98
Resubmit JAMA Cards 01 Sep 2017 1 1 Clinical Efficacy and Safety of Evolocumab in Patients with Baseline LDL-C 2 < 70 mg/dL and non-HDL-C > 100 mg/dL, and in Patients Already on 3 Maximal Statin: An Analysis from FOURIER 4 5 Robert P. Giugliano, Anthony C. Keech, Sabina A. Murphy, Kurt Huber, S. Lale Tokgozoglu, 6 Basil S. Lewis, Jorge Ferreira, Armando Lira, Ransi Somaratne, Peter S. Sever, Terje R 7 Pedersen, and Marc S. Sabatine 8 9 Author Affiliations: Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical 10 School, Boston, Massachusetts (Giugliano, Sabatine, Murphy), Sydney Medical School, 11 NHMRC Clinical Trials Centre, University of Sydney, Australia (Keech), 3 rd Department of 12 Medicine, Cardiology, and Intensive Care Medicine and Sigmund Freud University, Medical 13 School, Vienna, Austria (Huber), Hacettepe University Faculty of Medicine, Department of 14 Cardiology, Güven Sokak No: 9, Kavaklidere 06540, Ankara, Turkey (Tokgozoglu), Lady Davis

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1 Clinical Efficacy and Safety of Evolocumab in Patients with Baseline LDL-C

2 < 70 mg/dL and non-HDL-C > 100 mg/dL, and in Patients Already on

3 Maximal Statin: An Analysis from FOURIER

4

5 Robert P. Giugliano, Anthony C. Keech, Sabina A. Murphy, Kurt Huber, S. Lale Tokgozoglu,

6 Basil S. Lewis, Jorge Ferreira, Armando Lira, Ransi Somaratne, Peter S. Sever, Terje R

7 Pedersen, and Marc S. Sabatine

8

9 Author Affiliations: Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical

10 School, Boston, Massachusetts (Giugliano, Sabatine, Murphy), Sydney Medical School,

11 NHMRC Clinical Trials Centre, University of Sydney, Australia (Keech), 3rd Department of

12 Medicine, Cardiology, and Intensive Care Medicine and Sigmund Freud University, Medical

13 School, Vienna, Austria (Huber), Hacettepe University Faculty of Medicine, Department of

14 Cardiology, Güven Sokak No: 9, Kavaklidere 06540, Ankara, Turkey (Tokgozoglu), Lady Davis

15 Carmel Medical Center, Haifa, Israel (Lewis), Hospital de Santa Cruz, Lisbon, Portugal

16 (Ferreira), International Centre for Circulatory Health, National Heart and Lung Institute,

17 Imperial College London, United Kingdom (Sever), Amgen, Thousand Oaks, California (Lira,

18 Somaratne), and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo,

19 Norway (Pedersen)

20

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21 Corresponding Author: Robert P. Giugliano, MD, SM, TIMI Study Office, 60 Fenwood Road,

22 Suite 7122, Boston, MA 02115 ([email protected]).

23

24 Text word count: 1522

25 References: 15

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26 KEY POINTS

27

28 Question. Do patients with stable atherosclerotic cardiovascular disease treated with statin who

29 have an LDL-C <70 mg/dL and a non-HDL-C > 100 benefit from the addition of evolocumab?

30 Would patients already on maximal potency statin benefit from evolocumab?

31 Findings. Evolocumab safely reduced cardiovascular events compared to placebo whether

32 patients were starting with an LDL-C <70 mg/dL or not, and whether they were treated with

33 maximal potency statin or a less potent statin regimen.

34 Meaning. In high-risk patients with stable atherosclerotic cardiovascular disease treated with a

35 statin, even patients who have a low LDL-C and patients on maximal statin experience further

36 reduction of cardiovascular events with the addition of evolocumab.

37

38

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39 ABSTRACT

40 IMPORTANCE. Current guidelines focus on high-intensity statins and targeting or using a

41 threshold an LDL-C <70 mg/dL for highest risk patients. Whether further LDL-C reduction

42 beyond these boundaries would be beneficial is unknown.

43 OBJECTIVE. To compare outcomes with evolocumab vs. placebo in 2 subgroups of patients

44 with stable atherosclerotic cardiovascular disease: 1) Baseline LDL-C <70 and non-HDL-C >100

45 mg/dL, 2) Background treatment with maximal potency statin.

46 DESIGN. Comparison of randomized treatments in 2 subgroups from a large clinical trial.

47 SETTING. Patients with stable atherosclerotic cardiovascular disease on statin enrolled in the

48 FOURIER trial.

49 PARTICIPANTS. Patients were classified by baseline LDL-C <70 or >70 mg/dL, and by statin

50 intensity (maximal: atorvastatin 80 mg or rosuvastatin 40 mg daily, submaximal: all others).

51 MAIN OUTOCMES AND MEASURES: The primary efficacy end point was the composite of

52 cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or

53 coronary revascularization. The key secondary efficacy end point was the composite of

54 cardiovascular death, myocardial infarction, or stroke. Safety outcomes included adverse events

55 and special events of interest as identified in the FOURIER trial. Interaction testing was used to

56 assess the consistency of results in patients who did vs. did not satisfy the above criteria.

57 RESULTS. Of 2034 patients (7.4%) who had a baseline LDL-C <70 mg/dL and HDL-C >100

58 mg/dL, evolocumab reduced the risk of the primary endpoint (hazard ratio [HR], 0.80; 95% CI

59 0.60-1.07) to a similar degree as in the 25,529 patients who had a baseline LDL-C >70 mg/dL

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60 (HR 0.86; 95% CI 0.79-0.92; PINT=0.65). Of 7533 patients (27.3%) on maximal intensity statin,

61 evolocumab significantly reduced the primary (hazard ratio [HR], 0.86; 95% CI 0.75-0.98) to a

62 similar degree as in the 20,031patients not on maximal intensity statin (HR for primary endpoint

63 0.85; 95% CI 0.78-0.93; PINT=0.88). The key secondary endpoint was also reduced to a similar

64 degree in both analyses. No major safety concerns were identified.

65 Conclusions. Evolocumab was equally effective in reducing cardiovascular events in patients

66 with stable atherosclerotic cardiovascular disease regardless of whether the baseline LDL-C was

67 <70 or >70 mg/dL, and whether the background statin was maximal intensity or not.

68

69 Abstract word count: 350

70

71

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72 Several guidelines endorse a target LDL cholesterol (LDL-C) <70 mg/dL (to convert to

73 millimoles per liter, multiply by 0.0259) or a threshold for treatment ≥70 mg/dL in highest risk

74 patients for secondary prevention of cardiovascular events.1-4 Likewise, high-intensity statin

75 regimens (i.e., atorvastatin ≥40 or rosuvastatin ≥20 mg/d) are recommended as foundational

76 therapy. Whether even more intensive LDL-C lowering would benefit patients who already have

77 an LDL-C <70 mg/dL or patients who are currently being treated not just with high, but with

78 maximal intensity statin therapy (highest doses possible), is unknown. We explored the efficacy

79 and safety of evolocumab vs. placebo in such patients in the FOURIER trial.5,6

80

81 Methods

82 Study Design and Treatment

83 The design of FOURIER has been reported.5,6 In brief, 27,564 patients with prior myocardial

84 infarction (MI), non-hemorrhagic stroke, or symptomatic peripheral artery disease, as well as

85 additional characteristics that placed them at higher cardiovascular risk (including one major and

86 two minor criteria5), were randomized to the PCSK9 inhibitor evolocumab or placebo. Eligible

87 patients had either an LDL-C >70 mg/dL or a non-HDL cholesterol >100 mg/dL at the end of

88 screening while on a moderate or high intensity statin (defined as atorvastatin >20 mg/d or

89 equivalent). LDL-C was calculated based on the Friedewald equation, unless the calculated value

90 was <40 mg/dL or the measured triglycerides were >400 mg/dL, in which case

91 ultracentrifugation was performed In the current analysis, we compared outcomes with

92 evolocumab vs. placebo in 2 subgroups: (1) patients with a baseline LDL-C (the average of the

93 values obtained at the final screening visit and the day of randomization) <70 vs. ≥70 mg/dL; (2)

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94 patients on maximal potency background statin (i.e., atorvastatin 80 mg or rosuvastatin 40 mg

95 daily) at randomization. Ethics Committee approvals for the FOURIER trial were obtained from

96 all relevant organizations and each patient provided written informed consent.

97 Study Outcomes

98 The primary endpoint of FOURIER was the composite of cardiovascular death, MI, stroke,

99 hospitalization for unstable angina, or coronary revascularization; the key secondary endpoint

100 was the composite of cardiovascular death, MI or stroke.5,6 Safety endpoints included overall

101 adverse events as well as adverse events of interest including allergic and injection site reactions;

102 and adverse events related to muscle symptoms, elevations in creatine kinase or transaminases,

103 cataracts, new-onset diabetes, and neurocognitive events.

104 Statistical Analysis

105 Baseline categorical variables were compared using 2 or Fisher exact tests and continuous

106 variables using Wilcoxon rank-sum test. Efficacy analyses were performed in the intention-to-

107 treat population including all patients who underwent randomization and provided written

108 informed consent. Hazard ratios and 95% confidence intervals of the time to the first efficacy

109 event were generated using a Cox proportional-hazards model, and P values for time-to-event

110 analyses were calculated using log-rank tests. Safety evaluations included all the patients who

111 underwent randomization, received at least one dose of a study agent and for whom post-dose

112 data were available. Interaction testing was performed using Cox models for efficacy endpoints

113 and logistic regression for safety endpoints.

114

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115 Results

116 Patients with a baseline LDL-C <70 mg/dL

117 A total of 2034 (7.4%) of patients had a baseline LDL-C <70 mg/dL and non-HDL-C >100

118 mg/dL. Compared to patients with LDL-C >70 mg/dL at baseline, these patients tended to be

119 younger (62.1 vs. 62.5 years), heavier (88 vs. 85 kg), more likely male (80 vs. 75%) and to have

120 had a prior stroke (21 vs. 19%), hypertension (82 vs. 80%), diabetes (49 vs. 36%), and metabolic

121 syndrome (73 vs. 58%) (Table 1). The median baseline (IQR) LDL-C was 65.5 (61-68) mg/dL.

122 At 48 weeks, the least-squares mean percentage reduction in LDL-C with evolocumab, as

123 compared with placebo, was 66%, for a mean absolute reduction of 42 mg/dL, to a median of 21

124 [11.5-37] mg/dL. Evolocumab reduced the risk of the primary composite endpoint by 20% (HR

125 0.80, 95% CI 0.60-1.07) in patients with a baseline LDL-C <70 mg/dL, and by 14% (HR 0.86,

126 95% CI 0.79-0.92) in patients with an LDL-C >70 mg/dL, with no evidence of treatment effect

127 modification by baseline LDL-C (PINT 0.65, Figure 1). Likewise, evolocumab reduced the risk

128 of the key secondary endpoint by 30% (HR 0.70, 95% CI 0.48-1.01) in patients with a baseline

129 LDL-C <70 mg/dl, and by 19% (HR 0.81, 95% CI 0.73-0.89) in patients with an LDL-C >70

130 mg/dL, with no evidence for treatment effect modification due to baseline LDL-C (PINT 0.44).

131 There was no heterogeneity for any of the individual outcomes (Supplemental Table 2). Likewise

132 there was no heterogeneity in the safety profile of evolocumab as a function of baseline LDL-C

133 (Table 1).

134 Patients on maximal intensity statin

135 A total of 7533 (27.3%) of patients were on a maximal intensity statin (baseline characteristics in

136 Supplemental Table 3). The median baseline (IQR) LDL-C was 93 (80-111.5) mg/dL. At 48

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137 weeks, the least-squares mean percentage reduction in LDL-C levels with evolocumab, as

138 compared with placebo, was 58%, for a mean absolute reduction of 57 mg/dL, to a median of 32

139 [20-49] mg/dL. Evolocumab reduced the risk of the primary composite endpoint by 14% (HR

140 0.86, 95% CI 0.75-0.98) in patients on maximal intensity statin therapy, and by 15% (HR 0.85,

141 95% CI 0.78-0.93) in patients treated with sub on maximal statin therapy, with no evidence of

142 treatment effect modification due to background statin intensity (PINT 0.88, Figure 2). Likewise,

143 evolocumab reduced the risk of the key secondary endpoint by 22% (HR 0.78, 95% CI 0.66-

144 0.92) in patients on maximal intensity statin therapy, and by 19% (HR 0.81, 95% CI 0.72-0.90)

145 in patients on less potent statin regimens, with no evidence for treatment effect modification due

146 to intensity of background statin therapy (PINT 0.71). There was no heterogeneity for any of the

147 individual outcomes (Supplemental Table 4). Likewise there was no heterogeneity in the safety

148 profile of evolocumab as a function of intensity of background statin therapy (Table 1)

149

150 Discussion

151 The principal findings of this analysis were that high-risk patients with stable atherosclerotic

152 cardiovascular disease who were treated with statins derived similar clinical benefit with the

153 addition of evolocumab over 2.2 years median follow-up, regardless of whether the baseline

154 LDL-C was below or above 70 mg/dL, and regardless of the intensity of background statin

155 (maximal vs. submaximal). Given the FOURIER entry criteria, the patients enrolled with LDL-C

156 <70 mg/dL were required to have a non-HDL-C >100 mg/dL, thus as expected, these patients

157 were more likely to have diabetes or metabolic syndrome and on average were younger with

158 more cardiovascular risk factors.

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159 These findings extend prior observations reported with other lipid-lowering therapies. For

160 statins, the meta-analysis by the Cholesterol Treatment Trialists Collaboration7 noted consistent

161 benefit in patient starting with an LDL-C <2 mmol/L or 77 mg/dL, but given the range of

162 baseline LDL-C in these trials, very few patients would have had an LDL-C <70 mg/dL. The

163 JUPITER trial did report consistent benefit of statin therapy in patients starting with an LDL-C

164 ≤60 mg/dL, but there were only 511 individuals in that subgroup and the comparator was

165 placebo.8 We have recently shown that the addition of ezetimibe to background moderate

166 intensity statin (simvastatin 40 mg) in the IMPROVE-IT trial reduced cardiovascular events by

167 6.4% over an average of 6 years in patients post ACS, with consistent benefit even among

168 patients in the lowest quartile of baseline LDL-C (<64 mg/dL)9, however the achieved LDL-C in

169 that subgroup with the combination of ezetimibe + simvastatin was 45 mg/dL.10 More recently,

170 the HPS3/TIMI55-REVEAL Collaborative Group reported that patients with stable

171 atherosclerotic disease with a mean LDL-C of 61 mg/dL who were randomized to the CETP-

172 inhibitor anacetrapib, reduced LDL-C levels to a mean of 53 mg/dL and experienced an 11%

173 reduction in major coronary events compared to placebo.11 In this analysis we now show

174 consistent benefit not only when starting with an LDL-C <70 mg/dL, but when it is lowered by

175 66% to a median of 21 mg/dL, with 25% of patients having an LDL-C <11.5 mg/dL.

176 The consistent clinical benefit seen with randomized allocation to lipid-lowering therapy

177 that reduced LDL-C to unprecedented low levels <20 mg/dL supports and extends observational

178 analyses that have shown that lower achieved levels of LDL-C were associated with lower rates

179 of major cardiovascular events, most recently down to this same range of <20 mg/dL.12-14

180 Moreover, prior to FOURIER, no non-statin therapy had shown clinical benefit on a background

181 of maximal statin therapy. Lastly, and equally important, the safety profile of evolocumab was

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182 consistent regardless of baseline LDL-C or intensity of statin therapy. It is important to note that

183 all patients in FOURIER were at high-risk and those with an LDL-C <70 mg/dL were required to

184 have a non-HDL-C >100 mg/dL; whether patients at lower risk or with LDL-C <70 mg/dl and

185 non-HDL-C levels <100 mg/dL would have similar benefit requires additional studies.

186 Conclusions

187 Evolocumab safely reduced cardiovascular events in patients with stable atherosclerotic

188 cardiovascular disease to a similar degree whether the baseline LDL-C was above or below 70

189 mg/dL, and regardless of whether the background statin was maximal intensity or not. These

190 findings support using evolocumab beyond what is recommended in current guidelines and,

191 more broadly, the value of lowering LDL-C down to levels ~20 mg/dL15 even in those high-risk

192 patients starting below current guideline targets or thresholds for treatment.

193

194 Funding/Support: This FOURIER trial was supported by a research grant from Amgen,

195 Thousand Oaks, CA. No funding was provided for preparation of this manuscript.

196 Role of the Funder/Sponsor: The FOURIER trial was designed, conducted, and managed in a

197 collaborative effort between the FOURIER Executive and Steering Committees, the FOURIER

198 Investigators, and the sponsor, Amgen. The sponsor played no role in the analysis and

199 interpretation of the data; preparation, review, or approval of the manuscript; and decision to

200 submit the manuscript for publication.

201 Disclaimer: This work is solely the responsibility of the authors.

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202 Additional Contributions: We are indebted to all the patients who participated in the study, the

203 FOURIER Trial investigators, and members of the Data Safety Monitoring, Lipid Monitoring,

204 and Clinical Endpoint Committees. For a full list of the Trial Investigators, please see the

205 Supplemental Appendix

206 Access to Data and Data Analysis: Drs Giugliano and Sabatine had full access to all the data in

207 the study and take responsibility for the integrity of the data and the accuracy of the data

208 analysis.

209 Data Analysis: The data analysis was conducted by Ms. Sabina Murphy of the TIMI Study

210 Group, Brigham and Women’s Hospital, Boston, MA.

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References

Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. European heart journal. 2016;37(39):2999-3058.Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. Journal of the American College of Cardiology.2016;68(1):92-125.Orringer CE, Jacobson TA, Saseen JJ, et al. Update on the use of PCSK9 inhibitors in adults: Recommendations from an Expert Panel of the National Lipid Association. Journal of clinical lipidology. 2017.Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1-45.Sabatine MS, Giugliano RP, Keech A, et al. Rationale and design of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk trial. American heart journal. 2016;173:94-101.Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. The New England journal of medicine. 2017;376(18):1713-1722.Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681.Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Journal of the American College of Cardiology. 2011;57(16):1666-1675.Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. The New England journal of medicine. 2015;372(25):2387-2397.Giugliano RP, Cannon CP, Blazing MA, et al. Baseline LDL-C and clinical outcomes with addition of ezetimibe to statin in 18,144 patients post ACS. Journal of the American College of Cardiology. 2015;65(10S):A4.Group HTRC. Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. The New England journal of medicine. 2017.Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. Journal of the American College of Cardiology. 2014;64(5):485-494.Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL- cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017.Giugliano RP, Wiviott SD, Blazing MA, et al. Long-term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol : A Prespecified Analysis of the IMPROVE-IT Trial. JAMA Cardiol. 2017;2(5):547-555.Sabatine MS, Giugliano RP. Low-Density Lipoprotein Cholesterol Treatment in the Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Era: Getting Back on Target. JAMA Cardiol. 2017.

