ODYSSEY Outcomes Trial: Topline Results and Clinical Implications

ODYSSEY Outcomes Trial: Topline Results and Clinical Implications

By Kevin C Maki, PhD, CLS, FNLA; Kristen N Smith, PhD, RD, LD; Mary R Dicklin, PhD

 Background:

Cardiovascular disease (CVD) event risk is high in those with recent acute coronary syndromes (ACS), despite treatment with evidence-based preventive therapies. Prior research has shown that CVD event risk is lowered when low-density lipoprotein cholesterol (LDL-C) is lowered through various means, such as:

  • Statin therapy (compared with placebo)2
  • High-intensity statin therapy (compared with moderate-intensity statin therapy)3
  • Ezetimibe added to statin therapy (compared with placebo)4
  • Anacetrapib added to statin therapy (compared with placebo)5
  • Evolocumab added to statin therapy (compared with placebo)6

Alirocumab is a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), a validated target for risk reduction in patients with stable atherosclerotic CVD.7-8. Research outcomes on alirocumab show that it reduces LDL-C (sustained reductions) and other atherogenic lipoproteins7 with documented safety and tolerability.8

The hypothesis of the Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome During Treatment with Alirocumab (ODYSSEY Outcomes) trial was that alirocumab, versus placebo, reduces cardiovascular (CV) morbidity and mortality after recent ACS in patients with elevated levels of atherogenic lipoproteins despite intensive or maximum-tolerated statin therapy.9

 Methods:

This study was a randomized, double-blind, placebo-controlled, parallel group study of 18,924 patients randomized at 1315 sites in 57 countries between November 2, 2012 and November 11, 2017.1,9

Key inclusion criteria:

  • Age ≥40 years
  • ACS
    • 1 to 12 months prior to randomization [acute myocardial infarction (MI) or unstable angina]
  • High-intensity statin therapy
    • Atorvastatin 40 to 80 mg daily, or
    • Rosuvastatin 20 to 40 mg daily, or
    • Maximum tolerated dose of one of these agents for ≥2 weeks
    • Patients not taking statins were authorized to participate if tolerability issues were present and documented
  • Inadequate control of lipids
    • LDL-C ≥70 mg/dL (1.8 mmol/L), or
    • Non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL (2.6 mmol/L), or
    • Apolipoprotein B ≥80 mg/dL

 

Key exclusion criteria:

  • Uncontrolled hypertension
  • NYHA class III or IV heart failure; left ventricular ejection fraction <25% if measured
  • History of hemorrhagic stroke
  • Fasting triglycerides >400 mg/dL (4.52 mmol/L)
  • Use of fibrates, other than fenofibrate or fenofibric acid
  • Recurrent ACS within 2 weeks prior to randomization
  • Coronary revascularization performed within 2 weeks prior to or after randomization
  • Liver transaminases >3 x upper limit of normal; hepatitis B or C infection
  • Creatine kinase >3 x upper limit of normal
  • Estimated glomerular filtration rate <30 mL/min/1.73 m2
  • Positive pregnancy test

 

Primary Efficacy Outcome

Major Secondary Efficacy Endpoints

Other Secondary and Safety Endpoints

Time of first occurrence:

§  Coronary heart disease (CHD) death, or

§  Non-fatal MI, or

§  Fatal or non-fatal ischemic stroke, or

§  Unstable angina requiring hospitalization

Tested in the following hierarchical sequence:

§  CHD event: CHD death, non-fatal MI, unstable angina requiring hospitalization, or ischemia-driven coronary revascularization

§  Major CHD event: CHD death or non-fatal MI

§  CV event: CV death, non-fatal CHD event, or non-fatal ischemic stroke

§  All-cause death, non-fatal MI, non-fatal ischemic stroke

§  CHD death

§  CV death

§  All-cause death

Secondary endpoints:

§  Components of the primary endpoint considered individually:

·       CHD death

·       Non-fatal MI

·       Fatal and non-fatal ischemic stroke

·       Unstable angina requiring hospitalization

§  Ischemia-driven coronary revascularization

§  Congestive heart failure requiring hospitalization

 

Safety endpoints:

§  Adverse events

§  Laboratory assessments

Patients screened for this study completed a run-in period of 2 to 16 weeks on high-intensity or maximum-tolerated dose of atorvastatin or rosuvastatin. If at least one lipid entry criterion was met, then the subject was randomized to receive either subcutaneous alirocumab (75 or 150 mg) or placebo every 2 weeks. In order to maximize the number of patients in the target LDL-C range (25-50 mg/dL), alirocumab was blindly titrated or subjects were blindly switched to placebo if they were either substantially above or below (<15 mg/dL for LDL-C) the target range.

Results:

Of the 18,924 patients randomized for this study:

  • 9462 were assigned to alirocumab and 9462 received placebo
  • Median follow-up was 2.8 years (interquartile range limits 2.3-3.4 years)
  • 8242 (44%) patients with potential follow-up ≥3 years
  • 1955 patients experienced a primary endpoint; 726 patients died

Topline results showed that treatment with alirocumab was associated with significant reductions in LDL-C, and these reductions remained consistent over time.  Mean baseline and on-treatment LDL-C values are shown in the table below.

