OR [95% CI]1.02 [0.80;1.29] Isolated increase in non fatal Myocardial Infarction in PMO women N : number of patients and number of patient–years (PY) by group n(%) : number of patients with at least one emergent AE Per 1000 PY : number of patients with at least one AE per 1000 PY OR [95% CI]: odds ratio and confidence interval (Mantel-Haenszel estimate)

64. Signal only seen in randomised clinical trials No signal in real world No signal in Post-marketing (3 402 769 PY) No signal in Prescription-Event Monitoring (DSRU) 10 865 treated with strontium ranelate (9 534 PY) No signal in observational Cohort over 3 years 12 076 treated with Strontium ranelate (24 956 PY) No signal in nested case-control study in CPRD database Cohort of 141 221 OP-treated patients 6 177 treated with Strontium ranelate (3 903 PY)

65. Cardiac safety in the subgroup of patients without history of IHD, nor DBP > 90 mmHg, nor SBP > 160 mmHg 59% of Post-menopausal osteoporotic women Strontium ranelatePlacebo N=2238 (6467.5 PY)N=2192 (6393.8 PY) SMQ Myocardial Infarction (Standard MedDRA Queries) n (%)20 (0.9)19 (0.9) Per 1000 PY3.13.0 OR [95% CI]1.04 [0.55;1.95] Fatal Myocard. Infarct. n (%)3 (0.1)5 (0.2) SMQ Ischaemic Heart Disease n (%)95 (4.2)107 (4.9) Per 1000 PY14.716.7 OR [95% CI]0.86 [0.65;1.15] SMQ Embolic & thrombotic arterial events n (%)68 (3.0)65 (3.0) Per 1000 PY10.510.2 OR [95% CI]1.03 [0.73;1.45] CV death n (%) 39 (1.7)36 (1.6) Per 1000 PY 6.05.6 OR [95% CI] 1.06 [0.67;1.68] Sudden death n (%) 8 (0.4)17 (0.8) Per 1000 PY 1.22.7 OR [95% CI] 0.46 [0.20;1.06] N : number of patients and number of patient–years (PY) by group n(%) : number of patients with at least one emergent AE Per 1000 PY : number of patients with at least one AE per 1000 PY OR [95% CI]: odds ratio and confidence interval (Mantel-Haenszel estimate)