211

212 1.213214 2.215216217218219 3.220221222 4.223224225226 5.227228229 6.230231 7.232233234 8.235236237238 9.239240 10.241242243 11.244245 12.246247248 13.249250251 14.252253254 15.255

256

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257 Table 1: Patient Characteristics Stratified by Baseline LDL-Ca and Background Statin Intensity

Baseline LDL-C Baseline Statin IntensityCharacteristics <70 mg/dLb

(N=2034)> 70 mg/dL (N=25529) P

Maximal (N=7533)

Submaximal (N=20031) P

Age, mean + SD – yr 62.1 + 9.2 62.5 + 9.0 0.051 61.1 + 8.9 63.0 +9.0 <0.001Weight, mean + SD – kg 88.2 + 18.2 85.0 + 17.2 <0.001 88.2 + 17.6 84.2 + 17.2 <0.001Male 1632 (80.2) 19162 (75.1) <0.001 5722 (76.0) 15073 (75.2) 0.22White racec 1708 (84.0) 21749 (85.2) 0.14 7027 (93.3) 16431 (82.0) <0.001Region <0.001 <0.001

North America 348 (17.1) 4223 (16.5) 1877 (24.9) 2694 (13.4)Europe 1226 (60.3) 16108 (63.1) 4862 (64.5) 12473 (62.3)Latin America 178 (8.8) 1645 (6.4) 180 (2.4) 1643 (8.2)Asia, Pacific, South Africa 282 (13.9) 3553 (13.9) 614 (8.2) 3221 (16.1)

Type of atherosclerosisd

Myocardial infarction 1591 (78.2) 20759 (81.3) <0.001 6499 (86.3) 15852 (79.1) <0.001Non-hemorrhagic stroke 430 (21.1) 4907 (19.2) 0.035 1182 (15.7) 4155 (20.7) <0.001Peripheral artery disease 276 (13.6) 3366 (13.2) 0.62 1012 (13.4) 2630 (13.1) 0.51

Cardiovascular risk factorsHypertension 1673 (82.3) 20410 (80.0) 0.012 6019 (79.9) 16065 (80.2) 0.57Diabetes mellitus 987 (48.5) 9093 (35.6) <0.001 2536 (33.7) 7545 (37.7) <0.001Metabolic syndrome 1481 (72.8) 14869 (58.2) <0.001 4501 (59.8) 11850 (59.2) 0.38Current cigarette use 544 (26.7) 7232 (28.3) 0.13 2067 (27.4) 5710 (28.5) 0.079

TIMI Risk Score for secondary prevention e

Mean + SD, points 3.4 + 1.2 3.3 + 1.2 <0.001 3.3 + 1.3 3.3 + 1.2 0.002Statin intensity at baselinee 0.023 NA

High 1365 (67.1) 17737 (69.5) 7533 (100) 11570 (57.8)Atorvastatin 80 or rosuvastatin 40 mg 524 (25.8) 7008 (27.5) 0.10 7533 (100) 0

Moderate 667 (32.8) 7725 (30.3) 0 8392 (41.9)Low, unknown, or no data 2 (0.1) 67 (0.3) 0 69 (0.3)

Ezetimibe 83 (4.1) 1357 (5.3) 0.016 672 (8.9) 768 (3.8) <0.001Other cardiovascular medications

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Aspirin, P2Y12 inhibitor, or both 1875 (92.2) 23556 (92.4) 0.77 7122 (94.6) 18310 (91.5) <0.001Beta-blocker 1582 (77.8) 19232 (75.4) 0.017 6056 (80.4) 14759 (73.8) <0.001Renin-angiotensin-aldosterone inhibitor 1626 (79.9) 19906 (78.1) 0.047 6016 (79.9) 15517 (77.5) <0.001

Median [IQR] lipid measures, mg/dLLDL cholesterol 65.5

[61.0, 68.0]93.5

[82.0. 110.5]NA 93.0

[80.0, 111.5]91.0

[79.5, 107.5]<0.001

Total cholesterol 141.0[132.0, 152.0]

170.0[153.5, 190.5]

NA 168.0[150.5, 190.5]

167.0[151.0, 187.5]

0.004

HDL cholesterol 38.5[32.5. 47.0]

44.0[37.5, 52.5]

NA 43.0[36.5, 51.5]

44.0[37.0, 53.0]

<0.001

Triglycerides 181.0[115.0, 252.0]

131.0[99.5, 177.0]

NA 133.0 [98.5,181.0]

133.0[100.0, 182.0]

0.19

LDL C < 70 mg/dL at baseline 2034 (100) 0 NA 524 (7.0) 1510 (7.5) 0.10258 Baseline LDL-C data were not available for one patient.259 Maximal statin potency indicates either atorvastatin 80 mg or rosuvastatin 40 mg daily. All other statin regimens were considered260 submaximal.261 Date shown are n (%) unless otherwise specified262 aThere were no nominally significant differences between the randomized treatments in either group stratified by baseline LDL263 cholesterol. There were no nominally significant differences between the randomized treatments in either group stratified by baseline264 maximal statin potency except for baseline triglycerides and aspirin use in the submaximal subgroup (both p=0.05).265 bBy trial design, these patients were required to have a non-HDL-C > 100 mg/dL266 cRace was reported by the patients267 dPatients could have more than one type of atherosclerosis268 eCalculated as described by Bohula E et al. Circulation 2016;134: 304-13.269 fStatin intensity was categorized in accordance with the guidelines of the American College of Cardiology and American Heart270 Association4

271 HDL high-density lipoprotein, IQR interquartile range, LDL low-density lipoprotein, NA not applicable, and SD standard deviation272 SI conversion factors: to convert cholesterol (total, LDL, and HDL) to millimoles per liter, multiply by 0.0259; to convert triglycerides273 to millimoles per liter, multiply by 0.0113.274

275

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276 Table 2 – Safety Outcomes With Evolocumab vs. Placebo Stratified by Baseline LDL-C and Potency of Background Statin

Baseline LDL-C <70 mg/dLa

(N=2033) Baseline LDL-C >70 mg/dL (N=25491)

Outcome Evolocumab (N=1030)

Placebo (N=1003)

Evolocumab (N=12739)

Placebo (N=12752)

Serious adverse event 268 (26.0) 274 (27.3) 3142 (24.7) 3130 (24.5)Adverse event related to study drug and leading to drug discontinuation

19 (1.8) 19 (1.9) 207 (1.6) 182 (1.4)

Injection site reaction 30 (2.9)b 16 (1.6) 266 (2.1)a 203 (1.6)

Muscle-related event 49 (4.8) 60 (6.0) 633 (5.0) 596 (4.7)

Cataract 19 (1.8) 16 (1.6) 209 (1.6) 226 (1.8)

New onset diabetes, CEC adjudicatedc 45/509 (8.8) 53/475 (11.2) 632/7828 (8.1) 591/7864 (7.5)

Neurocognitive event 17 (1.7) 12 (1.2) 200 (1.6) 190 (1.5)

AST or ALT > 3 times normal 27 (2.7) 23 (2.3) 213 (1.7) 219 (1.7)

Creatine kinase >5 times normal 9 (0.9) 9 (0.9) 86 (0.7) 90 (0.7)

Maximal Potency Background Statin (N=7524)

Submaximal Potency Background Statin (N=20001)

Evolocumab (N=3754)

Placebo (N=3770)

Evolocumab (N=10015)

Placebo (N=9986)

Serious adverse event 979 (26.1) 1010 (26.8) 2431 (24.3) 2394 (24.0)Adverse event related to study drug and leading to drug discontinuation

53 (1.4) 53 (1.4) 173 (3.7) 148 (1.5)

Injection site reaction 84 (2.2) 68 (1.8) 212 (2.1)a 151 (1.5)

Muscle-related event 207 (5.5) 194 (5.1) 475 (4.7) 462 (4.6)

Cataract 53 (1.4) 64 (1.7) 175 (1.7) 178 (1.8)

New onset diabetes, CEC adjudicatedc 214/2385 (9.0)a 176/2383 (7.4) 463/5952 (7.8) 468/5956 (7.9)

Neurocognitive event 64 (1.7) 63 (1.7) 153 (1.5) 139 (1.4)

AST or ALT > 3 times normal 84 (2.3) 81 (2.2) 156 (1.6) 161 (1.6)

Creatine kinase >5 times normal 28 (0.8) 33 (0.9) 67 (0.7) 66 (0.7)

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277 Baseline LDL-C is not available for one patient. 39 patients who did not receive study drug are excluded.278 Data shown are n (%), unless otherwise indicated.279 a By trial design, these patients were required to have a non-HDL-C > 100 mg/dL280 b Nominal P value <0.05 vs. placebo281 c Patients with prevalent diabetes were excluded282 There were no significant treatment – subgroup interactions for either LDL-C at baseline or potency of background statin.283 ALT, alanine aminotransferase; AST, aspartate aminotransferase284 To convert LDL-C values from mg/dL to millimoles per liter, multiply by 0.0259.285286287

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288

289 Figure Legend

290

291 Figure. Efficacy Outcomes Stratified by Baseline LDL-C (Panels A and B) and by statin

292 intensity (Panels C and D). Panel A shows the hazard ratios and 95% confidence intervals at 3

293 years are shown for the primary (cardiovascular death, myocardial infarction, stroke,

294 hospitalization for unstable angina, and coronary revascularization) and the secondary

295 (cardiovascular death, myocardial infarction, and stroke) efficacy composite endpoints in the

296 total population and in patients with baseline LDL-cholesterol <70 mg/dL mad with non-HDL-C

297 > 100 mg/dL versus LDL-cholesterol > 70 mg/dL. Evolocumab significantly reduced both

298 composite endpoints to a similar degree regardless of the baseline LDL-cholesterol. Panel B

299 shows the cumulative event rate of the key secondary endpoint with evolocumab compared with

300 placebo in patients with baseline LDL-cholesterol <70 mg/dL and non-HDL-C >100 mg/dL.

301 Panel C shows the hazard ratios and 95% confidence intervals at 3 years are shown for the

302 primary (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina,

303 and coronary revascularization) and the secondary (cardiovascular death, myocardial infarction,

304 and stroke) efficacy composite endpoints in the total population and in patients on patient treated

305 with maximal and submaximal background statin therapy. Maximal statin therapy represents

306 either atorvastatin 80 mg or rosuvastatin 40 mg daily. Evolocumab significantly reduced both

307 composite endpoints to a similar degree regardless of the potency of background statin. Panel D

308 shows the cumulative event rate of the key secondary endpoint with evolocumab compared with

309 placebo in patients treated with maximal potency statin. To convert LDL-C values from mg/dL

310 to millimoles per liter, multiply by 0.0259.

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N=2034

Hazard ratio 0.70(95% CI, 0.48-1.01)

Placebo

Evolocumab

311 Figure 1

Figure 1A. Efficacy Outcomes Stratified by Baseline LDL-C

Primary Composite Endpoint HR (95% CI) Pinteraction

All Patients 0.85 (0.79-0.92)

Baseline LDL-C <70 mg/dL 0.80 (0.60-1.07)Baseline LDL-C ≥70 mg/dL 0.86 (0.79-0.92) 0.65

0.4 1.0 2.5

Secondary Composite Endpoint

All Patients 0.80 (0.73-0.88)

Baseline LDL-C <70 mg/dL 0.70 (0.48-1.01)Baseline LDL-C ≥70 mg/dL 0.81 (0.73-0.89) 0.44

0.4 1.0 2.5Evolocumab better Placebo better

312

Figure 1B. Cardiovascular Death, Myocardial Infarction, or Stroke in Patients with Baseline LDL Cholesterol <70 mg/dL

9%

8%7.7%

7%

6%

5% 5.2%

4%

3%

2%

1%

0%

313

314

315

CV

Dea

th, M

I, St

roke

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0 6 1224 30

Months from Randomization

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N=7533

Hazard ratio 0.78(95% CI, 0.66-0.92) Placebo

Evolocumab

316

Figure 1C. Efficacy Outcomes Stratifiedby Potency of Background Statin

Primary Composite Endpoint HR (95% CI) Pinteraction

All Patients 0.85 (0.79-0.92)

On maximum intensity statin 0.86 (0.75-0.98)

On less intense statin 0.85 (0.78-0.93) 0.88

0.4 1.0 2.5

Secondary Composite Endpoint

All Patients 0.80 (0.73-0.88)

On maximum intensity statin 0.78 (0.66-0.92)

On less intense statin 0.81 (0.72-0.90) 0.71

0.4 1.0 2.5Evolocumab better Placebo better

317

Figure 1D. Cardiovascular Death, Myocardial Infarction, or Strokein Patients on Maximal Potency Background Statin

10%

9%

8%

7%

6%

8.9%

6.8%

5%

4%

3%

2%

1%

0%

318319

0 6 12 18 24 30Months from Randomization

CV

Dea

th, M

I, St

roke

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320 On-Line Supplement – Table of Contents

321

322 List of Investigators

323 Table S1. Efficacy Outcomes With Evolocumab vs. Placebo Stratified by Baseline LDL-C

324 Table S2. Efficacy Outcomes With Evolocumab vs. Placebo Stratified Potency of325 Background Statin

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326 List of FOURIER Investigators

327 Steering Committee and National Lead Investigators328 Jose Luis Accini Mendoza (Colombia), John Amerena (Australia), Jolita Badariene (Lithuania),329 Lesley Burgess (South Africa), Richard Ceska (Czech Republic), Min-Ji Charng (Taiwan),330 Donghoon Choi (South Korea), Jorge Leonardo Cobos (Chile), Gheorghe Andrei Dan331 (Romania), Gaetano M. De Ferrari (Italy), Prakash C. Deedwania and Vijay Kumar Chopra332 (India), Andrejs Erglis (Latvia), Marat Vladislavovich Ezhov (Russia), Jorge Ferreira (Portugal),333 Slavomíra Filipová (Slovakia), Zbigniew A. Gaciong (Poland), Borislav Georgiev Georgiev334 (Bulgaria), Robert P. Giugliano (United States), Guillermo Gonzalez-Galvez (Mexico), Ioanna335 Gouni-Berthold (Germany), Atsushi Hirayama (Japan), Kurt Huber (Austria), Henrik Kjaerulf336 Jensen (Denmark), Lixin Jiang (China), J. Wouter Jukema (Netherlands), Oleg Kraydashenko337 (Ukraine), Lawrence A. Leiter (Canada), Basil S. Lewis (Israel), José López-Miranda (Spain),338 Alberto J. Lorenzatti (Argentina), François Mach (Switzerland), Brendan McAdam (Ireland),339 Lennart Nilsson (Sweden), Terje R. Pedersen (Norway), Loukianos Rallidis (Greece), Gregorio340 G. Rogelio (Philippines), José Francisco Kerr Saraiva (Brazil), André Scheen (Belgium),341 François Schiele (France), Peter S. Sever (United Kingdom), Chung-Wah Siu (Hong Kong),342 Leslie Tay (Singapore), Gudmundur Thorgeirsson (Iceland), Matti J. Tikkanen (Finland), S. Lale343 Tokgozoglu (Turkey), Kalman Toth (Hungary), Margus Viigimaa (Estonia), Wan Azman Wan344 Ahmad (Malaysia)345346 Site Investigators by Country347 Participating Enrolling Centers: Included below are representatives from the 1242 enrolling348 centers in 49 participating countries. Countries are listed alphabetically. Within each country349 centers are listed in order of enrollment contribution.350351 Argentina:352 I. Mackinnon, Instituto de Investigaciones Clinicas Mar del Plata, Mar del Plata; D. R. Vogel,353 Instituto de Investigaciones Clinicas Bahia Blanca, Bahia Blanca; R. Leon de la Fuente, Centro354 Cardiovascular Salta, Salta; E. Perna, Instituto de Cardiologia de Corrientes Juana Francisca355 Cabral, Corrientes; M. Amuchastegui, Hospital Privado Centro Medico de Cordoba, Cordoba; F.356 Pacora, Centro Medico Colon, Cordoba; A. Hershson, Fundacion Favaloro, Ciudad Autonoma de357 Buenos Aires; A. Lorenzatti, Instituto Medico DAMIC - Fundacion Rusculleda, Córdoba; E.358 Blumberg, Centro de Medicina Integral e Investigacion Clinica Medeos, Ciudad Autonoma de359 Buenos Aires; J. A. Glenny, Center Clinical and Basic Research, Ciudad Autonoma de Buenos360 Aires; H. Colombo, Clinica Privada Colombo, Cordoba; J. A. Cuadrado, Framingham Centro361 Medico, La Plata; L. Nicolosi, Hospital Español de Buenos Aires, Ciudad Autonoma de Buenos362 Aires; C. G. Rojas, Center Clinical and Basic Research, San Miguel de Tucuman; M. R. Ulla,363 Instituto Latinoamericano de Investigaciones Medicas, Cordoba; E. G. Hasbani, Investigaciones364 Clinicas Tucuman, San Miguel de Tucuman; C. Cuneo, Cardiomed, Salta; R. G. Lopez Santi,365 Fundacion Ciclo, La Plata; H. D. Sanabria, Centro de Osteopatias Medicas, Ciudad Autonoma de366 Buenos Aires; A. Hrabar, Instituto de Investigaciones Clinicas Quilmes Sociedad de367 Responsabilidad Limitada, Quilmes; A. Lozada, Fundacion para la Lucha contra las368 Enfermedades Neurologicas de la Infancia, Ciudad Autonoma de Buenos Aires.369370 Australia:371 A. Begg, SA Heart, Ashford, SA; S. Lehman, Adelaide Medical Research, Ashford, SA; G.

