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HPS2-THRIVE: Treatment of HDL to Reduce the Incidence of Vascular Events Jane Armitage on behalf of the THRIVE Collaborative Group Financial Disclosure:

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Presentation on theme: "HPS2-THRIVE: Treatment of HDL to Reduce the Incidence of Vascular Events Jane Armitage on behalf of the THRIVE Collaborative Group Financial Disclosure:"— Presentation transcript:

1 HPS2-THRIVE: Treatment of HDL to Reduce the Incidence of Vascular Events Jane Armitage on behalf of the THRIVE Collaborative Group Financial Disclosure: Designed, conducted and analysed by Oxford University independently of the grant source (Merck & Co). No honoraria or consultancy fees accepted.

2 25,673 high-risk patients with occlusive arterial disease from China, Scandinavia and UK Randomized comparison: ER niacin/laropiprant (ERN/LRPT) 2g daily versus placebo Primary end point: Major vascular events after median follow-up of 4 years Pre-specified safety analyses: Median follow-up of 3.4 years (to January 2012) Background LDL-lowering therapy with: Simvastatin 40mg (+/- ezetimibe 10mg) daily

3 HPS2-THRIVE: Design and randomization

4 Reasons for withdrawal (%) before randomization LDL-lowering stabilisation phase Active ERN/LRPT phase Entered phase36059 (100%)38369 (100%) Mean duration of phase (wk)4.67.4 Reason excluded Medical2209 (6.1%)9762 (25.4%) Non-medical1998 (5.5%)3858 (10.1%) Any reason4055 (11.2%)12696 (33.1%)

5 Medical reasons for withdrawal before randomization LDL-lowering stabilisation phase Active ERN/LRPT phase Number entering phase3605938369 Muscle symptoms270 (0.7%)499 (1.3%) Any GI symptoms455 (1.3%)2124 (5.5%) New onset diabetes0 (0.0%)3 (<0.1%) Other diabetes related26 (<0.1%)661 (1.7%) Any skin170 (0.5%)4331 (11.3%) Flushing20 (<0.1%)647 (1.7%) Pruritus80 (0.2%)2539 (6.6%) Rash65 (0.2%)1418 (3.7%) Any medical reason2209 (6.1%)9762 (25.4%)

6 Lipid levels by region: effect of 8 weeks ERN/LRPT during pre-randomization run-in N Baseline Mean (SD) Change Absolute% LDL cholesterol mmol/L China109321.51 (0.41)-0.32 Europe147411.74 (0.43)-0.36 All256731.64 (0.44)-0.34-20% HDL cholesterol mmol/L China109321.06 (0.24)+0.15 Europe147411.19 (0.31)+0.20 All256731.14 (0.29)+0.18+17%

7 Characteristics of randomized participants % or mean (SD)ChinaEuropeAll regions Number randomized109321474125673 Men79%85%21229 (83%) Age (years)62.965.464.4 (7.5) Prior disease Coronary77%80%20137 (78%) Cerebrovascular41%25%8170 (32%) Peripheral arterial05% 18%3214 (13%) Diabetes42%26% 8432 (33%)

8 Pre-specified interim safety assessments Reasons for discontinuation of study treatment overall and in various categories Myopathy (muscle symptoms with CK >10x ULN) and rhabdomyolysis (subset with end-organ damage) Confirmed elevation of ALT >3x ULN on 2 occasions within about one week Presumed drug-related hepatitis: symptoms with either (i) ALT >5x ULN; or (ii) ALT >3x ULN with bilirubin >3x ULN or ALP >3x ULN plus no other cause identified ULN = upper limit of normal

9 Reasons for stopping study treatment in pre-specified categories after 3.4 years ERN/LRPT 12838 Placebo 12835 Any medical2011 (15.7%)958 (7.5%) Skin659 (5.1%)151 (1.2%) Diabetes-related116 (0.9%)51 (0.4%) Gastrointestinal465 (3.6%)200 (1.6%) Musculoskeletal205 (1.6%)114 (0.9%) Liver49 (0.7%)39 (0.5%) Other518 (4.0%)404 (3.1%) Any non-medical1073 (8.4%)1014 (7.9%) Any reason3084 (24.0%)1972 (15.4%) Overall 88% were non-serious reasons ####

10 Skin and gastrointestinal reasons for stopping study treatment after 3.4 years ERN/LRPT 12838 Placebo 12835 Any skin659 (5.1%)151 (1.2%) Flushing 98 13 Pruritus 413 85 Rash 124 44 Other skin 24 9 Any gastrointestinal465 (3.6%)200 (1.6%) Upper gastrointestinal 216 94 Lower gastrointestinal 190 66

11 Myopathy by study treatment and by region after 3.4 years ERN/LRPT 12838 Placebo 12835Risk ratio China 62 (1.13%) 10 (0.18%) Europe 7 (0.09%) 2 (0.03%) All cases 69 (0.54%) 12 (0.09%) 5.8 (3.1 – 10.7) Rhabdomyolysis7 (0.05%) 03 (0.02%) Two-thirds of myopathy cases presented within the first year

12 Effect of ERN/LRPT on liver safety after 3.4 years ERN/LRPT (12838) Placebo (12835) Number with ALT: Consecutive >3x ULN81 (0.6%)31 (0.2%) Any >3x ULN286 (2.2%)119 (0.9%) >10x ULN42 (0.3%)22 (0.2%) >3x ULN + bilirubin ≥2x ULN15 (0.1%)18 (0.1%) Presumed drug-related hepatitis4 (0.031%)2 (0.016%)

13 HPS2-THRIVE summary Largest ever randomized trial of effects of ER niacin on safety and CV events in diverse high-risk patients Among those tolerating ERN/LRPT for 8 weeks, 76% remain compliant with active treatment after 3 years (vs 85% allocated placebo) ERN/LRPT increases risk of myopathy among patients on statin therapy, particularly in the Chinese No clear adverse effects of ERN/LRPT on liver, but known niacin side-effects on skin & GI confirmed Effects of 4 years of ERN/LRPT on vascular events in HPS2-THRIVE available in 2013

14

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