Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial

Schwartz, Gregory G.; Bessac, Laurence; Berdan, Lisa G.; Bhatt, Deepak L.; Bittner, Vera; Dı́az, Rafael; Goodman, Shaun G.; Hanotin, Corinne; Harrington, Robert A.; Jukema, J. Wouter; Mahaffey, Kenneth W.; Moryusef, Angèle; Pordy, Robert; Roe, Matthew T.; Rorick, Tyrus; Sasiela, William J.; Shirodaria, C; Szarek, Michael; Tamby, Jean-François; Tricoci, Pierluigi; White, Harvey D.; Zeiher, Andreas M.; Steg, Philippe Gabriel

doi:10.1016/j.ahj.2014.07.028

Cited by 377 publications

(248 citation statements)

References 30 publications

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“…Furthermore, although the CTT Collaboration had a greater number of women than our study (4416 versus 1887), the LDL‐C achieved was much higher; the findings in our analysis, therefore, add to earlier results. Indeed, demonstration of a continuum of benefit through to very‐low levels of LDL‐C, in a lower‐risk population in this pooled analysis than the populations studied in the FOURIER8 and ODYSSEY OUTCOMES12 trials, should be considered complimentary data.…”

Section: Discussionmentioning

confidence: 96%

“…MACE were defined according to the primary end point of the ODYSSEY OUTCOMES trial as the composite of coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or diagnosis of unstable angina (limited to events with evidence of ischemia and fulfilling additional severity criteria, requiring hospitalization or emergency department visit until at least the following day), whichever came first 10, 12. As per the ODYSSEY OUTCOMES trial, all cardiovascular events were adjudicated by a central Clinical Events Committee 19…”

Section: Methodsmentioning

confidence: 99%

“…In addition, we explored the association between percentage reductions in LDL‐C levels from baseline and risk of MACE in both women and men. More importantly, the populations we studied in this analysis are at an overall lower risk than those in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) and ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab) trials,8, 12 and include ezetimibe controls. Hence, evidence of benefit in a lower‐risk population, especially in women who are often perceived to be at lower cardiovascular risk and therefore perhaps benefit less from LDL‐C lowering, would be an important additional piece of data informing the wider clinical community.…”

Section: Introductionmentioning

confidence: 99%

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Lower On‐Treatment Low‐Density Lipoprotein Cholesterol and Major Adverse Cardiovascular Events in Women and Men: Pooled Analysis of 10 ODYSSEY Phase 3 Alirocumab Trials

Vallejo‐Vaz

Ginsberg

Davidson

et al. 2018

JAHA

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BackgroundIn statin trials, men and women derived similar relative risk reductions in cardiovascular events per 39 mg/dL low‐density lipoprotein cholesterol (LDL‐C) reduction. We explored whether lower LDL‐C levels and greater LDL‐C percentage reductions than those achieved with statins are associated with reduced major adverse cardiovascular event (MACE) rates in women as well as men.Methods and ResultsData pooled from 10 phase 3 ODYSSEY randomized trials (n=4983) comparing alirocumab with control (placebo/ezetimibe) were assessed for association between 39 mg/dL lower on‐treatment LDL‐C and percentage LDL‐C change from baseline, and MACE risk by sex, using multivariable Cox regression. Mean baseline LDL‐C was 135 mg/dL (women) and 121 mg/dL (men). Average on‐treatment LDL‐C levels with alirocumab, ezetimibe, and placebo were 71, 114, and 134 mg/dL, respectively, in women (n=1882) and 52, 93, and 122 mg/dL, respectively, in men (n=3090). Overall, 36.5% and 58.7% of women and men, respectively, achieved on‐treatment LDL‐C <50 mg/dL. Each 39 mg/dL lower LDL‐C was associated with a 33% and 22% lower risk of MACE in women (P=0.0209) and men (P=0.0307), respectively, with no significant between‐sex difference (P for heterogeneity=0.4597). Results were similar when analyzed per 50% LDL‐C reduction, 24% (P=0.1094) and 29% (P=0.0125) lower MACE risk in women and men, respectively (P for heterogeneity=0.7499). Alirocumab was generally well tolerated in both sexes.ConclusionsThe present analysis reinforces the notion that both sexes derive a similar cardiovascular benefit from LDL‐C lowering. Although women had slightly higher on‐treatment LDL‐C than men, both sexes showed a similar lower MACE risk with lower LDL‐C.