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372 Wittert, Royal Adelaide Hospital, Adelaide, SA; C. Juergens, Liverpool Hospital, Liverpool,373 NSW; K. Kostner, Dr Heart Pty Ltd, Woolloongabba, QLD; J. Beltrame, The Queen Elizabeth374 Hospital, Woodville South, SA; J. Amerena, Barwon Health Geelong Hospital, Geelong, VIC; R.375 Simpson, C. Gilfillan, S. L. Goh, J. Y. Mah, Eastern Health, Box Hill Hospital, Box Hill, VIC;376 A. Sinhal, Heart and Vascular Institute, Fullarton, SA; M. Adams, Royal Prince Alfred Hospital,377 Camperdown, NSW; L. Kritharides, Concord Repatriation General Hospital, Concord, NSW; P.378 Roberts Thomson, Royal Hobart Hospital, Hobart, TAS; D. Cross, HeartCare Partners,379 Auchenflower, QLD; P. Thompson, Sir Charles Gairdner Hospital, Nedlands, WA; W. Van380 Gaal, The Northern Hospital, Epping, VIC; N. Cox, Footscray Hospital, Footscray, VIC; A.381 Farshid, Canberra Hospital, Woden, ACT; C. Hammett, Royal Brisbane and Womens Hospital,382 Herston, QLD; P. Garrahy, Princess Alexandra Hospital, Woolloongabba, NSW; A. Prasan, St383 George Hospital, Kogarah, NSW; M. Horrigan, Austin Health, Austin Hospital, Heidelberg,VIC.384385 Austria:386 C. Ebenbichler, Medizinische Universitaet Innsbruck, Innsbruck; U. Hanusch, Zentrum fuer387 klinische Studien - Dr. Hanusch GmbH, Wien; R. Prager, Krankenhaus Hietzing mit388 Neurologischem Zentrum Rosenhuegel, Wien; G. Schernthaner, Medizinische Universitaet389 Wien, Wien; A. Luger, Medizinische Universitaet Wien, Wien; P. Siostrzonek, Krankenhaus der390 Barmherzigen Schwestern Linz, Linz; H. Toplak, Medizinische Universitaet Graz, Graz; J.391 Bergler-Klein, Medizinische Universitaet Wien, Wien; K. Huber, Wilhelminenspital der Stadt392 Wien, Wien; B. Paulweber, Landeskrankenhaus Salzburg, Salzburg; M. Rammer, Klinikum393 Wels Grieskirchen GmbH, Wels; H. Sinzinger, Institut Athos, Wien.394395 Belgium:396 I. Buysschaert, Algemeen Stedelijk Ziekenhuis Aalst, Aalst; J. Thoeng, Algemeen Ziekenhuis397 Turnhout, Turnhout; A. Scheen, Centre Hospitalier Universitaire de Liege - Sart Tilman, Liege;398 H. Vandekerckhove, Algemeen Ziekenhuis Sint Lucas, Gent; E. Catez, Centre Hospitalier399 Universitaire Brugmann, Brussels; S. Verheye, Ziekenhuis Netwerk Antwerpen Middelheim,400 Antwerpen; O. Descamps, Centres Hospitaliers Jolimont - Hopital de Jolimont, La Louvière; E.401 Hoffer, Centre Hospitalier Regional de la Citadelle, Liège; B. Wollaert, Ziekenhuis Netwerk402 Antwerpen Stuivenberg, Antwerpen; P. Chenu, Universite Catholique de Louvain Cliniques403 Universitaires Saint Luc, Bruxelles; P. van de Borne, Cliniques universitaires de Bruxelles404 Hopital Erasme, Brussels; M. De Meulemeester, Medif sprl, Gozee; A. Friart, Centre Hospitalier405 Universitaire de Tivoli, La Louviere; F. Charlier, Imelda Ziekenhuis vzw, Bonheiden; H. De406 Raedt, Onze Lieve Vrouw Ziekenhuis Aalst, Aalst; E. Rietzschel, Universitair Ziekenhuis Gent,407 Gent; R. Roelandt, Jan Yperman Ziekenhuis, Ieper; J. Lalmand, Centre Hospitalier Universitaire408 de Charleroi - Hôpital Civil Marie Curie, Lodelinsart.409410 Brazil:411 L. A. Tavares Russo, Center for Clinical and Basic Research Brasil, Rio De Janeiro; J. F. K.412 Saraiva, Hospital e Maternidade Celso Pierro, Campinas; G. Reis, Cardresearch Cardiologia413 Assistencial de Pesquisa, Belo Horizonte; E. C. Duarte Barbosa, Associacao Hospitalar Moinhos414 de Vento, Porto Alegre; M. H. Vidotti, Centro Especializado em Cardiologia, Campinas; E. R.415 Fernandes Manenti, Hospital Mae de Deus, Porto Alegre; O. Dutra, Instituto de Cardiologia do416 Rio Grande do Sul, Porto Alegre; P. E. Leaes, Irmandade da Santa Casa de Misericordia de Porto417 Alegre, Porto Alegre; R. L. Rech, Hospital Universitario Mae de Deus, Canoas; D. Bertolim

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418 Precoma, Sociedade Hospitalar Angelina Caron, Campina Grande do Sul; J. C. Nicolau, Instituto419 do Coracao do Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo,420 São Paulo; R. Amoedo, Centro Paulista de Investigacoes Clinicas Cepic, São Paulo; F. G.421 Eliaschewitz, Centro de Pesquisas Clinicas Cpclin, Sao Paulo; A. Pereira, Hospital de Clinicas422 de Porto Alegre, Porto Alegre; H. R. Kurtz Lisboa, Hospital Sao Vicente de Paulo, Passo Fundo;423 L. Soares Piegas, Hospital do Coracao, Sao Paulo; J. L. Cunha Borges, Centro de Pesquisa424 Clinica do Brasil, Brasília; P. R. Ferreira Rossi, Nucleo de Pesquisa Clinica, Curitiba; P.425 Pimentel Filho, Hospital Nossa Senhora da Conceicao, Porto Alegre; L. C. Bodanese, Hospital426 Sao Lucas da Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre; R. de Sa427 Cunha, Hospital Universitario Cassiano Antonio Moraes, Vitória; J. C. Moura Jorge, Irmandade428 da Santa Casa de Misericordia de Curitiba, Curitiba; W. R. Ardito, Instituto de Molestias429 Cardiovasculares, Sao Jose do Rio Preto; W. K. Barroso de Souza, Via Medica Centro Clinico,430 Goiania; M. Hissa, Centro de Pesquisas em Diabetes e Doencas Endocrino Metabolicas,431 Fortaleza; M. C. Izar, Hospital Sao Paulo Universidade Federal de Sao Paulo, São Paulo.432433 Bulgaria:434 A. Manolova, Multiprofile Hospital for Active Treatment - Haskovo AD, Haskovo; L. Kitova,435 University Multiprofile Hospital for Active Treatment Sveti Georgi Ltd, Plovdiv; E. Kinova,436 University Multiprofile Hospital for Active Treatment Tsaritsa Yoanna - ISUL EAD, Sofia; M.437 Tzekova, University Multiprofile Hospital for Active Treatment Dr Georgi Stranski EAD,438 Pleven; B. Georgiev, Multiprofile Hospital for Active Treatment National Heart Hospital EAD,439 Sofia; V. Velchev, Diagnostic-Consultative Center Sveta Anna EOOD, Sofia; R. Tarnovska-440 Kadreva, University Multiprofile Hospital for Active Treatment Alexandrovska EAD, Sofia; D.441 Gotchev, Military Medical Academy - Multiprofile Hospital for Active Treatment Sofia, Sofia; I.442 Petrov, City Clinic University Multiprofile Hospital for Acute Care EOOD, Sofia; D. Raev,443 University Multiprofile Hospital for Active Treatment, Sveta Anna, Sofia; D. Trendafilova-444 Lazarova, University Multiprofile Hospital for Active Treatment Sveta Ekaterina EAD, Sofia; Y.445 Yotov, Multiprofile Hospital for Active Treatment Sveta Marina EAD, Varna; P. Lazov,446 Multiprofile Hospital for Active Treatment Pazardzhik JSK, Pazardzhik.447448 Canada:449 S. Rahimi, Multiprofile Hospital for Active Treatment Dr Hristo Stambolski Ltd, Kazanlak; E. St450 Amour, Q and T Recherche Outaouais Incorporated, Gatineau, QC; C. Constance, Clinique451 Sante Cardio MC, Montreal, QC; Y. Pesant, St Jerome Medical Research Incorporated, St-452 Jérôme, QC; A. Hess, Newmarket Cardiology Research Group, Newmarket, ON; T. Anderson,453 University of Calgary Health Sciences Centre, Foothills Campus, Calgary, AB; B. Sussex,454 Health Sciences Centre-Eastern Health, St. Johns, NL; S. Henein, SKDS Research Incorporated,455 Newmarket, ON; G. Tsoukas, Applied Medical Informatics Research, Westmout, QC; A. S.456 Pandey, Cambridge Cardiac Care Centre, Cambridge, ON; J. Bergeron, Clinique des Maladies457 Lipidiques de Quebec Incorporated, Quebec, QC; R. Hart, White Hills Medical Clinic, St.458 John’s, NL; G. Gosselin, Centre Integre de Sante et de Services Sociaux de Lanaudiere - Hôpital459 Pierre-Le Gardeur, Terrebonne, QC; R. Chehayeb, ViaCar Recherche Clinique Incorporated,460 Greenfield Park, QC; P. Hamet, Clinique de recherché Medpharmgene, Montreal, QC; M.461 Hartleib, Kawartha Cardiology Clinical Trials, Peterborough, ON; A. Mukherjee, Scarborough462 Cardiology Research, Scarborough, ON; F. Halperin, Medical Arts Health Research Group a463 division of PCT Networks, Kelowna, BC; R. Petrella, Western Centre for Public Health and

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464 Family Medicine - Western University, London, ON; R. Bhargava, Heart Care Canada, Oshawa,465 ON; E. Lonn, Hamilton Health Sciences Hamilton General Hospital, Hamilton, ON; E. Sabbah,466 Le Centre de Depistage et de Recherche Cardiovasculaire Rive-Sud, Longueuil, QC; I. Bata,467 Queen Elizabeth II Health Sciences Centre, Halifax Infirmary, Halifax, NS; J. Cha, Dr James468 Cha, Oshawa, ON; D. Gaudet, Ecogene-21, Chicoutimi, QC; K. Chapman, Inspiration Research469 Limited, Toronto, ON; D. Murthy, Regina General Hospital Regina Qu Appelle Health Region,470 Regina, SK; F. Nigro, Thunder Bay Regional Research Institute, Thunder Bay, ON; D. Rupka,471 Fraser Clinical Trials, New Westminster, BC; D. Gossard, CardioVasc HR Incorporated, St Jean472 sur Richelieu, QC; M. Gupta, Brampton Research Associates, Brampton, ON; A. Dowell,473 Dynamik Research Incorporated, Pointe-Claire, QC; S. Mansour, Centre Hospitalier Universite474 de Montreal- Hotel Dieu, Montreal, QC; A. Baass, McGill University Health Center Glen Site,475 Montreal, QC; C. Geadah, Recherches Cliniques Theradev, Granby, QC; T. Huynh, McGill476 University Health Centre - Montreal General Hospital, Montreal, QC; S. Peterson, Sarnia477 Institute of Clinical Research, Sarnia, ON; P. Poirier, Institut Universitaire de cardiologie et de478 pneumologie de Quebec, Québec, QC; G. Sabe-Affaki, Medialpha Research Centre, Lachine,479 QC; G. Vertes, Scarborough General Hospital Cardiology Research Associates, Scarborough,480 ON; D. Crowley, DCTM Clinical Trials Group Limited, Strathroy, ON; L. Duchesne, University481 of Ottawa Heart Institute, Ottawa, ON.482483 Chile:484 J. L. Cobos Segarra, Cardiocob, Santiago; C. P. Pincetti Jofre, Centro de Investigacion Clinica485 del Sur, Temuco; S. Potthoff Cardenas, Corporacion de Beneficiencia Osorno Clinica Alemana,486 Osorno; C. Conejeros Kindel, Sociedad Medica Cardiologica El Llano, Santiago; V. A. Saavedra487 Gajardo, Center for Clinical and Basic Research Chile, Santiago; F. Lanas Zanetti, Centro de488 Estudios Cardiovasculares, Temuco; P. A. Sepulveda Varela, Clinica Tabancura, Santiago; B. A.489 Stockins Fernandez, Centro de Investigacion Medica Stockins y Larenas, Temuco.490491 China:492 W. Li, The First Affiliated Hospital of Harbin Medical University, Harbin; D. Li, The Affiliated493 Hospital of Xuzhou Medical College, Xuzhou; S. Zhao, The Central Hospital of Wuhan, Wuhan;494 Z. Li, The Peoples Hospital of Liaoning Province, Shenyang; J. Wang, Siping City Center495 Peoples Hospital, Siping; Y. Yang, Chinese Medical Science Academy Fuwai Hospital, Beijing;496 L. Zhang, The First Affiliated Hospital of Harbin Medical University, Harbin; P. Yang, China-497 Japan Union Hospital of Jilin University, Changchun; X. Zhang, Jilin Province Peoples Hospital,498 Changchun; H. Huang, Xiangtan Central Hospital, Xiangtan; L. Xue, The General Hospital of499 Ningxia Medical University, Yinchuan; Z. Zheng, Chinese Medical Science Academy Fuwai500 Hospital, Beijing; W. Huang, The First Affiliated Hospital of Wenzhou Medical University,501 Wenzhou; H. Dai, Changsha Central Hospital, Changsha; W. Li, Tai Yuan City centre hospital,502 Taiyuan; H. Su, Inner Mongolia Autonomous Region Hospital of Traditional Chinese Medicine,503 Hohhot; X. Zeng, Wuhan Puai Hospital, Wuhan; Y. Zheng, The First Hospital of Jilin504 University, Changchun; Y. Tang, Chinese Medical Science Academy Fuwai Hospital, Beijing; Z.505 Yao, Tianjin Peoples Hospital, Tianjin; Y. Sun, Tianjin Medical University General Hospital,506 Tianjin; Y. Du, Jilin Province Peoples Hospital, Changchun; Z. Ge, Inner Mongolia Baogang507 Hospital, Baotou; J. Yan, Zhejiang Hospital, Hangzhou; X. Chen, Tai Yuan City centre hospital,508 Taiyuan; F. Liu, Suzhou Kowloon Hospital,Shanghai Jiaotong University school of medicine,509 Suzhou; H. Pei, The Affiliated Hospital of Qingdao University, Qingdao; X. Yang, Beijing

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510 Chao-Yang Hospital, Capital Medical University, Beijing; H. Cui, Ningbo First Hospital,511 Ningbo; Y. Gu, Wuhan Puai Hospital, Wuhan; Z. Yang, Wuxi Peoples Hospital, Wuxi; J. Li,512 Chinese Medical Science Academy Fuwai Hospital, Beijing; Y. Lian, The First Affiliated513 Hospital of Zhengzhou University, Zhengzhou; Y. Cui, The First Automobile Works Hospital,514 Changchun; Z. Li, Peking University Third Hospital, Beijing; D. Wang, Inner Mongolia515 Baogang Hospital, Baotou; J. Jiang, Taizhou Hospital of Zhejiang Province, Linhai; X. Li, The516 Second Hospital of Tianjin Medical University, Tianjin; J. Chen, Guangdong General Hospital,517 Guangzhou; Z. Mo, The Third Xiangya Hospital of Central South University, Changsha; P. Xu,518 The First Peoples Hospital of Changde, Changde; Y. He, Zhuzhou Central Hospital, Zhuzhou; C.519 Zhou, The Affiliated Hospital of Qingdao University, Qingdao; P. Qu, The Second Hospital of520 Dalian Medical University, Dalian; Y. Zhu, The Second Affiliated Hospital of Harbin Medical521 University, Harbin; Y. Liu, Xiangya Hospital Central South University, Changsha; X. Shen, The522 Affiliated Hospital of Xuzhou Medical College, Xuzhou; Y. Yang, The First Affiliated Hospital523 of Xinjiang Medical University, Urumqi; X. Gao, The People's Hospital Of Hunan Province,524 Changsha.525526 Colombia:527 M. A. Terront Lozano, Center for Clinical and Basic Research Colombia, Bogota; M. A.528 Moncada Corredor, Center for Clinical and Basic Research Colombia, Medellin; E. Hernandez529 Triana, Endocare, Bogota; J. L. Accini Mendoza, Instituicion Prestadora de Salud Centro530 Cientifico Asistencial Jose Luis Accini SAS, Barranquilla; R. Botero Lopez, Rodrigo Botero531 SAS, Medellin; J. A. Coronel Arroyo, Centro Medico Julian Coronel, Santiago de Cali; A. E.532 Quintero Baiz, Fundacion del Caribe para la Investigacion Biomedica, Barranquilla; G. Sanchez533 Vallejo, Fundacion Cardiomet Eje Cafetero Cequin, Armenia; C. Arana Londoño, Centro de534 Investigaciones Clinicas SAS, Santiago de Cali; D. I. Molina de Salazar, Asociacion Instituicion535 Prestadora de Salud Medicos Internistas de Caldas, Manizales; R. Castellanos Bueno, Fundacion536 Oftalmologica de Santander Foscal, Floridablanca; F. Manzur Jattin, Centro de Diagnostico537 Cardiologico, Cartagena; C. A. Cure Cure, Biomelab, Barranquilla; A. Sotomayor Herazo,538 Centro Cardiovascular Aristides Sotomayor Santa Lucia SAS, Cartagena.539540 Czech Republic:541 J. Spinar, Fakultni nemocnice Brno, Brno; T. Hala, Center for Clinical and Basic Research542 Pardubice, as, Pardubice; M. Machkova, CCBR Czech Prague sro, Praha 3; Z. Klimsa,543 Nemocnice Jihlava po, Jihlava; R. Polasek, Krajska nemocnice Liberec as, Liberec; O. Jerabek,544 Poliklinika Ravak Pribram, Pribram VIII; P. Kazdera, Nemocnice Znojmo, po, Znojmo; Z.545 Pozdisek, Pozdisek sro, Kardiologicka ambulance, Mohelnice; J. Vaclavik, Kardio Vaclavik sro,546 Interni a kardiologicka ambulance, Prerov; P. Frana, Centrum pro zdravi sro, Brno; L. Elbl, prof547 MUDr Lubomir Elbl, CSc, Kardiologicka ambulance, Brno; D. Kucera, Kardiologicka a548 angiologicka ambulance, Ostrava - Zabreh; R. Kryza, Mestska nemocnice Ostrava, Ostrava; J.549 Malecha, Ordinace pro choroby srdce sro, Chomutov; P. Reichert, AeskuLab ks, Lipidova550 poradna, Teplice; K. Sochor, Jessenia as, Nemocnice Beroun, Beroun; O. Ludka, MUDr Karel551 Kamenik sro, Privatni kardiologicka ambulance, Brno; I. Kellnerova, Nemocnice Pardubickeho552 kraje as, Svitavska nemocnice, Svitavy; R. Ceska, Vseobecna fakultni nemocnice v Praze, Praha553 2; K. Peterka, Nemocnice Havlickuv Brod, Havlickuv Brod; E. Zidkova, Interni a kardiologicka554 ordinace, Praha 5; V. Cech, Clinical Trials Service sro, Uherske Hradiste; T. Brabec, Vojenska555 nemocnice Brno, Brno; N. Fiserova, Center for Clinical and Basic Research Czech Brno sro,

