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ODYSSEY Outcomes and FOURIER in context

Highlights from ACC.2018

In the swirling milieu after presentation of the top-line data from ODYSSEY Outcomes, it is important to put the two cardiovascular outcomes studies in context, especially given the all-cause mortality benefit observed in ODYSSEY Outcomes but not in FOURIER.1,2  It is also worthwhile considering the SPIRE-2 trial in parallel, which despite termination of bococizumab, showed a significant 21% reduction in the primary endpoint at 12 months.3

Clearly these studies differ in patient and design characteristics which are likely to have impacted he results, as summarised below.  A key feature is the higher prevalence of high-intensity statin treatment in ODYSSEY Outcomes compared with the other two studies (89% versus 69-73%), which reflects the different patient populations: post-acute coronary syndrome (ACS) versus stable atherosclerotic vascular disease (ASCVD) or at high risk of cardiovascular disease (CVD). In addition, both ODYSSEY Outcomes and SPIRE incorporated some form of dose titration scheme to prevent patients attaining excessively low LDL cholesterol levels.

Table 1. Comparison of design features of ODYSSEY Outcomes, FOURIER and SPIRE-2

Design feature ODYSSEY Outcomes FOURIER SPIRE-2 (terminated)
Patient population Post ACS, 2-4-52 weeks from index event (median 2,6 months) Stable ASCVD, i.e. MI, stroke or PAD (median ~3 years from index event) High risk primary prevention or CVD
No. of patients 18,924 27,564 10,621
Age, years 58 (median) 63 (mean) 63 (mean)
Women 25% 25% 35%
LDL-C entry criteria mg/dl (mmol/L) ≥70 (1.8) ≥70 (1.8) ≥100 (2.6)
Baseline LDL-C mg/dl (mmol/L) 87 (2.3) 92 (2.4) 133 (3.3)
High intensity statin 89% 69% 73%
No statin <1% - 17%
Ezetimibe 3% 5% 13%
PCSK9 inhibitor dose regimen Alirocumab 75 or 150 mg every 2 weeks, titrated to target LDL-C (25-50 mg/dl) Evolocumab 140 mg every 2 weeks or 420 mg every 4 weeks Bococizumab 150 mg every 2 weeks, down titrated if LDL-C <10 mg/dl
Duration of follow-up, yr 2.8 (44% with ≥3 years) 2.2 1
Primary endpoint 4-point: CHD death, MI, ischaemic stroke, unstable angina requiring hospitalisation 5-point: CV death, MI, stroke, hospitalisation for unstable angina, coronary revascularisation 4-point: CV death, MI, stroke, urgent revascularisation

ACS acute coronary syndrome; ASCVD atherosclerotic cardiovascular disease; CHD coronary heart disease; CV cardiovascular; MI myocardial infarction; PAD peripheral arterial disease

Reduction in the primary endpoint (which differed between the studies) was similar in ODYSSEY Outcomes and FOURIER, but higher in SPIRE-2 (albeit over 12 months), a reflection of higher risk associated with higher baseline LDL cholesterol levels. However, ODYSSEY Outcomes was the only study to show a significant reduction in all-cause mortality; reductions in cardiovascular death, although not statistically significant showed the same trend in both ODYSSEY Outcomes and SPIRE. In contrast, there was a marginal increase in cardiovascular death in FOURIER.  However, a detailed interrogation into the differences between these studies is not possible in the absence of publication of the full results from ODYSSEY Outcomes.

Table 2. Comparison of top-line data from ODYSSEY Outcomes, FOURIER and SPIRE-2

Design feature ODYSSEY Outcomes FOURIER SPIRE-2 (terminated)
Absolute change in LDL-C (mg/dl) 54 at 12 months, 48 at 4 years 56 62
% change in LDL-C 61% 59% 52%
Relative reduction in primary endpoint 15% (0.85, 0.78-0.93) 15% (0.85, 079-0.92) 21% (0.79, 065-0.97)
MI 14% 27% 24%
Stroke 27% 21% 34%
Unstable angina 39% 1% 5%
CVD death 12% (NS) 5% increase (NS) 18% (NS)
All-cause death 15% (*P=0.026) 4% increase (NS) 9% (NS)

* Nominal p-value due to hierarchical statistical testing

For a pragmatic consideration of the trial differences, view Professor Marc Sabatine (Brigham and Women’s Hospital and Harvard Medical School, Boston, USA) as he discusses the ODYSSEY Outcomes and FOURIER studies.


References

  1. Schwartz GG, Szarek M, Bhatt DL et al. The ODYSSEY Outcomes Trial: Topline Results. Alirocumab in Patients after Acute Coronary Syndrome. Clinical Latebreaker, 67th Scientific Sessions of the American College of Cardiology, March 10th, 2018.
  2. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/28304224
  3. Ridker PM, Revkin J, Amarenco P et al. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients. N Engl J Med. 2017 Apr 20;376(16):1527-1539. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/28304242

Related articles

ODYSSEY Outcomes Rationale: Schwartz GG, Bessac L, Berdan LG et al. 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. Am Heart J 2014 v;168(5):682-9 PUBMED https://www.ncbi.nlm.nih.gov/pubmed/25440796

VIDEO: Prof Greg Schwartz Rationale and design of ODYSSEY Outcomes https://www.pcsk9forum.org/rationale-design-odyssey-outcomes/

VIDEO: Prof Kausik Ray: Analyses FOURIER, SPIRE-2 and ODYSSEY outcomes https://www.pcsk9forum.org/prof-kausik-ray-analyses-fourier-spire-2-and-odyssey-outcomes/

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