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Section: Discussionmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lower On‐Treatment Low‐Density Lipoprotein Cholesterol and Major Adverse Cardiovascular Events in Women and Men: Pooled Analysis of 10 ODYSSEY Phase 3 Alirocumab Trials

Vallejo‐Vaz

Ginsberg

Davidson

et al. 2018

JAHA

Self Cite

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“…The ongoing ODYSSEY OUTCOMES trial will capture diabetes and prediabetes reported by investigators, as well as by serial HbA 1c and FPG measurements in >18 000 high‐risk individuals with 2–5 years of follow‐up, and will allow further analyses and provide longer‐term data on whether alirocumab has any effects on glycaemic measures and the development of diabetes 25.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of alirocumab in people with prediabetes vs those with normoglycaemia at baseline: a pooled analysis of 10 phase III ODYSSEY clinical trials

et al. 2017

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AimTo assess the lipid‐lowering efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in people with hypercholesterolaemia and prediabetes at baseline vs people with normoglycaemia at baseline in a pooled analysis of 10 ODYSSEY phase III trials.MethodsPeople classified as having prediabetes had baseline HbA1c ≥39 mmol/mol (5.7%) and <48 mmol/mol (6.5%), or two baseline fasting plasma glucose values ≥5.6 mmol/l (100 mg/dl) but no more than one fasting plasma glucose value ≥7.0 mmol/l (126 mg/dl), or had specific terms reported in their medical history; people diagnosed with diabetes at baseline were excluded, and the remainder were classified as having normoglycaemia. Participants received alirocumab or control (placebo/ezetimibe) for 24–104 weeks, with maximally tolerated statin in most cases. The primary efficacy endpoint was LDL cholesterol reductions from baseline to week 24 in the intention‐to‐treat population using the mixed‐effect model with a repeated measures approach.ResultsReductions in LDL cholesterol from baseline to week 24 with alirocumab were 44.0–61.8% (prediabetes group) and 45.8–59.5% (normoglycaemia group). In both subgroups, LDL cholesterol reductions were generally similar in those with and without baseline triglycerides ≥1.7 mmol/l (150 mg/dl). Alirocumab was not associated with changes in HbA1c or fasting plasma glucose over time in either subgroup (up to 24 months' follow‐up). Adverse event rates were generally similar in those with and without prediabetes.ConclusionsOver a mean follow‐up of 24–104 weeks, alirocumab treatment resulted in significant LDL cholesterol reductions from baseline that were similar in participants with prediabetes and those with normoglycaemia at baseline, with no effect on glycaemia and a safety profile similar to that of the control.

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“…Recently, the SPIRE (bococizumab) has been terminated, probably due to signs of an immune response to the drug (25). The ODYSSEY outcomes (alirocumab) and FOURIER (evolocumab) trials are still underway to provide confirmation of the actual clinical benefit of PCSK9 inhibitors (26). While waiting for the results of those hard endpoint phase III clinical trials, the imaging GLAGOV trial (evolocumab) has shown that the reduction in lipid levels translates into a significant effect on atherosclerotic plaque stabilisation and regression (27).…”

Section: Presentmentioning

confidence: 99%

Therapeutic strategies for atherosclerosis and atherothrombosis: Past, present and future

et al. 2017

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SummaryEven two centuries after they were first described, atherosclerosis and atherothrombosis remain among the leading causes of death worldwide. Over the last decades it has become clear that atherosclerosis is not only a lipid-driven disease but also a multifactorial process largely driven by inflammatory mediators, an insight that has instigated additional research and drug development focussing on anti-inflammatory therapies. In this review, we will provide a brief historical overview, followed by a more general synopsis of the range of currently available state-of-the-art therapies for atherosclerosis and atherothrombosis. Finally, we will highlight some of the promising therapeutic strategies that are currently under intense investigation. We believe that the next years will witness highly interesting developments and clinical trials investigating yet more novel therapies, and at the same time looking into potential combinations of all available therapies. This prospect closes in on the ultimate goal, which is to reduce the residual risk that still persists despite present therapeutic options.

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Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial

Abstract: ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.

Cited by 377 publications

References 30 publications

Lower On‐Treatment Low‐Density Lipoprotein Cholesterol and Major Adverse Cardiovascular Events in Women and Men: Pooled Analysis of 10 ODYSSEY Phase 3 Alirocumab Trials

Lower On‐Treatment Low‐Density Lipoprotein Cholesterol and Major Adverse Cardiovascular Events in Women and Men: Pooled Analysis of 10 ODYSSEY Phase 3 Alirocumab Trials

Efficacy and safety of alirocumab in people with prediabetes vs those with normoglycaemia at baseline: a pooled analysis of 10 phase III ODYSSEY clinical trials

Therapeutic strategies for atherosclerosis and atherothrombosis: Past, present and future

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