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556 Brno; J. Kvasnicka, Ordinace pro choroby srdce a cev, Praha 10; H. Rosolova, Fakultni557 nemocnice Plzen, Plzen; E. Nemecek, Vseobecna fakultni nemocnice v Praze, Praha 2; V.558 Adamkova, Institut klinicke a experimentalni mediciny, Praha 4; M. Dunaj, Nemocnice559 Pardubickeho kraje as, Litomyslska nemocnice, Litomysl; S. Pojsl, Mestska nemocnice v560 Litomericich, Litomerice; M. Cepelak, Kardio Michal Cepelak sro, Klatovy IV; I. Podpera,561 Oblastni nemocnice Kladno as, Kladno; L. Kuchar, Vseobecna intermi ambulance sro, Milevsko;562 D. Rysava, Oblastni nemocnice Kolin as, nemocnice Stredoceskeho kraje, Nemocnice Kutna563 Hora, Kutna Hora; H. Burianova, Interni a kardiologicka ambulance, Bilovec; L. Spinarova,564 Fakultni nemocnice u sv Anny v Brne, Brno; J. Skrobakova, Kardiologicke centrum MUDr565 Janky Skrobakove sro, Praha 5 - Smichov; J. Charvat, Fakultni nemocnice v Motole, Praha 5; M.566 Homza, Benedor sro - Kardiologicka, cevni a interni ambulance, Ostrava-Poruba; J. Zemanek,567 Poliklinika Moravske Budejovice sro, Moravske Budejovice; P. Koleckar, Policska nemocnice568 sro, Policka; I. Karen, MUDr Igor Karen, Benatky nad Jizerou; J. Krupicka, Medicus Services569 sro, Brandys nad Labem; V. Blaha, MUDr Ladislava Harrerova, kardiologicka ordinace, Hradec570 Kralove; J. Matuska, Clinical Trial Center Hodonin sro, Hodonin; J. Brotanek, Thomayerova571 nemocnice, Praha 4; R. Cifkova, Thomayerova nemocnice, Praha 4; R. Kuchar, Innera sro,572 Benesov; Z. Vomacka, MUDr Zdenek Vomacka, kardiologie a interna sro, Olomouc; Z. Kosek,573 MUDr Zbynek Kosek, kardiologicka ambulance sro, Mlada Boleslav; V. Hulinsky, Nemocnice574 Nymburk sro, Nymburk; H. Krejcova, Kardiologicka ambulance, Prachatice; J. Kuchar,575 Kardiologie Cesky Krumlov, Cesky Krumlov; Z. Jelinek, Nemocnice Hranice as, Hranice na576 Morave; P. Jelinek, Kardio LPV ambulance sro, Ceske Budejovice.577578 Denmark:579 L. Markdanner Lindgren, Centre for Clinical and Basic Research Ballerup, Ballerup; A. Saetre580 Lihn, Center for Clinical and Basic Research Aalborg, Aalborg; K. Korsgaard Thomsen,581 Sydvestjysk Sygehus, Esbjerg; S. Wermuth, Center for Clinical and Basic Research Vejle, Vejle;582 H. Kjaerulf Jensen, Aarhus Universitetshospital, Skejby, Aarhus N; J. Bronnum-Schou, Amager583 Hospital, København S; H. Nielsen, Bispebjerg Hospital, København; T. Nielsen, Sjaellands584 Universitetshospital Koge, Køge; K. Egstrup, Svendborg Sygehus, Svendborg; I. C. Klausen,585 Regionshospitalet Viborg, Viborg; H. Mickley, Odense Universitetssygehus, Odense; J. Hove,586 Hvidovre Hospital, Hvidovre; J. Jeppesen, Glostrup Hospital, Glostrup; T. Melchior, Sjaellands587 Universitetshospital, Roskilde, Roskilde; E. B. Schmidt, Aalborg Hospital, Aalborg.588589 Estonia:590 I. Valter, Center for Clinical and Basic Research Tallinn, Tallinn; A. Rosenthal, Dr Arvo591 Rosenthal LLC, Tallinn; J. Kaik, Fertilitas, Harjumaa; A. Kork, East Tallinn Central Hospital,592 Tallinn; I. Alt, Vee Perearstikeskus, Paide; M. Viigimaa, North Estonia Medical Centre593 Foundation, Tallinn.594595 Finland:596 J. Strand, Terveystalo Oulu, Diapolis, Oulu; S. Nieminen, IteLasaretti, Kuopio; J. Kahri,597 Helsingin ja Uudenmaan sairaanhoitopiiri - HUS, Helsinki; J. Suomi, Terveystalo Pulssi, Turku;598 K. Nyman, Terveystalo Jyvaskyla, Jyväskylä; T. E. Strandberg, Geri-Med, Helsinki; T. Piippo,599 Tampereen Lääkärikeskus Oy, Tampere; M. Savolainen, Oulu University Hospital, Oulo; S.600 Vikman, Tampereen yliopistollinen sairaala, Tampere.601602 France:

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603 F. Schiele, Centre Hospitalier Regional Universitaire de Besancon, Hopital Jean Minjoz, 604 Besançon Cedex; Y. Pucheu, Centre Hospitalier Universitaire de Bordeaux, Hopital Haut- 605 Leveque, Pessac Cedex; B. Cariou, Centre Hospitalier Universitaire de Nantes - Hopital606 Guillaume et Rene Laennec, Nantes Cedex 1; P. Henry, Hopital Lariboisiere, Paris; E. Ferrari, 607 Center Hospitalier Universitaire de Nice - Hopital Pasteur, Nice; G. Montalescot, P. Sabouret, 608 Hopital Pitie-Salpetriere, Paris; J. Ferrieres, M. Elbaz, M. Galinier, Centre Hospitalier609 Universitaire de Toulouse - Hopital Rangueil, Toulouse Cedex 9; F. Roubille, Centre Hospitalier 610 Regional Universitaire de Montpellier - Hopital Arnaud de Villeneuve, Montpellier cedex 05; B. 611 Bonnet, Centre Hospitalier Intercommunal Haute Saone, Vesoul; D. Angoulvant, Centre612 Hospitalier Régional Universitaire de Tours - Hôpital Trousseau, Chambray les Tours; G. Range, 613 Hopital Louis Pasteur, Le Coudray; A. Bammert, Nouvelles Cliniques Nantaises, Nantes Cedex 614 2; N. Delarche, Centre Hospitalier de Pau - Hopital Francois Mitterrand, Pau; C. Mariat, Centre 615 Hospitalier Universitaire Nord de Saint Etienne - Hopital Nord, Saint Priest en Jarez; G. Cayla, 616 Centre Hospitalier Universitaire de Nimes, Nimes; V. Durlach, Centre Hospitalier Universitaire 617 de Reims - Hopital Robert Debre, Reims cedex; D. Coisne, Centre Hospitalier Universitaire de 618 Poitiers, Poitiers; F. Paillard, Centre Hospitalier Universitaire de Rennes - Hopital Pontchaillou, 619 Rennes; R. Rouzier, Centre Cap, Montpellier cedex 5; M. Goralski, Centre Hospitalier Regional 620 d'Orleans - Hopital de la Source, Orleans; P. Khanoyan, Hopital Saint-Joseph, Marseille Cedex 621 08; Y. Cottin, Centre Hospitalier Universitaire de Dijon - Hopital du Bocage, Dijon cedex; O.622 Ziegler, T. Delmas, Centre Hospitalier Universitaire de Nancy - Hôpital de Brabois,623 Vandoeuvre les Nancy; K. Khalife, Centre Hospitalier Regional Metz Thionville - Hopital de624 Mercy, Metz cedex 03; P. Le Corvoisier, Hopital Henri Mondor, Créteil; P. Motreff, Hopital625 Gabriel Montpied, Clermont Ferrand; C. Spaulding, Hôpital Européen Georges Pompidou, Paris; 626 E. VanBelle, Centre Hospitalier Regional Universitaire de Lille - Hopital Cardiologique, Lille 627 Cedex.628629 Germany:630 H. Bourhaial, Sankt-Johannes-Hospital, Dortmund; C. Opitz, Deutsches Rotes Kreuz Kliniken 631 Berlin Köpenick, Berlin; G. Kahrmann, Forschungszentrum Ruhr, Witten; C. Contzen, Synexus 632 Clinical Research GmbH, Frankfurt am Main; K. Appel, Studienzentrum Dr Appel, Kassel; I.633 Schenkenberger, Klinische Forschung Berlin GbR, Berlin; A. Rinke, Synexus Clinical Research634 GmbH, Bochum; D. Trenk, Universitaets-Herzzentrum Freiburg - Bad Krozingen, Bad635 Krozingen; I. Gouni-Berthold, Universitätsklinikum Köln, Köln; O. Maus, Synexus Clinical636 Research GmbH, Leipzig; M. Karakas, Universitätsklinikum Hamburg-Eppendorf, Hamburg; M. 637 Hanefeld, Gesellschaft f Wissens u Technologietransfer der Tech Uni Dresden Studienzentrum 638 Prof Hanefeld, Dresden; H. Darius, Vivantes Klinikum Neukölln, Berlin; T. G. Schäufele,639 Robert Bosch Krankenhaus, Stuttgart; G. Hetzel, DaVita Clinical Research Deutschland,640 Düsseldorf; T. Münzel, Johannes Gutenberg Universität Mainz, Mainz; J. Wöhrle,641 Universitätsklinikum Ulm, Ulm; P. Stawowy, Deutsches Herzzentrum Berlin, Berlin; I. Marten,642 Klinische Forschung Hannover-Mitte GmbH, Hannover; B. Isermann, Otto von Guericke 643 Universität Magdeburg, Magdeburg; P. Kast, Asklepios Klinik Sankt Georg, Hamburg; M. 644 Vorpahl, Helios Universitätsklinikum Wuppertal, Wuppertal; P. Bosiljanoff, Herz-Gefäß- 645 Zentrum Nymphenburg am Klinikum Dritter Orden, München; C. Hengstenberg, Deutsches 646 Herzzentrum München des Freistaates Bayern, München; U. Kassner, Charite647 Universitätsmedizin Berlin, Charité Campus Virchow-Klinikum, Berlin; P. Salbach, zero Praxen648 GbR, Mannheim; M. Fischer, Universitätsklinikum Regensburg, Regensburg; S. Steiner, Sankt

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649 Vincenz-Krankenhaus, Limburg; S. Wagner, Georg-Haas-Dialysezentrum, Giessen; U. Kraatz, 650 Praxis Dr Kraatz, Demmin; E. von Hodenberg, MediClin Herzzentrum Lahr-Baden, Lahr; K. 651 Weyland, Praxis für Allgemeinmedizin Dr Klaus Weyland, Ingelheim.652653 Greece:654 I. Mantas, General Hospital of Chalkida, Chalkida; D. Tziakas, G. Chalikias, University655 Hospital of Alexandroupolis, Alexandroupoli; S. Bousboulas, S. Pappas, General Hospital of656 Nikaia Piraeus Agios Panteleimon, Nikaia, Piraeus; S. Patsilinakos, Konstantopoulio - Agia Olga657 Hospital of Nea Ionia, Athens; G. Mertzanos, D. Babalis, General Hospital of Attica KAT,658 Athens; C. Panagoulis, General Hospital of Athens Georgios Gennimatas, Athens; H. Bilianou,659 Tzaneio General Hospital, Piraeus; I. Skoumas, C. Pitsavos, General Hospital of Athens660 Ippokrateio, Athens; M. Elisaf, E. Liberopoulos, University Hospital of Ioannina, Ioannina; A. 661 Manolis, General Hospital Asklipieio Voulas, Athens; N. Moschos, General Hospital of Rhodes, 662 Rhodes; L. Rallidis, Attikon Hospital, Athens; G. Kochiadakis, University Hospital of Heraklion, 663 Heraklion; G. Ntaios, G. Dalekos, University Hospital of Larissa, Larissa; D. Richter, Athens 664 Euroclinic, Athens; V. Athyros, Ippokrateio Hospital of Thessaloniki, Thessaloniki; G. Kolovou, 665 Onassis Cardiac Surgery Center, Athens; P. Danias, Hygeia Hospital, Athens; A. Melidonis,666 Tzaneio General Hospital, Piraeus.667668 Hong Kong:669 C. W. D. Siu, University of Hong Kong, Queen Mary Hospital, Hong Kong; K. Y. Y. Fan,670 Grantham Hospital, Hong Kong; S. C. Siu, Tung Wah Eastern Hospital, Hong Kong.671 Page 12 of 57672673 Hungary:674 A. Hornyik, CRU Hungary Kft, Miskolc; F. Lakatos, Dr Lakatos Ferenc Private Cardiology675 Practice, Bekescsaba; Z. Zilahi, Medifarma 98 Kft, Nyiregyhaza; K. Nagy, Synexus676 Magyarorszag Kft, Budapest; Z. Laszlo, Szent Janos Korhaz es Eszak-budai Egyesitett677 Korhazak, Budapest; E. Peterfai, Drug Research Center Kft, Balatonfured; G. Lupkovics, Zala678 Megyei Szent Rafael Korhaz, Zalaegerszeg; P. Andreka, Gottsegen Gyorgy Orszagos679 Kardiologiai Intezet, Budapest; B. Merkely, Semmelweis Egyetem, Budapest; B. Herczeg, Jasz- 680 Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet, Szolnok; G. A. Piros, Szegedi 681 Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont Altalanos Orvostudomanyi Kar, 682 Szeged; C. Salamon, Clinfan Kft, Szekszard; L. Mark, Bekes Megyei Kozponti Korhaz Pandy 683 Kalman Tagkorhaz, Gyula; A. Papp, Szent Rokus Korhaz es Intezmenyei, Budapest; I. Szakal, 684 Selye Janos Korhaz, Komarom; K. Toth, Pecsi Tudomanyegyetem Klinikai Kozpont, Pecs; A. 685 Papp, Grof Tisza Istvan Korhaz, Berettyoujfalu; I. Edes, Debreceni Egyetem Klinikai Kozpont, 686 Debrecen; A. Mohacsi, Pharma4 Trial Kft, Gyongyos; J. Tomcsanyi, Betegapolo Irgalmas Rend 687 - Budai Irgalmasrendi Korhaz, Budapest; E. Hajko, Toldy Ferenc Korhaz-Rendelointezet,688 Cegled; A. Nagy, Bacs-Kiskun Megyei Korhaz, Kecskemet; E. Papp, Somogy Megyei Kaposi 689 Mor Oktato Korhaz, Kaposvar; R. Kiss, Magyar Honvedseg Egeszsegugyi Kozpont, Budapest; I. 690 Karadi, Semmelweis Egyetem, Budapest.691692 Iceland:693 G. Thorgeirsson, Landspitali National University Hospital, Reykjavik; A. Sigurdsson,694 Hjartamidstodin, Kopavogur.695

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696 India:697 A. Jain, Shah Alloys Limited Hospital and Medical Institute, Ahmedabad; R. Pai, Oyster and 698 Pearl Hospital, Pune; V. Kothiwale, Karnataka Lingayat Education Societys Dr Prabhakar Kore 699 Hospital & Medical Research Centre, Belgaum; G. Kulkarni, Shree Hospital, Pune; A. Mahajan, 700 Lokmanya Tilak Muncipal General Hospital, Mumbai; S. Aggarwal, Maulana Azad Medical 701 College, New Delhi; V. Mehta, Govind Ballabh Pant Hospital, New Delhi; G. Rajadhyaksha, 702 Topiwala National Medical College and B Y L Nair Charitable Hospital, Mumbai; V. Chopra, 703 Medanta MediCity, Gurgaon; A. Joshi, Niramaya Hospital Private Limited, Pune; V. Khandait, 704 Government Medical College and Hospital, Nagpur; M. Parmar, Shree Sayaji General Hospital 705 and Baroda Medical College, Vadodara; S. Tyagi, AMC MET Medical College and Seth L G 706 General Hospital, Ahmedabad; R. Airody Govinda, Mysore Mdical College and Research707 Institute, Mysore; S. K. Dwivedi, King Georges Medical University, Lucknow; K. Parikh, Care708 Institute Of Medical Sciences, Ahmedabad; R. B. Pothineni, Dr Ramesh Cardiac and709 Multispeciality Hospital Private Limited, Vijayawada; B. Solanki, B J Medical College and Civil710 Hospital, Ahmedabad.711712 Ireland:713 B. McAdam, Beaumont Hospital, Dublin; M. O’Donnell, National University of Ireland, 714 Galway; P. Crean, St James Hospital, Dublin; J. Barton, Portiuncula Hospital, Galway. 715716 Israel:717 M. Shechter, Sheba Medical Center, Tel Hashomer; B. Lewis, The Lady Davis Carmel Medical 718 Center, Haifa; A. Shotan, Hillel Yaffe Medical Center, Hadera; M. Klutstein, Shaare Zedek, 719 Jerusalem; E. Chorin, Tel-Aviv Sourasky Medical Center, Tel Aviv; D. Gavish, Wolfson720 Medical Center, Holon; O. Kracoff, Kaplan Medical Center, Rehovot; S. Atar, Western Galilee721 Hospital, Nahariya; S. Rigler, Clalit Health Services, Netanya; Y. Hasin, Herzliya Medical722 Center, Herzliya-on-sea; E. Schiff, Bnai-Zion Medical Center, Haifa.723724 Italy:725 G. M. De Ferrari, Fondazione IRCCS Policlinico San Matteo, Pavia; P. Merlini, Azienda Socio 726 Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Milano; C. Rapezzi, Azienda 727 Ospedaliero Universitaria di Bologna Policlinico S. Orsola Malpighi, Bologna; M. Pirro,728 Ospedale Santa Maria della Misericordia Università degli Studi di Perugia, Perugia; S. Gonnelli, 729 Policlinico Santa Maria alle Scotte, Siena; A. M. Floresta, Azienda Ospedaliera Ospedali Riuniti 730 Villa Sofia Cervello Presidio Ospedaliero V. Cervello, Palermo; M. Mennuni, Ospedale731 Leopoldo Parodi Delfino, Colleferro RM; D. Ardissino, Azienda Ospedaliera Universitaria di 732 Parma, Parma; M. Senni, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo; 733 G. Marenzi, Centro Cardiologico Monzino, Milano; R. Marcucci, Azienda Ospedaliera734 Universitaria Careggi, Firenze; T. Sampietro, Fondazione Toscana Gabriele Monasterio,735 Stabilimento Ospedaliero di Pisa, Pisa; F. Cosmi, Ospedale Santa Margherita, Cortona AR; P. 736 Perrone Filardi, Azienda Ospedaliera Universitaria Federico II, Napoli; R. De Caterina, Ospedale 737 Santissima Annunziata Università degli Studi G. D’Annunzio, Chieti; F. Fedele, Umberto I738 Policlinico di Roma, Roma; L. Moretti, Ospedale Generale Provinciale C. G. Mazzoni, Ascoli 739 Piceno; L. M. Biasucci, Policlinico Universitario Agostino Gemelli, Roma; C. Ferri, Presidio 740 Ospedaliero San Salvatore, L Aquila.741

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742 Japan:743 Y. Go, Go Neurosurgical Clinic, Chikushi-gun; A. Kiyosue, Tokyo-Eki Center-building Clinic,744 Chuo-ku; Y. Higashi, Himeji Central Hospitals Clinic, Himeji-shi; A. Hirayama, Nihon745 University School of Medicine Itabashi Hospital, Itabashi-ku; T. Tokunaga, JA Toride Medical 746 Center, Toride-shi; T. Kawasaki, Tenjinkai Shin-Koga Hospital, Kurume-shi; S. Sakagami, 747 National Hospital Organization Kanazawa Medical Center, Kanazawa-shi; S. Namba, Japan 748 Organization of Occupational Health and Safety Okayama Rosai Hospital, Okayama-shi; K.749 Saku, Fukuoka University Hospital, Fukuoka-shi; K. Oku, National Hospital Organization750 Nagasaki Medical Center, Omura-shi; T. Arakawa, Social Medical Corporation Kojunkai Daido751 Hospital, Nagoya-shi; H. Iida, National Hospital Organization Hamada Medical Center,752 Hamada-shi; Y. Nakamura, Nakamura Cardiovascular Clinic, Itoshima-shi; K. Yamamoto, Saga753 Memorial Hospital, Saga-shi; Y. Hata, Minamino Cardiovascular Hospital, Hachioji-shi; Y.754 Katsuda, Fukuoka city Medical Association Adult Medical Centre, Fukuoka-shi; Y. Koga,755 Sagaken Medical Centre Koseikan, Saga-shi; M. Shimizu, National Hospital Organization Kobe 756 Medical Center, Kobe-shi; H. Uehara, Urasoe Sogo Hospital, Urasoe-shi; S. Kajiyama, Medical 757 Corporation Keisei-kai Kajiyama Clinic, Kyoto-shi; H. Okamoto, Meitetsu Hospital, Nagoyashi; 758 T. Shinozaki, National Hospital Organization Sendai Medical Center, Sendai-shi; Y. Fujino,759 New Tokyo Heart Clinic, Matsudo-shi; T. Funazaki, Saiseikai Kawaguchi General Hospital, 760 Kawaguchi-shi; N. Higa, Okinawa Tokushukai Medical Corporation Chubu Tokushukai 761 Hospital, Nakagami-gun; K. Kaigawa, Daiyukai Clinic, Ichinomiya-shi; A. Koike, National 762 Hospital Organization Fukuoka-Higashi Medical Center, Koga-shi; H. Nakane, National 763 Hospital Organization Fukuoka-Higashi Medical Center, Koga-shi; K. Sato, Social Medical764 Corporation Tokeidai Memorial Clinic, Sapporo-shi; Y. Satoh, National Hospital Organization 765 Disaster Medical Center, Tachikawa-shi; K. Shirasawa, Osaka Hospital of Japan Seafarers relief 766 Association, Osaka-shi; H. Sugino, National Hospital Organization Kure Medical Center and 767 Chugoku Cancer Center, Kure-shi; J. Tanabe, National Hospital Organization Shizuoka Medical 768 Center, Sunto-gun; O. Uemura, National Hospital Organization Murayama Medical Center,769 Musashimurayama-shi; G. Yoshimichi, National Hospital Organization Oita Medical Center, 770 Oita-shi; A. Akai, Tokai Memorial Hospital, Kasugai-shi; H. Himeno, Fujisawa City Hospital, 771 Fujisawa-shi; T. Inage, Takagi Hospital, Okawa-shi; M. Inoko, Tazuke Kofukai Foundation 772 Medical Research Institute Kitano Hospital, Osaka-shi; T. Kadokami, Saiseikai Futsukaichi 773 Hospital, Chikushino-shi; Y. Noguchi, Tsukuba Medical Center Foundation Tsukuba Medical 774 Center Hospital, Tsukuba-city; K. Yamashita, Nagoya Medical Center, Nagoya-shi; Y.775 Yasumura, Osaka Police Hospital, Osaka-shi; M. Yuge, Odawara Municipal Hospital,776 Odawarashi; S. Hosokawa, Tokushima Red Cross Hospital, Komatsushima-shi; K. Kawamitsu,777 Okinawa Tokushukai Medical Corporation Nanbu Tokushukai Hospital, Shimajiri-gun; K.778 Kozuma, Teikyo University Hospital, Itabashi-ku; H. Matsuo, National Hospital Organization 779 Nagasaki Kawatana Medical Center, Higashisonogi-gun; E. Nakashima, Chubu Rosai Hospital, 780 Nagoyashi; M. Okada, Yoshida Hospital, Asahikawa-shi; A. Wada, Kusatsu General Hospital, 781 Kusatsushi; K. Yokoya, National Hospital Organization Toyohashi Medical Center, Toyohashi- 782 shi; K.Iwade, National Hospital Organization Yokohama Medical Center, Yokohama-shi; K.783 Kawabata, University of Yamanashi Hospital, Chuo-shi; H. Tanno, National Hospital784 Organization Chiba Medical Center, Chiba-shi; J. Ako, Kitasato University Hospital,785 Sagamihara-shi; H. Fujita, Murakami Memorial Hospital, Saijo-shi; Y. Izumiya, Kumamoto786 University Hospital, Kumamoto-shi; M. Kanno, Southern Tohoku Research Institute for787 Neurosciense Southern Tohoku Medical Clinic, Koriyama-shi; T. Nunohiro, Nagasaki Harbor

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788 Medical Center City Hospital, Nagasaki-shi; H. Ohmura, Juntendo University Hospital, Bunkyo-789 ku; T. Ueno, Kurume University Hospital, Kurume-shi.790791 Latvia:792 N. Kakurina, Daugavpils Regional Hospital, Daugavpils; A. Erglis, Pauls Stradins Clinical 793 University Hospital, Riga; I. Jasinkevica, Inga Jasinkevica Cardiologist Practice, Ogre; I. 794 Stukena, Riga First Hospital, Riga; I. Veze, Outpatient Clinic Veselibas Centrs 4, Riga; R.795 Eglite, Rutas Eglites private practice, Kuldiga; D. Teterovska, Dace Teterovska Doctor Practice796 in Endocrinology, Ogre; I. Sime, Regional Hospital of Liepaja, Liepaja.797798 Lithuania:799 J. Badariene, Vilnius University Hospital Santariskiu Clinic Public Institution, Vilnius; V.800 Strazdiene, Center for Clinical and Basic Research, Vilnius; L. Venceviciene, Vilnius University801 Hospital Santariskiu Clinic Public Institution, Vilnius; O. Gustiene, Hospital of Lithuanian 802 University of Health Sciences Kaunas Clinics Public Institution, Kaunas; R. Radzeviciene- 803 Jurgute, Mano seimos gydytojas, Klaipeda; A. Kucinskiene, INMEDICA, Kaunas.804805 Malaysia:806 W. A. Wan Ahmad, University Malaya Medical Centre, Kuala Lumpur; O. Maskon, Universiti 807 Kebangsaan Malaysia Medical Centre, Kuala Lumpur; C. Y. Lee, Hospital Sultanah Aminah, 808 Johor Bahru; T. Erng, Hospital Melaka, Melaka; H. W. Gan, Gleneagles Medical Centre,809 Penang; A. K. Mohamed Yusof, Institut Jantung Negara, Kuala Lumpur; G. L. Ramanathan,810 Hospital Taiping, Taiping; H. Liew, Hospital Queen Elizabeth II, Kota Kinabalu.811812 Mexico:813 A. Lopez Alvarado, Hospital Pedro Loza S.A. de C.V., Guadalajara; L. A. Nevarez Ruiz,814 Investigacion en Salud y Metabolismo SC, Chihuahua; M. O. De los Rios Ibarra, Centro para el 815 Desarrollo de la Medicina y de Asistencia Medica Especializada SC, Culiacan; A. E. Bazzoni 816 Ruiz, CIMAB SA de CV, Torreon; G. A. Ramos Lopez, Nuevo Hospital Civil de Guadalajara Dr 817 Juan I Menchaca, Guadalajara; G. A. Llamas Esperon, Hospital Cardiologica Aguascalientes, 818 Aguascalientes; G. D. J. De la Peña Topete, ICLE SC, Guadalajara; G. Gonzalez-Galvez,819 Instituto Jalisciense de Investigacion en diabetes y obesidad SC, Guadalajara; R. M. Violante 820 Ortiz, Centro de Estudios de Investigacion Metabolicos y Cardiovasculares SC, Tampico; J. J. 821 Illescas Diaz, Unidad de Investigacion Clinica Cardiometabolica de Occidente SC, Guadalajara; 822 S. Leon Gonzalez, Centro de Estudios Clinicos de Queretaro SC, Queretaro; C. J. Sanchez Diaz, 823 Unidad de Investigacion Clinica en Medicina SC, Monterrey; G. F. Mendez Machado, Hospital 824 Angeles Xalapa, Xalapa; L. A. Venegas Carrillo, Investigacion Clinica de Leon SC, Leon; J. A. 825 Aldrete Velasco, Paracelsus SA de CV, Mexico; E. G. Cardona Muñoz, Centro Universitario de 826 Ciencias de la Salud, Guadalajara; J. L. Leiva Pons, Hospital Central Dr Ignacio Morones Prieto, 827 San Luis Potosi; J. C. Perez Alva, U de Inv Clinica Inst Tec y de Estudios Sup de Monterrey828 Campus Cd de Mex, Mexico.829830 Netherlands:831 C. van der Zwaan, Ziekenhuis Rivierenland, Tiel; A. Oomen, Antonius Ziekenhuis, Sneek; R.832 van de Wal, Ziekenhuis Bernhoven, Uden; M. Magro, Elisabeth-TweeSteden Ziekenhuis,833 Tilburg; D. Boswijk, Noordwest Ziekenhuisgroep, Den Helder; C. Janus, Vasculair Onderzoek

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834 Centrum Hoorn, Hoorn; R. Groutars, Sint Lucas Andreas Ziekenhuis, Locatie Sint Lucas,835 Amsterdam; W. Tonino, Catharina Ziekenhuis, Eindhoven; J. H. Cornel, Noordwest836 Ziekenhuisgroep, Alkmaar; A. Oude Ophuis, Canisius-Wilhelmina Ziekenhuis, Nijmegen; R.837 Troquay, VieCuri Medisch Centrum, Venlo; A. Liem, Franciscus Gasthuis, Rotterdam; I. 838 Westendorp, Rode Kruis Ziekenhuis, Beverwijk; M. Van Hessen, Groene Hart Ziekenhuis, 839 Gouda; D. Lok, Deventer Ziekenhuis, Deventer; C. De Nooijer, Maxima Medisch Centrum, 840 Veldhoven; F. Den Hartog, Ziekenhuis Gelderse Vallei, Ede; E. Van Beek, Sint Jansdal841 Ziekenhuis, Harderwijk; P. Bendermacher, Elkerliek Ziekenhuis, Helmond; R. Jansen,842 Slingeland Ziekenhuis, Doetinchem; T. Römer, Alrijne Ziekenhuis, Leiden; B. Rensing, Sint843 Antonius Ziekenhuis, locatie Nieuwegein, Nieuwegein; F. Hersbach, Maasstad Ziekenhuis,844 Rotterdam; J. Herrman, Onze Lieve Vrouwe Gasthuis, Amsterdam; G. Ladyjanskaia, Ziekenhuis 845 Amstelland, Amstelveen; I. Karalis, Leids Universitair Medisch Centrum, Leiden; G. Linssen, 846 Ziekenhuisgroep Twente, Almelo; M. Bokern, Waterland Ziekenhuis, Purmerend; A. Visman, 847 Beatrix Ziekenhuis, Gorinchem; A. Kooij, Bethesda Diabetes Research Center, Hoogeveen; H. 848 Monajemi, Rijnstate, Arnhem; A. Lieverse, Maxima Medisch Centrum, Eindhoven.849850 New Zealand:851 R. Scott, Lipid and Diabetes Research Group, Christchurch; J. Baker, Middlemore Hospital,852 Papatoetoe, Auckland; S. Tie, Tauranga Hospital, Tauranga.853854 Norway:855 K. Risberg, Skedsmo Medisinske Senter, Skedsmokorset; J. Hysing, Sykehuset Telemark, Skien;856 T. Pedersen, Oslo universitetssykehus, Oslo; H. O. Hoivik, M3 Helse, Hamar; P. Norheim,857 Forusakutten-Kolibri, Stavanger; L. Solnor, Heiaklinikken, Lierskogen; A. Hovland,858 Nordlandssykehuset, Bodø; T. Kjaernli, Medi 3 Klinikk, Ålesund.859860 Philippines:861 G. Jocson, J. Sibal, Angeles University Foundation, Angeles; R. M. Coching, Davao Doctors 862 Hospital, Davao City; E. Batalla, Davao Doctors Hospital, Davao City; A. Go, Baguio General 863 Hospital, Baguio City; R. Habaluyas, Amang Rodriguez Memorial Medical Center, Marikiina; 864 R. Barcinas, Alexian Brothers Health and Wellness Center, Davao City; R. A. Sy, Ospital ng865 Makati, Makati City; R. A. Estepar, St Pauls Hospital Iloilo, Iloilo; G. Rogelio, St Lukes Medical866 Center, Quezon City; A. Germar, Veterans Memorial Medical Center, Quezon City.867868 Poland:869 J. Trebacz, Centrum Medyczne Zdrowa, Krakow; K. Szymkowiak, Synexus Polska Spzoo,870 Wroclaw; R. Wnetrzak-Michalska, Synexus Polska Spzoo, Katowice; J. Kopaczewski, 871 Specjalistyczne Gabinety Lekarskie Medicor Plus - Jerzy Kopaczewski, Wloclawek; M. 872 Przekwas-Jaruchowska, Synexus Polska Spzoo, Gdynia; G. Kania, Centrum Medyczne 873 Ogrodowa, Skierniewice; M. Zabowka, Centrum Szybkiej Diagnostyki Kardiologicznej 874 Kardiomed M Zabowka E Zabowka Spolka cywilna, Tarnow; E. Mirek-Bryniarska,875 Specjalistyczny Gabinet Lekarski Ewa Mirek-Bryniarska, Krakow; M. Dabrowska, Synexus876 Polska Spzoo, Warszawa; P. Napora, Centrum Badan Klinicznych Przychodnia Badan877 Klinicznych, Wroclaw; M. Konieczny, KO-MED Marek Konieczny Centrum878 Wielospecjalistycznej Opieki Ambulatoryjnej z AmbulatorOsrodkZabieg, Pulawy; J. Spyra, 879 NZOZ Przychodnia Specjalistyczna Andrzej Wittek Henryk Rudzki spolka jawna, Ruda Slaska; 880 R. Lysek, Lecznice Citomed Spzoo, Torun; Z. Pijanowski, NZOZ Twoja Przychodnia Spzoo,

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881 Lublin; B. Grzegorzewski, Centrum Medyczne Clinport, Katowice; Z. Bednarkiewicz, 882 Wojewodzki Specjalistyczny Szpital im dr Wl Bieganskiego w Lodzi, Lodz; Z. Gaciong, 883 Samodzielny Publiczny Centralny Szpital Kliniczny, Warszawa; L. Kinasz, Polsko-884 Amerykanskie Kliniki Serca, Bielsko-Biala; K. Antkowiak-Piatyszek, Synexus Polska Spzoo, 885 Poznan; K. Stania, Nyskie Centrum Sercowo Naczyniowe Polsko-Amerykanskich Klinik Serca, 886 Nysa; M. Szpajer, Poliklinika Evi-Med, Gdynia; P. Staneta, NZOZ Specjalistyczna Przychodnia 887 Lekarska Medikard, Plock; G. Skonieczny, Wojewodzki Szpital Zespolony im Ludwika888 Rydygiera w Toruniu, Torun; E. Ksiezycka-Majczynska, Instytut Kardiologii im Prymasa 889 Tysiaclecia Stefana Kardynala Wyszynskiego, Warszawa; T. Blicharski, Lubelskie Centrum 890 Diagnostyczne, Swidnik; M. Piepiorka, Gabinet Kardiologiczno-Internistyczny, Gdynia; B.891 Wozakowska-Kaplon, NZOZ Centrum Usług Medycznych Promont-Med, Kielce; T. Zechowicz,892 Zechowicz Medeusz-Plus Lekarska Spolka Partnerska, Olsztyn; J. Ilkowski, NZOZ Neuro-Kard,893 Poznan; B. Lubiszewska, Instytut Kardiologii im Prymasa Tysiaclecia Stefana Kardynala 894 Wyszynskiego, Warszawa; J. Hiczkiewicz, NZOZ Kardiologia Nowa Sol, Nowa Sol; K. 895 Wierzbicka, Specjalistyczny Osrodek Medycyny Wieku Dojrzalego Spzoo, Warszawa; D. 896 Kosior, Centralny Szpital Kliniczny Ministerstwa Spraw Wewnetrznych w Warszawie,897 Warszawa; P. Garbocz, Medica Centrum Spzoo, Pszczyna; J. Kubica, Szpital Uniwersytecki nr 1898 im dr Antoniego Jurasza w Bydgoszczy, Bydgoszcz; G. Raczak, Uniwersyteckie Centrum899 Kliniczne, Gdansk; I. Wozniak, KO-MED Centra Kliniczne Staszow, Staszow; J. Cygler, NZOZ 900 Medica, Gizycko; E. Kramarczuk, KO-MED Centra Kliniczne Zamosc, Zamosc; L. Bystryk, 901 Wojewodzkie Centrum Szpitalne Kotliny Jeleniogorskiej, Jelenia Gora; J. Pentela-Nowicka,902 Somed Lodzkie Centrum Osteoporozy, Lodz; M. Dabrowski, SPZOZ Szpital Bielanski im903 Ksiedza Jerzego Popieluszki, Warszawa; P. Podolec, Krakowski Szpital Specjalistyczny im Jana904 Pawła II, Krakow; B. Zieba, Gdanskie Centrum Zdrowia, Gdansk; J. Mosiewicz, Centrum905 Medyczne Luxmed Spzoo, Lublin; T. Pasierski, Miedzyleski Szpital Specjalistyczny w906 Warszawie, Warszawa; W. Dubaniewicz, Pomorskie Centra Kardiologiczne, Starogard Gdanski; 907 M. Banach, SPZOZ Uniwersytecki Szpital Kliniczny, Lodz; G. Tyszecka, Wromedica, Wroclaw; 908 T. Lepich, Indywidualna Specjalistyczna Praktyka Lekarska Roman Spyra, Katowice; A.909 Rychlewska-Hanczewska, Ai Centrum Medyczne, Poznan; T. Guzik, Malopolskie Centrum910 Alergii i Immunoterapii Allmedis Sp. z o.o, Krakow.911912 Portugal:913 P. Monteiro, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra; H. Pereira, Hospital 914 Garcia de Orta, EPE, Almada; L. Oliveira, Centro Hospitalar Cova da Beira, EPE - Hospital Pero 915 da Covilha, Covilha; P. Matos, Hospital Cuf Infante Santo, Lisboa; S. Soares Goncalves, Centro 916 Hospitalar de Setubal EPE Hospital de Sao Bernardo, Setubal; A. Leitao, Centro Hospitalar de 917 Lisboa Ocidental, EPE - Hospital Sao Francisco Xavier, Lisboa; J. Ferreira, Centro Hospitalar de 918 Lisboa Ocidental, EPE - Hospital de Santa Cruz, Carnaxide; A. Vasco Salgado, Hospital919 Professor Doutor Fernando Fonseca, EPE, Amadora; A. T. Timoteo, Centro Hospitalar de Lisboa920 Central, E.P.E. - Hospital de Santa Marta, Lisboa.921922 Romania:923 E. Pintilei, Consultmed SRL, Iasi; E. Badila, Policlinica Center for Clinical and Basic Research 924 SRL, Bucuresti; C. Militaru, Cardiomed SRL, Craiova; M. Tudoran, Spitalul Clinic Judetean de 925 Urgenta Timisoara, Timisoara; C. Arsenescu-Georgescu, Institutul de Boli Cardiovasculare Prof 926 Dr George I.M. Georgescu Iasi, Iasi; F. Mitu, Spitalul Clinic de Recuperare Iasi, Iasi; D.

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927 Zdrenghea, Spitalul Clinic de Recuperare Cluj-Napoca, Cluj-Napoca; D. Lighezan, Spitalul928 Clinic Municipal de Urgenta Timisoara, Timisoara; I. Teodorescu, Spitalul Clinic de Urgenta Sf 929 Ioan Bucuresti, Bucuresti; A. G. Dan, Spitalul Clinic Colentina, Bucharest; M. I. Popescu, Spital 930 Clinic Judetean de Urgenta Oradea, Oradea; I. Coman, Alcor Med SRL, Bucuresti; M. M.931 Vintila, Spitalul Clinic de Urgenta Sfantul Pantelimon, Bucuresti.932933 Russia:934 A. Vishnevsky, Saint Petersburg State Budget Healthcare Institution Pokrovskaya City Hospital, 935 Saint-Petersburg; Y. Lukyanov, SBEI of HPE First Saint-Petersburg State Medical University na 936 Academic I P Pavlov of MoH of the RF, Saint-Petersburg; A. Blokhin, FSBI Outpatient Clinic 3 937 of Russian Federation Presidents Management Department, Moscow; V. Kostenko, Saint938 Petersburg State Budget Healthcare Institution City Polyclinic 109, Saint-Petersburg; Y. Shvarts, 939 Clinical Hospital named after S R Mirotvortsev, Saratov; V. Markov, FSBSI Research Institute 940 for ical Hospi, Tomsk; I. Motylev, SBHI of Nizhniy Novgorod region City Clinical Hospital 33 941 of city Nizhniy Novgorod Leninskyi region, Nizhniy Novgorod; D. Dronov, Budget Healthcare 942 Institution of Omsk region Medical-sanitary unit 9, Omsk; A. Sherenkov, Spb SBHI Medical and 943 sports dispensary of Krasnogvardeisky district of Saint Petersburg, Saint Petersburg; O.944 Barbarash, FSBI Heart and Vessels Diseases complex problems Scientific Research Institution,945 Kemerovo; E. Shutemova, Regional Budget Healthcare Institution Cardiology Dispensary,946 Ivanovo; O. Bolshakova, SBEI of HPE First Saint-Petersburg State Medical University na947 Academic I P Pavlov of MoH of the RF, Saint Petersburg; Z. Kobalava, SBHI of Moscow City948 clinical hospital 64 of Moscow Healthcare department, Moscow; M. Ezhov, FSBI Russian949 Cardiology Research and Production Complex, Moscow; M. Voevoda, FSBI SRI of Therapy of 950 Siberian Branch of RAMS, Novosibirsk; T. Treshkur, FSBI V.A.Almazov Federal Center of 951 heart, blood and endocrinology of Ministry of Health and SD of RF, Saint Petersburg; K.952 Zrazhevskiy, Saint Petersburg SBHI City Hospital 38 named after N A Semashko, Saint-953 Petersburg; L. Pimenov, BHI of Republic Udmurtiya City clinical hospital 9 of Ministry of954 healthcare of Republic Udmurtiya, Izhevsk; O. Solovev, Kirov Regional State Budget Healthcare955 Institution Kirov City Clinical Hospital 1, Kirov; N. Tarasov, FSHI Medical-sanitary unit of956 Chief Administration of IA of Kemerovo region, Kemerovo; M. Arkhipov, State Budget Medical 957 Institution Sverdlovsk Regional Clinical Hospital N1, Ekaterinburg; M. Freidlin, SBHI of SR 958 SPC of specialized types of medical care Ural cardiology institute, Ekaterinburg; S. Shalaev,959 State Autonomy Health care Institution of Tyumen region Scientific and Practical Medical960 Center, Tyumen; P. Yakhontova, SBHI of Novosibirsk Region Novosibirsk regional clinical 961 cardiology dispensary, Novosibirsk; S. Shustov, FSMEI of HPE Military Medical Academy n.a. 962 S.M.Kirov of Ministry of Defense of RF, St. Petersburg; B. Goloshchekin, St Petersburg State 963 Budget Institution of Public Health City Hospital 15, Saint Petersburg; A. Panov, FSBI964 V.A.Almazov Federal Center of heart, blood and endocrinology of Ministry of Health and SD of 965 RF, Saint-Petersburg; B. Bart, Diagnostic and Clinical Center No1 Moscow Health Department, 966 branch No2, Moscow; M. Bubnova, FSBI State Scientific Research Center for Preventive967 Medicine of MoH of RF, Moscow; I. Gordeev, Moscow SBHI City Clinical Hospital 15 n a O M 968 Filatov of Moscow Healthcare Department, Moscow; I. Osipova, NSHI Departmental Hospital at 969 the station Barnaul of OJSC Russian Railways, Barnaul; S. Tereshenko, FSBI Russian970 Cardiology Research and Production Complex, Moscow; E. Solovieva, FSBI Russian971 Cardiology Research and Production Complex, Moscow; A. Meshkov, FSBI State Scientific972 Research Center for Preventive Medicine of MoH of RF, Moscow; D. Zateyshchikov, Moscow

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973974975976977978979980981982983984985986987988989990991992993994995996997998999

1000100110021003100410051006100710081009101010111012101310141015101610171018

State Budget Healthcare Institution City Clinical Hospital 51 of Moscow Healthcare Department, Moscow.

Singapore:L. Tay, Changi General Hospital, Singapore; J. L. Tan, National Heart Centre Singapore, Singapore; T. Subramaniam, Khoo Teck Puat Hospital, Singapore.

Slovakia:D. Pella, Cardio D and R sro Kosice, Kosice; P. Fulop, Interna SK sro, Svidnik; L. Antalik, Nemocnica s poliklinikou Brezno, no, Brezno; A. Dzupina, Alian sro, Bardejov; A. Banikova, KardioMed sro, Lucenec; D. Sosovec, Diab sro, Roznava; L. Urgeova, Kardiomed, NZ sro, Nove Zamky; J. Mazur, Kardio - Onkologia sro, Dolny Kubin; M. Hranai, Kardiocentrum Nitra s.r.o., Nitra; M. Banik, Medi M and M sro, Moldava nad Bodvou; D. Vinanska, Medispol sro, Presov; J. Lennerova, Medilex sro, Rimavska Sobota; F. Kovar, Univerzitna nemocnica Martin, Martin; E. Pastrnakova, Agto spol sro, Kosice; R. Uhliar, Nemocnica svateho Michala as, Bratislava; P. Blasko, MUDr Peter Blasko sro, Banovce nad Bebravou; S. Filipova, Narodny ustav srdcovych a cievnych chorob, a.s., Bratislava; J. Gonsorcik, NZZ - internistu, kardiologa, Kosice; J. Lukacova, Mediluk sro, Snina; R. Oriesek, CardiOr sro, Trencin; K. Hatalova, Cardioconsult sro, Bratislava.

South Africa:M. du Toit, Synexus Clinical Research South Africa, Val de Grace; L. Burgess, Tygerberg Hospital, Parow; I. Ebrahim, Unitas Hospital, Centurion; G. Vawda, Inkosi Albert Luthuli Central Hospital, Durban; S. Lipschitz, Apollo Clinical Research Pty Ltd, Johannesburg; S. Blignaut, Paarl Research, Paarl; J. Engelbrecht, Doctor JM Engelbrecht, Somerset West; T. F. Coetzer, Clinresco Centres Suites, Kempton Park; M. Pretorius, Tiervlei Trial Centre, Cape Town; D. Urbach, Synexus Helderberg Clinical Research Centre, Somerset West; A. Badat, Wits Clinical Research, Soweto; S. Pillay, Seadoone Medical Centre, Amanzimtoti; L. Van Zyl, Clinical Projects Research South Africa, Worcester; M. Abelson, Vergelegen Mediclinic, Somerset West; E. van der Walt, Medicross Roodeport Research Centre, Johannesburg; R. Moodley, Umhlanga Hospital Netcare, Durban; A. Jacovides, Midrand Medical Centre, Midrand; W. M. Oosthuysen, Limaro Research, Bloemfontein; E. Klug, Sunninghill Hospital, Sunninghill; H. Lottering, SCION Clinical Research, Pretoria; J. Kok, Union Hospital, Alberton;J. Saaiman, Kuils River Hospital, Kuils River; S. Dawood, Vincent Pallotti Hospital, Cape Town; D. M. De Jong, Jongaie Research, Pretoria west; C. Kapp, Cardiology Clinical Research, Alberton; E. Makotoko, Universitas Hospital, Bloemfontein; J. Bayat, Durban Medical Centre, Durban; A. Badat, Wits Clinical Research, Soweto; M. Sarvan, Mediclinic Victoria, Tongaat; E. Klug, Sunward Park Hospital, Boksburg; T. Vally, Synexus SA - Stanza Bopape Clinical Research Centre, Pretoria; A. Stapelberg, Syzygy Clinical Research Services Pty Ltd, Pretoria.

South Korea:M. Kim, Dong-A University Hospital, Busan, Seo-gu; J. Bae, Konyang University Hospital, Daejeon; Y. Cho, Seoul National University Bundang Hospital, Seongnam-si; S. Kim, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul; K. H. Han, Asan Medical Center, Seoul; S. Her, The Catholic University of Korea Daejeon St Marys Hospital, Daejeon; D. Choi, Yonsei University Health System Severance Hospital, Seoul; B.

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Kim, Kangbuk Samsung Hospital, Seoul; S. Lee, Ilsan-Paik Hospital, Goyang-si, Gyeonggi-do;B. Hong, Gangnam Severance Hospital, Seoul; W. Kim, Kyung Hee University Hospital, Seoul;S. Rha, Korea University Guro Hospital, Seoul; M. Jeong, Chonnam National University Hospital, Gwangju; G. J. Shin, Ewha Womans University Mokdong Hospital, Seoul.

Spain:M. Vida Gutierrez, Hospital Virgen del Mar, Almeria; J. Lopez Miranda, Hospital Universitario Reina Sofia, Cordoba; M. Valdes Chavarri, Hospital Universitario Virgen de la Arrixaca, El Palmar; X. Pinto Sala, Hospital Universitari de Bellvitge, L Hospitalet de Llobregat; J. R. Gonzalez Juanatey, Hospital Clinico Universitario de Santiago, Santiago de Compostela; F. Civeira Murillo, Hospital Universitario Miguel Servet, Zaragoza; J. L. Zamorano Gomez, Hospital Universitario Ramon y Cajal, Madrid; I. Lekuona Goya, Hospital de Galdakao, Galdakao; A. Iñiguez Romo, Hospital Alvaro Cunqueiro, Vigo; A. Cordero Fort, Hospital Universitario San Juan de Alicante, San Juan de Alicante; J. F. Ascaso Gimilio, Hospital Clinico Universitario de Valencia, Valencia; J. Millan Nuñez-Cortes, Hospital General Universitario Gregorio Marañon, Madrid.

Sweden:C. Lindholm, Capio Citykliniken, Lund; L. Nilsson, University Hospital, Linköping; Å. Olsson, A-plus Science AB, Stockholm; S. Söderberg, Norrlands Universitetssjukhus, Umeå; A. Suutari, Höglandssjukhuset Eksjö, Eksjö; S. Berglund, Falu Lasarett, Falun; T. Mooe, Östersunds sjukhus, Östersund; D. Kusiak, Länssjukhuset Ryhov, Jönköping; S. Bandh, Västmanland sjukhus Västerås, Västerås; G. Dahlén, Vårdcentralen Silentzvägen, Uddevalla; S. Olsson, Helsingborgs lasarett, Helsingborg; N. Witt, Södersjukhuset, Stockholm; P. Tydén, Skånes Universitetssjukhus, Lund; P. Johansson, Sunderby Sjukhus, Luleå; S. Cizinsky, Universitetssjukhuset Örebro, Örebro; G. Falck, Aleris Specialistvård Bollnäs, Bollnäs; S. I. Pettersson, Mälarsjukhuset, Eskilstuna; G. Rasmanis, Karolinska Universitetssjukhuset Huddinge, Stockholm; J. Östergren, Karolinska University Hospital, Stockholm.

Switzerland:F. Mach, Hopitaux Universitaires de Geneve, Geneva 14; T. Moccetti, G. Ponti, Fondazione Cardiocentro Ticino, Lugano; H. J. Beer, K. Steden, Kantonsspital Baden, Baden; F. Eberli, C. Liedtke, Stadtspital Triemli, Zurich; S. Krähenbühl, Universitaetsspital Basel, Basel; A. Linka,B. Brinkers, Kantonsspital Winterthur, Winterthur; D. Ackermann, M. Winter-Pauling, Inselspital Bern, Bern; P. Michel, Centre Hospitalier Universitaire Vaudois, Lausanne.

Taiwan:H. Yeh, Mackay Memorial Hospital Tamsui Branch, New Taipei City; C. F. Tsai, K. Ueng, Chung Shan Medical University Hospital, Taichung City; M. Charng, Taipei Veterans General Hospital, Taipei; C. Wu, C. J. Chen, C. I. Cheng, C. H. Yang, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung; C. Hsia, Changhua Christian Hospital, Changhua; J. Juang, F. Chiang, National Taiwan University Hospital, Taipei; I. Hsieh, Linkou Chang Gung Memorial Hospital of Chang Gung Medical Foundation, Taoyuan; W. Lai, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung; C. Huang, Cathay General Hospital, Taipei; Y. Hsieh, Chi Mei Medical Center, Tainan.

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Turkey:T. Sahin, Kocaeli Universitesi Tip Fakultesi, Kocaeli; M. Duzenli, Necmettin Erbakan Universitesi Meram Tip Fakultesi, Konya; Z. Yigit, Istanbul University Cardiology Institute, Istanbul; M. Demir, Cukurova Universitesi Tip Fakultesi, Adana; M. B. Yilmaz, Cumhuriyet Universitesi Tip Fakultesi, Sivas; I. H. Muderrisoglu, Baskent Universitesi Ankara Hastanesi, Ankara; C. Kirma, Kartal Kosuyolu Yuksek Ihtisas Egitim ve Arastirma Hastanesi, Istanbul; E. Ercan, Izmir Medicalpark Hastanesi, Izmir; L. Kayikcioglu, Ege Universitesi Tip Fakultesi, Izmir; Y. Balbay, Turkiye Yuksek Ihtisas Hastanesi, Ankara; S. Tokgozoglu, Hacettepe Universitesi Tip Fakultesi Hastanesi, Ankara.

Ukraine:O. Kraydashenko, Communal Institution City Clinical Hospital No 6, Zaporizhzhia; I. Lymar, Communal Noncommercial Institution Consultative and Diagnostic Center of Desnianskyi District of Kyi, Kyiv; O. Kulynych, Communal Institution Zaporizhzhia Regional Clinical Hospital of Zaporizhzhia Regional Council, Zaporizhzhya; O. Prokhorov, Communal Healthcare Institution Kharkiv City Clinical Hospital No27, Kharkiv; O. Karpenko, Kyiv City ClinicalHospital 1, Kyiv; I. Kraіz, Railway Transport Kharkiv Clinical Hospital No1 of HealthcareCenter Branch of Public Joint Stock, Kharkiv; I. Vakaliuk, vano-Frankivsk Regional Clinical Cardiological Dispensary, Ivano-Frankivsk; M. Stanislavchuk, Vinnytsia M I Pyrogov Regional Clinical Hospital Vinnytsia M I Pyrogov National Medical University, Vinnytsia; O. Korzh, Medical and Sanitary Unit of Open Joint Stock Company Kharkiv S Ordzhonikidze Tractor Plant, Kharkiv; I. Rudyk, Government Institution L T Malaya Therapy National Institute of NAMS of Ukraine, Kharkiv; S. Zhurba, Cherkasy Region Cardiological Center, Cherkasy; Y. Svishchenko, State Institution National Scientific Center Acad Strazhesko Institute of Cardiology, Kyiv; V. Tseluyko, Communal Healthcare Institution Kharkiv City Clinical Hospital No8 Kharkiv Medical Academy of Post g, Kharkiv; O. Gyrina, Limited Liability Company Treatment and Diagnostic Center Adonis plus, Kyiv; D. Reshotko, Oleksandrivska Clinical Hospital of Kyiv, Kyiv; M. Kopytsya, Government Institution L T Malaya Therapy National Institute of NAMS of Ukraine, Kharkiv; V. Volkov, Government Institution L T Malaya Therapy National Institute of NAMS of Ukraine, Kharkiv; G. Myshanych, Synexus State Institution Road Clinical Hospital 2 of Kyiv Station, Kyiv; B. Rebrov, Luhansk Regional Clinical Hospital State Institution Luhansk State Medical University, Lugansk; M. Rishko, Transcarpathian Regional Clinical Cardiological Dispensary, Uzhgorod; L. Rudenko, Kyiv City Clinical Emergency Medical Care Hospital, Kyiv; V. Shatylo, State Institution D F Chebotariov Institute of Gerontology of NAMS of Ukraine, Kyiv; O. Parkhomenko, State Institution National Scientific Center Acad MD Strazhesko Institute of cardiology of NAMS Ukr, Kyiv; L. Yena, State Institution D F Chebotariov Institute of Gerontology of NAMS of Ukraine, Kyiv; O. Golovchenko, Medical Clinical Investigational Center of Medical Center Health Clinic LLC, Vinnytsia; I. Sorokina, Synexus Medical Center of Private Educational Institution Institute, Kyiv; Y. Malynovsky, Communal Inst regional Medical Centre of Cardiovascular Diseases of Zaporizhzhia Regional Council, Zaporizhzhia.

United Kingdom:P. Ivan, Synexus Merseyside Clinical Research Centre, Liverpool; M. Blagden, Ashgate Medical Practice, Chesterfield; H. Dear, Synexus Scotland Clinical Research Centre, Glasgow; A. Mathew, Synexus Midlands Clinical Research Centre, Birmingham; S. Lagocki, Synexus

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Lancashire Clinical Research Centre, Chorley; V. Kondagunta, Synexus Thames Valley Clinical Research Centre, Reading; A. Ahsan, Nottingham City Hospital, Nottingham; C. McKinnon, Castlemilk Group Practice, Glasgow; F. Douglas, Synexus North East Clinical Research Centre, Hexham; S. Thom, Imperial College Healthcare NHS Trust, London; G. Fiore, Synexus Manchester Clinical Research Centre, Manchester; M. Caulfield, D. Collier, Barts Health NHS Trust, London; M. Lynch, Lister Hospital, Stevenage; H. Thomas, Synexus Wales Clinical Research Centre, Cardiff; S. Bain, Singleton Hospital, Swansea; A. Hall, Leeds General Infirmary, Leeds; D. McNally, Ormeau Health Centre, Belfast; M. Fisher, Royal Liverpool University Hospital, Liverpool; P. Keeling, Torbay Hospital, Torquay; A. Al-Bahrani, A. Baksi, St Marys Hospital, Newport; G. Lip, City Hospital, Birmingham; A. Ellery, Cape Cornwall Surgery, Penzance; J. Purohit, Brannel Surgery, St Austell; C. Travill, Luton and Dunstable NHS Foundation Trust Hospital, Luton; F. Cappuccio, University Hospital Coventry, Coventry; G. Davis, Aintree University Hospital, Liverpool; R. Gaunt, Rowden Surgery, Chippenham; D. Adlam, Glenfield Hospital, Leicester; N. Asamoah, P. Harvey, S. Maxwell, Crouch OakFamily Practice, Addlestone; F. Jaafar, R. Falk, South Axholme Practice, Haxey, Doncaster; T. McCormack, Whitby Group Practice, Whitby; B. Jupp, D. Jenkinson, Royal Bournemouth Hospital, Bournemouth; M. Pye, York Hospital, York; P. Ainsworth, Sherbourne Medical Centre, Leamington Spa; A. Chauhan, Blackpool Teaching Hospital, Blackpool; D. Connolly, Sandwell General Hospital, West Bromwich; N. Paul, Ashfield Primary Care Centre, Sandbach;H. Fairlie, Connor Downs Surgery, Hayle; C. Fox, Northampton General Hospital, Northampton;S. Muzulu, Rotherham General Hospital, Rotherham; J. Trevelyan, Worcestershire Royal Hospital, Worcester; R. Aggarwal, Basildon University Hospital, Basildon; B. Issa, Wythenshawe Hospital, Manchester; P. Saravanan, George Eliot Hospital, Nuneaton; K. Cruickshank, Guys and St Thomas NHS Foundation Trust, London; D. Gorog, Queen Elizabeth II Hospital, Welwyn Garden City; S. Heller, Northern General Hospital, Sheffield; D. Newby, Edinburgh Royal Infirmary, Edinburgh; A. Nicolson, West Suffolk Hospital, Bury St Edmunds;P. O Hare, Hospital of St Cross, Rugby; P. Donnelly, Ulster Hospital, Belfast; S. Rutherfurd, N. Armstrong, Morrab Surgery, Penzance; M. de Belder, James Cook University Hospital, Middlesbrough; J. Finlayson, Highlands Clinical Research Facility, Inverness; J. Harvey, Wrexham Maelor Hospital, Wrexham; A. Hoye, Castle Hill Hospital, Cottingham; D. Kingston,P. Cormie, Penalverne Surgery, Penzance; D. Sarkar, Derriford Hospital, Plymouth; A. Negahban, A. Ahmed, M. Al-Bazzaz, Barnsley Hospital, Barnsley; P. Saravanan, M. Banerjee, Arrowe Park Hospital, Wirral; J. Webster, Aberdeen Royal Infirmary, Aberdeen; N. Wyatt, The Bradford on Avon and Melsham Health Partnership, Wiltshire; S. Muir, Southern General Hospital, Glasgow; M. Cummings, Queen Alexandra Hospital, Portsmouth; I. Mackenzie, T. MacDonald, Ninewells Hospital and Medical School, Dundee; R. Senior, Northwick Park Hospital, Harrow; N. Capps, Princess Royal Hospital, Telford; K. Fotherby, New Cross Hospital, Wolverhampton; H. McIntyre, Conquest Hospital, St. Leonards-on-Sea; J. Aldegather, Portmill Surgery, Hitchin; L. Dixon, Royal Victoria Hospital, Belfast; R. Saksena, Colchester General Hospital, Colchester; R. Butler, University Hospital of North Staffordshire, Stoke-on-Trent.

United States:D. Ramstad, Hampton Roads Center for Clinical Research, SUFFOLK, VA; B. Pierpont, Advance Medical Research, Saint Petersburg, FL; D. Levinson, Apex Medical Research Incorporate, Chicago, IL; A. Mohammed, Apex Medical Research, Inc, Springfield, OH; T. Haddad, Virginia Heart, Falls Church, VA; A. Goel, Kansas City Veterans Affairs Medical

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Center, Kansas City, MO; K. Dave, Heart Care Associates, Hopewell, VA; W. H. Haught, Heart Center Research LLC, Huntsville, AL; A. Desire, Andre P Desire MD PA, Wichita Falls, TX; K. Hershon, North Shore Diabetes and Endocrine Associates, New Hyde Park, NY; M. Napoli, Clinical Trials of America Inc, Monroe, LA; L. Tami, M. Abdurrahman, Research Physicians Network Alliance, Hollywood, FL; R. Rothschild, Cabrillo Cardiology Medical Group, Oxnard, CA; S. Khurana, Healthy Heart Cardiology, Grandville, MI; D. Gupta, Tennessee Center for Clinical Trials, Tullahoma, TN; D. Cheung, Long Beach Center for Clinical Research, Long Beach, CA; S. Hearne, Delmarva Heart Research Foundation Inc, Salisbury, MD; S. Grubb, Tabor City Family Medicine, Tabor City, NC; A. Miller, Alta Pharmaceutical Research Center Inc, Dunwoody, GA; I. Baird, Remington Davis Clinical Research Inc, Columbus, OH; A. Marcus, South Orange County Endocrinology, Laguna Hills, CA; S. Srivastava, Pentucket Medical Associates, Haverhill, MA; L. Forgosh, HealthEast Medical Research Institute, Saint Paul, MN; R. Fritz, Kootenai Heart Clinics, LLC, Coeur D'Alene, ID; M. Mays, Portland Preventive Cardiology, Portland, OR; B. Bertolet, Cardiology Associates Research LLC, Tupelo, MS; J. Reddy, Sierra Clinical Research, Roseville, CA; M. Khan, AngioCardiac Care of Texas, Houston, TX; S. Nakhle, Palm Research Center Inc, Las Vegas, NV; S. Dill, S Bar D Inc, Pryor, OK; G. Fishbein, Dayton Heart Center, Dayton, OH; B. Khan, Atlanta Clinical Research Centers LLC, Atlanta, GA; H. Marais, Beaver Medical Group, Banning, CA; M. Reschak, Medex Healthcare Research Inc- St Louis, Saint Louis, MO; M. Malone, Charlotte Heart Group Research Center, Port Charlotte, FL; V. Nadar, Capital Area Research LLC, Camp Hill, PA; R. Whitney, Bryan Heart, Lincoln, NE; A. Reichman, Clinical Trial Network, Houston, TX; H. Reyes, MediSphere Medical Research Center LLC, Evansville, IN; M. El Shahawy, Cardiovascular Center of Sarasota, Sarasota, FL; A. Rabinowitz, South Texas Cardiovascular Consultants, Kerrville, TX; D. Weinstein, Zasa Clinical Research, Boynton Beach, FL; N. Farhat, North Ohio Heart Center-Elyria, Elyria, OH; D. Onyema, Healthwise Medical Associates, NewYork, NY; R. Potu, Nature Coast Clinical Research LLC, Crystal River, FL; L. Runquist, Piedmont Medical Group Research of Charleston, Charleston, SC; O. Barnum, Keyser Avenue Medical Park Medical Research Inc, Natchitoches, LA; T. Crater, Hutchinson Clinic PA, Hutchinson, KS; J. Fialkow, Cardiovascular Research Center of South Florida, Miami, FL; A. Shah, Piedmont Research Partners, Indian Land, SC; C. Thompson, Craig S Thompson MD LLC, Marion, OH; A. Wiseman, Eastern Maine Medical Center, Bangor, ME; T. Doyle, Northeast Ohio Heart Associates, LLC, Willoughby, OH; D. Henderson, Cardiology Research Associates Daytona Beach, FL; W. Herzog, Johns Hopkins University, Columbia, MD; R. Schnitzler, Mercury Medical LLC, San Antonio, TX; K. Carr, Carr Cardiology, Oceanside, CA;M. Davis, Rochester Clinical Research Inc, Rochester, NY; N. Nagajothi, Aultman Cardiology Clinical Trials, Canton, OH; S. Olsen, Utah Cardiology PC, Layton, UT; W. Rogers, University of Alabama at Birmingham Medical Center, Birmingham, AL; J. Rubino, Piedmont Medical Group Research of Raleigh, Raleigh, NC; I. Singh, Mercy Medical Group, Sacramento, CA; G. Tarleton, Clinical Trials of America Inc, Winston-Salem, NC; R. Bhagwat, Cardiovascular Research of Northwest Indiana LLC, Munster, IN; D. Clardy, Sanford Heart Center, Fargo, ND;M. Jardula, Desert Medical Group, Palm Springs, CA; J. Robinson, The University of Iowa College of Public Health, Iowa City, IA; M. Torres, A Plus Research Inc, Miami, FL; N. Vijay, Aurora Denver Cardiology Associates PC, Denver, CO; N. Farris, The Research Group of Lexington LLC, Lexington, KY; J. Lillo, Elite Clinical Studies LLC, Phoenix, AZ; P. Moriarty, University of Kansas Medical Center, Kansas City, KS; C. Recknor, Chris Recknor MD PC,

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Gainesville GA; P. Berlacher, ProMedica Northwest Ohio Cardiology Consultants, Toledo, OH;T. Christensen, Calabash Medical Center, Calabash, NC; N. Gabra, Burke Internal Medicine and Research, Burke, VA; M. Issa, Clinical Research of Hollywood PA, Pembroke Pines, FL; M. Janik, Piedmont Medical Group Research of Wilmington, Wilmington, NC; A. Lawless, Biofortis Inc, Addison, IL; D. Molter, North Myrtle Beach Family Practice, North Myrtle Beach, SC; E. Stout, Crossroads Clinical Research Inc, Mooresville, NC; B. Brezina, Southeastern Clinical Research and Management LLC, Augusta, GA; E. Claxton, Maine Research Associates, Auburn, ME; R. Linsky, University of Colorado Memorial Health System, Colorado Springs, CO; J. Poock, Northeast Iowa Medical Education Foundation, Waterloo, IA; R. Remler, Fellows Research Alliance Inc, Savannah, GA; H. Roseman, Cardiology Wellness Center, Nashville, TN;E. Schramm, D. Schlager, St Johns Center for Clinical Research, Ponte Vedra, FL; T. Al-Joundi, Gateway Cardiovascular Research Center Inc, St Louis, MO; J. Amin, Clearwater Cardiovascular and Interventional Consultants Bardmoor, Largo, FL; J. Hitchcock, Belleville Family Medical Associates, Belleville, IL; S. Isserman, Clinical Trials of America Inc, Hickory, NC; J. Kirstein, Advanced Clinical Research, West Jordan, UT; J. Rider, Cardiology Associates of Bellin Health, Green Bay, WI; M. Shalek, Legacy Heart Center Plano, Plano, TX; H. Sherman, Southern Maine Health Care, Biddeford, ME; M. Bernstein, Louisiana Heart Center, Slidell, LA; L. Chandra, Chicago Medical Research LLC, Hazel Crest, IL; R. Hatharasinghe, Piedmont Healthcare, Statesville, NC; H. Ibrahim, North Ohio Heart Center-Sandusky, Sandusky, OH; B. Iteld, Louisiana Heart Center, Hammond, LA; K. Linzmeyer, St Lukes Idaho Cardiology Associates, Meridian, ID; B. Seaton, Research Institute of the Carolinas, Mooresville, NC; S. Zeig, Pines Clinical Research Inc, Hollywood, FL; E. Christofides, Endocrinology Associates Inc, Columbus, OH; R. Dunbar, Perelman Center for Advanced Medicine, Philadelphia, PA; S. Griffin, Head to Toe Research and Wellness LLC, Athens, GA;N. Kohli, Discovery Clinical Trials, Austin, TX; M. Koren, Jacksonville Center for Clinical Research, Jacksonville, FL; W Pharr, Medication Management LLC, Greensboro, NC; D. Purdy, Black Hills Cardiovascular Research, Rapid City, SD; R. Spencer, Cardiology Consultants, Pensacola, FL; G. Yeoman, Founders Research Corporation, Philadelphia, PA; S. Banerjee, Veterans Affairs North Texas Health Care System, Dallas, TX; H. B. Cheek, University of North Carolina Regional Physicians Carolina Cardiology, High Point, NC; E. Engel, Bayview Research Group LLC, Valley Village, CA; G. Hamroff, New York University Langone at Hudson Valley Cardiology, Cortlandt Manor NY; R. Huling, Olive Branch Family Medical Center, Olive Branch, MS; L. Kozlowski, Buffalo Medical Group, Buffalo, NY; P. Levin, Model Clinical Research Inc, Baltimore, MD; S. Makam, Mid Hudson Medical Research PLLC, New Windsor, NY; M. Meengs, Mercy Health Partners, Muskegon, MI; R. Bhushan, Metabolic Center of Louisiana Research Foundation, Baton Rouge, LA; B. Erickson, Saint Cloud Hospital, Saint Cloud, MN; L. Herman, Herman Clinical Research LLC, Suwanee, GA; E. Lo, Edgewater Medical Research, Edgewater, FL; E. McDowell, Ilumina Clinical Associates, Indiana, PA; F. McGrew, Stern Cardiovascular Foundation Inc, Germantown, TN; M. Miller, University of Maryland Medical Center, Baltimore, MD; J. Ord, Aurora Denver Cardiology Associates, Aurora, CO; R. Webel, University of Missouri Health System, Columbia, MO; G. Wilhoit, PMG Research of Charleston, Moncks Corner, SC; J. Wise, Crescent City Clinical Research, Metairie, LA; E. Yang, University of Washington, Seattle, WA; M. Budoff, Harbor University of California Medical Center, Torrance, CA; J. Collins, Saint Marys of Michigan, Saginaw, MI; I. Dauber, South Denver Cardiology Associates, Littleton, CO; L. Dobkin, Clinical Trials Research Services LLC, Pittsburgh, PA; A. Focil, Diverse Research Solutions, Oxnard, CA; W. Gandy,

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Ellipsis Group, Atlanta, GA; J. Pasquini, Novant Health Heart and Vascular Institute, Charlotte, NC; M. Ramos, Intercoastal Medical Group, Sarasota, FL; D. Rodriguez, Advanced Research Institute Inc, New Port Richey, FL; R. Rosenson, Mount Sinai Medical Center, New York, NY;K. Sanford, Project Management Institute of Health Inc, Atlanta, GA; A. Schlau, Palm Harbor Medical Associates, Palm Harbor, FL; B. Snyder, Southgate Medical Group, West Seneca, NY;L. Stonesifer, Larry D Stonesifer MD Inc PS, Federal Way, WA; A. Tang, Chambersburg Hospital, Chambersburg, PA; J. De Souza, Glacier View Research Institute Endocrinology, Kalispell, MT; M. Elam III, Memphis Veterans Affairs Medical Center, Memphis, TN; J. French, Cor Healthcare Medical Associates, San Pedro, CA; J. Guyton, Duke University Medical Center, Durham, NC; E. Hage Korban, Kore Cardiovascular Research, Jackson, TN; D. Kereiakes, The Christ Hospital, Cincinnati, OH; M. King, Clearwater Cardiovascular Consultants, Clearwater, FL; I. Loh, Westlake Medical Research, Thousand Oaks, CA; J. Navarro, Genesis Clinical Research Inc, Tampa, FL; R. Simons, Nanticoke Cardiology Associates, Seaford, DE; T. Tobin, Portland Preventive Cardiology, LLC, Longview, TX; L. Younis, Gateway Cardiology, PC, Jerseyville, IL; R. Aboufakher, Altru Health System, Grand Forks, ND; D. Baldari, Cardiology Partners Clinical Research Institute, Wellington, FL; C. Ballantyne, Baylor College of Medicine, Houston, TX; S. Banerjee, University of Texas Southwestern Medical Center, Dallas, TX; R. Broughton, CB Flock Research Corporation, Mobile, AL; C. Eaton, Memorial Hospital of Rhode Island, Pawtucket, RI; J. Johnston, Arrowhead Health Centers, Glendale, AZ; W. Simon, Professional Research Network Of Kansas, Wichita, KS; S. Thomson, Southern Arizona Veterans Administration Health Care System, Tuscon, AZ; K. Vora, Research Integrity LLC, Owensboro, KY; D. Youngman, Kansas Nephrology Research Institute LLC, Wichita, KS; O. Alzohaili, Alzohaili Medical Consultants, Dearborn, MI; E. Auerbach, Oklahoma Heart Institute, Tulsa, OK; C. Brown, Mobile Heart Specialists PC, Mobile, AL; B. Burrough, McFarland Clinic PC, Ames, IA; Y. Chen, Bendel Medical Research Center, Lafayette, LA; M. Gilpatrick, Neurocare Center for Research, Newton, MA; J. Landzberg, Westwood Cardiology Associates, Westwood, NJ; C. Mitchell, MedTrial, LLC, Columbia, SC; L. Rice, Clinical Study Center of Asheville, LLC, Asheville, NC; M. Rubenfire, University of Michigan Health System, Dominos Farms, Ann Arbor, MI; C.W. Sofley, Internal Medicine Associates of Anderson PA, Anderson, SC; D. Strobl, Sparrow Clinical Research Institute, Lansing, MI; K. Atassi, Porter Physician Services, Valparaiso, IN;W. Davila, Fleming Island Center for Clinical Research, Fleming Island, FL; J. Diogo, New England Center for Clinical Research/ Internal Medicine and Cardiology Associates, LLC, Fall River, MA; T. Fagan, Arizona Endocrine and Rheumatology Associates, Tucson, AZ; I. Joffe, Lourdes Cardiology Services, Voorhees, NJ; J. Krishna, UnityPoint Health Meriter Heart and Vascular Institute, Madison, WI; E. Osea, Innovative Clinical Research, Harbor City, CA; W. Penny, Veterans Affairs San Diego Healthcare System, San Diego, CA; W. Rowe, Great Falls Clinic LLP, Great Falls, MT; M. Shapiro, Oregon Health and Science University, Portland, OR;J. Welker, Anne Arundel Medical Center, Annapolis, MD; R. Benton, Capital Cardiology Associates, Troy, NY; D. Dobratz, College Park Family Care Center Physicians Group, Overland Park, KS; F. Fortuin, Mayo Clinic Hospital, Phoenix, AZ; J. Graham, Saint Francis Medical Group Indiana Heart Physicians, Indianapolis, IN; B. Henry, Therapeutic Research Institute of Orange County, Laguna Hills, CA; B. Kusnick, Cardiovascular Associates Research LLC, Covington, LA; M. Lutskiy, Beacon Clinical Research LLC, Quincy, MA; A. McRae, Centennial Heart Cardiovascular Consultants, LLC, Nashville, TN; K. Sanford, Health First Physicians Inc, Atlanta; W. Saway, Columbia Medical Practice, Columbia, MD; J. Scott,

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National Clinical Research Richmond Inc, Richmond, VA; M. Shah, Shah Associates, MD LLC, Charlotte Hall, MD; B. Weinberg, Community Hospital South, Indianapolis, IN; S. Zarich, Bridgeport Hospital, Bridgeport, CT; R. Acheatel, Escondido Cardiology Associates Incorporated, Escondido, CA; C. Case, Jefferson City Medical Group PC, Jefferson City, MO; J. Earl, Piedmont Medical Group Research of Hickory LLC, Hickory, NC; S. Fernandez, State University of New York- University at Buffalo, Buffalo, NY; G. Giugliano, Baystate Medical Practice, Springfield, MA; Y. Handelsman, Metabolic Institute of America, Tarzana, CA; P. Hermany, Grand View Lehigh Valley Health Services, Sellersville, PA; S. Holder, International Clinical Research LLC, Sanford, FL; M. Kashyap, Veterans Affairs Long Beach Healthcare System, Long Beach, CA; A. Khan, The Iowa Clinic, PC, Des Moines, IA; E. Lader, Mid Valley Cardiology, Kingston, NY; J. Peniston, Feasterville Family Health Care Center, Feasterville, PA;T. Raoof, TJoseph Raoof MD Inc Encino Research Center, Encino, CA; J. Sacco, Stratton Veterans Affairs Medical Center, Albany, NY; K. Shore, Kenneth A Shore, MD, Plano, TX; D. Spriggs, Clearwater Cardiovascular and Interventional Consultants Countryside, Safety Harbor, FL; S. Stringam, Saint Lukes Regional Medical Center, Nampa, ID; N. Tahirkheli, South Oklahoma Heart Research, Oklahoma City, OK; E. Delgado, Family Medical Center dba Discovery Clinical Trials, Orlando; W. Derian, Quincy Medical Group, Quincy, IL; J. Greenwald, Medex Healthcare Research Inc, New York, NY; M. Harris, Bend Memorial Clinic, Bend, OR; R. Jackson, Dominion Medical Associates Incorporated, Richmond, VA; G. Marhefka, Thomas Jefferson University Hospital, Philadelphia, PA; W. McElveen, Bradenton Research Center, Bradenton, FL; A. Mooss, Chi Health Alegent Creighton Clinic, Omaha, NE;P. Morris, Medical University of South Carolina, Charleston, SC; J. Murray, Meharry Medical College, Nashville, TN; P. Pearlstein, Pearl Clinical Research Inc, Norristown, PA; A. Raisinghani, University of California San Diego Medical Center, San Diego, CA; S. Rezkalla, Marshfield Clinic, Marshfield, WI; L. Sakhrani, Comprehensive Research Institute, Alhambra;D. Schreibman, Sarasota Memorial Hospital Clinical Research Center, Sarasota, FL; E. Shaoulian, Pacific Coast Cardiology and Research, Newport Beach, CA; J. Steinsapir, Metabolic Research Institute Inc, West Palm Beach, FL; A. Yataco, IRC Clinics Inc, Towson, MD; A. De La Cruz, Genesis Research Center LLC, Miami, FL; M. Fredrick, HealthCare Partners Department of Research, Huntington Beach, CA; E. Goldenberg, Christiana Care Health System, Christiana Hospital, Newark, DE; D. Lee, California Cardiac Institute Medical Group, Glendale, CA; K. McCullum, York Hospital, York, PA; B. McLellan, Saint Charles Heath Center, Bend, OR; L. Stephens, Palmetto Clinical Trial Services, LLC, Fountain Inn, SC; S. Wilson, Partners in Clinical Research, Cumberland, RI; A. Alfieri, Alfieri Cardiology Research Company Inc, Wilmington, DE; M. Mandviwala, Northwest Heart Center, Tomball, TX; D. ORourke, Veterans Affairs Medical Center, White River Junction, VT; A. Samal, Northwest Houston Cardiology, Houston, TX; K. Sanford, Blair Medical Associates, Atlanta, GA; J. Schmedtje, Roanoke Heart Institute, Roanoke, VA; F. Waxman, GSA Medical Research LLC, Hollywood; R. Carhart, State University of New York Upstate Medical University, Syracuse, NY; B. Clements, Intermountain Medical Center, Murray, UT; C. Dyke, Alaska Heart Institute, Anchorage, AK; J. Ghali, Mercer University School of Medicine, Macon, GA; L. Gruberg, Stony Brook University Medical Center, Stony Brook, NY; T. Hack, Primary Care Cardiology Research, Inc, Ayer; A. Jehle, International Heart Institute of Montana, Missoula, MT; B. Pogue, Selah Medical Center, Boise;C. Schooley, Centrura Health Research Center, Colorado Springs, CO; G. Shifrin, Cleveland Clinic Cardiology Associates, Atlantis.

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Table S1 – Efficacy Outcomes With Evolocumab vs. Placebo Stratified by Baseline LDL-C

Baseline LDL-C <70 mg/dLa

(N=2034)Baseline LDL-C >70 mg/dL

(N=25529)Outcome Evolocumab

(N=1030)Placebo

(N=1004)Hazard Ratio

(95% CI)Evolocumab (N=12754)

Placebo (N=12775)

Hazard Ratio (95% CI) PINT

Primary endpointb 86 (8.3) 106 (10.6) 0.80 (0.60-1.07) 1258 (9.9) 1457 (11.4) 0.86 (0.79-0.92) 0.65Key secondary endpointc 48 (4.7) 68 (6.8) 0.70 (0.48-1.01) 768 (6.0) 945 (7.4) 0.81 (0.73-0.89) 0.44

Other endpointsCardiovascular death 14 (1.4) 14 (1.4) 0.97 (0.46-2.04) 237 (1.9) 226 (1.8) 1.05 (0.87-1.26) 0.88

Myocardial infarction 25 (2.4) 43 (4.3) 0.58 (0.35-0.94) 443 (3.5) 596 (4.7) 0.74 (0.65-0.84) 0.32

Stroke 17 (1.7) 20 (2.0) 0.85 (0.44-1.62) 190 (1.5) 242 (1.9) 0.78 (0.65-0.95) 0.84

Hospitalized for unstable angina 16 (1.6) 19 (1.9) 0.84 (0.43-1.64) 220 (1.7) 220 (1.7) 1.00 (0.83-1.20) 0.63

Coronary revascularization 51 (5.0) 65 (6.5) 0.78 (0.54-1.13) 708 (5.6) 900 (7.0) 0.78 (0.71-0.86) 0.97

Baseline LDL-C data were not available for one patient randomized to placebo. To convert LDL-C to millimoles per liter, multiply by 0.0259.Data shown are n (%)a By trial design, these patients had non-HDL-C > 100 mg/dLb Cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularizationc Cardiovascular death, myocardial infarction, stroke

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1349 Table S2: Patient Characteristics Stratified Potency of Background Statina

Characteristics Maximal (N=7533)

Submaximal (N=20031)

P-value

Age, mean + SD – yr 61.1 + 8.9 63.0 +9.0 <0.001Male 5722 (76.0) 15073 (75.2) 0.22White raceb 7027 (93.3) 16431 (82.0) <0.001Region <0.001

North America 1877 (24.9) 2694 (13.4)Europe 4862 (64.5) 12473 (62.3)Latin America 180 (2.4) 1643 (8.2)Asia, Pacific, South Africa 614 (8.2) 3221 (16.1)

Type of atherosclerosisc

Myocardial infarction 6499 (86.3) 15852 (79.1) <0.001Non-hemorrhagic stroke 1182 (15.7) 4155 (20.7) <0.001Peripheral artery disease 1012 (13.4) 2630 (13.1) 0.51

Cardiovascular risk factorsHypertension 6019 (79.9) 16065 (80.2) 0.57Diabetes mellitus 2536 (33.7) 7545 (37.7) <0.001Current cigarette use 2067 (27.4) 5710 (28.5) 0.079

Statin intensity at baselined NAHigh 7533 (100) 11570 (57.8)Moderate 0 8392 (41.9)Low, unknown, or no data 0 69 (0.3)

Ezetimibe 672 (8.9) 768 (3.8) <0.001Other cardiovascular medications

Aspirin, P2Y12 inhibitor, or both 7122 (94.6) 18310 (91.5) <0.001Beta-blocker 6056 (80.4) 14759 (73.8) <0.001Renin-angiotensin-aldosterone

inhibitor6016 (79.9) 15517 (77.5) <0.001

Median lipid measures in mg/dL [IQR]LDL cholesterol 93.0 [80.0,

111.5]91.0 [79.5, 107.5] <0.001

Total cholesterol 168.0 [150.5,190.5]

167.0 [151.0, 187.5] 0.004

HDL cholesterol 43.0 [36.5, 51.5] 44.0 [37.0, 53.0] <0.001Triglycerides 133.0 [98.5, 181.0] 133.0 [100.0, 182.0] 0.19

LDL cholesterol < 70 mg/dL at baseline 524 (7.0) 1510 (7.5) 0.10

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Table S2 – Efficacy Outcomes With Evolocumab vs. Placebo Stratified by Potency of Background Statin

Maximal Potency Background Statin Submaximal Potency Background Statin

OutcomeEvolocumab

(N=3758)Placebo

(N=3775)Hazard Ratio

(95% CI)Evolocumab (N=10026)

Placebo (N=10005)

Hazard Ratio (95% CI) PINT

Primary endpointa 421 (11.2) 489 (13.0) 0.86 (0.75-0.98) 923 (12.4) 1074 (13.9) 0.85 (0.78-0.93) 0.88Key secondary endpointb 246 (6.5) 315 (8.3) 0.78 (0.66-0.92) 570 (7.9) 698 (9.7) 0.81 (0.72-0.90) 0.71

Other endpointsCardiovascular death 74 (2.0) 67 (1.8) 1.11 (0.80-1.54) 177 (2.6) 173 (2.3) 1.02 (0.83-1.26) 0.67

Myocardial infarction 141 (3.8) 222 (5.9) 0.63 (0.51-0.78) 327 (4.3) 417 (5.8) 0.78 (0.67-0.90) 0.11

Stroke 60 (1.6) 60 (1.6) 1.00 (0.70-1.44) 147 (2.3) 202 (2.8) 0.72 (0.58-0.89) 0.11

Hospitalized for unstable angina 75 (2.0) 90 (2.4) 0.84 (0.62-1.14) 161 (2.4) 149 (1.9) 1.08 (0.86-1.35) 0.20

Coronary revascularization 248 (6.6) 316 (8.4) 0.78 (0.66-0.93) 511(6.5) 649 (8.8) 0.78 (0.69-0.88) 0.95

Maximal potency statin = atorvastatin 80 mg or rosuvastatin 40 mg daily. Data shown are n (%).aCardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularizationbCardiovascular death, myocardial infarction, stroke

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Figure 1A. Efficacy Outcomes Stratified by Baseline LDL-C

Primary Composite Endpoint

All Patients •Baseline LDL-C <70 mg/dLI

Baseline LDL-C 2:70 mg/dl 0II

HR (95°/o Cl}

0.85 (0.79-0.92)

0.80 (0.60-1.07)

0.86 (0.79-0.92)

Pinteraction

0.65

0.4 1.0 2.5

Secondary Composite Endpoint

All Patients

II

0.80 (0.73-0.88)

Baseline LDL-C <70 mg/dL

Baseline LDL-C 2:70 mg/dl0.70 (0.48-1.01)

I

0.81 (0.73-

0.89)

II

•I

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0.44OA 1D 2.5

Evolocumab better Placebo better

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N=2034

Hazard ratio o.70(95°/o C l, 0.48-1.01)

- -

Placebo

Evolocumab

Figure 1B. Cardiovascular Death, Myocardial Infarction, or Stroke in Patients with Baseline LDL-C <70 mg/dL

9%

8%

7%4)

.ll::0 6%u,

7.7°/o

- 5%5.2°/o

J:.4%

4)C> 3%u

2%

1%

0%

0 6 12 18 24 30MonthsfromRandomization

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Figure 2A. Efficacy Outcomes Stratified by Potency of Background Statin

Primary Composite Endpoint

All Patients

On maximum intensity statin

On less intense statin

0.4

Secondary Composite Endpoint

All Patients

On maximum intensity statin

On less intense statin

•I

0II

1.0

II

I I I

I

-frII

HR (95°/o Cl)

0.85 (0.79-0.92)

0.86 (0.75-0.98)

0.85 (0.78-0.93)

2.5

0.80 (0.73-0.88)

0.78 (0.66-0.92)

0.81 (0.72-0.90)

Pinteraction

0.88

0.71

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OA 1D 2.5Evolocumab better Placebo better

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.

N=7533

Hazard ratio o.78(95°o/Cl, 0.66-0.92) Placebo

Evolocumab

Figure 28. Cardiovascular Death, Myocardial Infarction, or Stroke in Patients on Maximal Potency Background Statin

10%

9%

8%

4>.ll:: 7%0

-u, 6%5%

4%

3%

2%

1%

0%0 6 12 18 24 30

MonthsfromRandomization