 

 

Placebo

(n = 9462)

Alirocumab

(n = 9462)

Baseline

  87.0 mg/dL

87.0 mg/dL

4 months

  93.3 mg/dL

39.8 mg/dL

12 months

  96.4 mg/dL

48.0 mg/dL

48 months

101.4 mg/dL

66.4 mg/dL

The “on-treatment” analysis showed that mean LDL-C was lowered by 55.7 mg/dL (-62.7%) in the alirocumab group vs. placebo at 4 months, 54.1 mg/dL (-61.0%) at 12 months and 48.1 mg/dL (-54.7%) at 48 months.

Several endpoints were significantly less frequent in the alirocumab group vs. placebo. Major adverse cardiac events (MACE; includes CHD death, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization) are shown in the table below, along with other endpoints.

 

Endpoint

Alirocumab

(n = 9462)

n (%)

Placebo

(n = 9462)

n (%)

Hazard Ratio (95% Confidence Interval)

Log-rank

P-value

MACE

903 (9.5)

1052 (11.1)

0.85 (0.78, 0.93)

0.0003

     CHD death

205 (2.2)

222 (2.3)

0.92 (0.76, 1.11)

0.38

     Non-fatal MI

626 (6.6)

722 (7.6)

0.86 (0.77, 0.96)

0.006

     Ischemic stroke

111 (1.2)

152 (1.6)

0.73 (0.57, 0.93)

0.01

     Unstable angina

37 (0.4)

60 (0.6)

0.61 (0.41, 0.92)

0.02

Secondary

       

     CHD event

1199 (12.7)

1349 (14.3)

0.88 (0.81, 0.95)

0.001

     Major CHD

     event

793 (8.4)

899 (9.5)

0.88 (0.80, 0.96)

0.006

     CV event

1301 (13.7)

1474 (15.6)

0.87 (0.81, 0.94)

0.0003

     Death, MI,

     ischemic stroke

973 (10.3)

1126 (11.9)

0.86 (0.79, 0.93)

0.0003

     CHD death

205 (2.2)

222 (2.3)

0.92 (0.76, 1.11)

0.38

     CV death

240 (2.5)

271 (2.9)

0.88 (0.74, 1.05)

0.25

     All-cause death

334 (3.5)

392 (4.1)

0.85 (0.73, 0.98)

0.026*

(nominal)

Several pre-specified subgroup analyses for the primary outcome variable were presented, including, notably, an analysis by baseline LDL-C categories of <80, 80-99, and ≥100 mg/dL.  Although the test for heterogeneity of response across subgroups was not statistically significant (p = 0.09), the hazard ratio (HR) for the comparison of alirocumab to placebo was numerically lower for the subgroup with baseline LDL-C ≥100 mg/dL [HR 0.76, 95% confidence interval (CI) 0.65 to 0.87] than for those with baseline LDL-C <80 mg/dL (HR 0.86, 95% CI 0.74 to 1.01) or 80-99 mg/dL (HR 0.96, 95% CI 0.92 to 1.14).

Comment by Kevin C Maki, PhD, CLS, FNLA:

When compared with placebo, the use of alirocumab 75 or 150 mg every two weeks, aiming for LDL-C levels of 25-50 mg/dL (and allowing levels as low as 15 mg/dL), led to reduced MACE, MI and ischemic stroke, and was associated with reduced all-cause death. Treatment was safe and well tolerated. CV and CHD death were not significantly reduced. Therefore, the results for total mortality should be viewed with caution, since roughly 70% of total mortality was attributable to CV causes. 

Subgroup analyses identified numerically larger benefits for the primary outcome in subjects with baseline levels of LDL-C ≥100 mg/dL (median LDL-C 118 mg/dL). However, the test for heterogeneity of effect across subgroups was not statistically significant (p = 0.09).  The proportional risk reductions for subjects with baseline LDL-C <80, 80-99 and ≥100 mg/dL were 14%, 4% and 24%, respectively. Only the subgroup with LDL-C ≥100 mg/dL showed a statistically significant reduction in the alirocumab group compared with placebo. That was also true for all-cause mortality, which was reduced by 29% in the alirocumab group vs. placebo in subjects with baseline LDL-C ≥100 mg/dL, but was not significantly reduced in the other subgroups. This finding should also be interpreted with caution because the test for heterogeneity was, again, not significant (p = 0.12). 

The US Institute for Clinical and Economic Review (ICER) provided new estimates of the price range that would be acceptable for the drug, based on the results of the ODYSSEY Outcomes trial.10 ICER calculated two updated value-based price benchmarks, net of rebates and discounts, for alirocumab in patients with a recent acute coronary event:  $2300-$3400 per year if used to treat all patients who meet trial eligibility criteria, and $4500-$8000 per year if used to treat higher-risk patients with LDL-C ≥100 mg/dL despite intensive statin therapy. The manufacturers of alirocumab (Sanofi and Regeneron Pharmaceuticals, Inc.) have announced plans for a reduced price for the drug that will be in the range of the $4500-$8000 identified by ICER, which is substantially below the “list price” of approximately $14,000 per year that had been charged initially.

A number of commentaries from experts in the field have suggested that this class of medications is appropriate for use mainly in patients in whom LDL-C is ≥100 mg/dL, based on the results from the analyses presented at the American College of Cardiology meeting (and not yet published in a peer reviewed journal), including the cost-effectiveness evaluation by ICER. For example, the highly respected cardiologist Milton Packer, MD wrote a piece in which he stated:11

“…the benefit in the entire trial was driven entirely by the effect seen in 5,629 patients who started with LDL cholesterol >100 mg/dL. There was no benefit in patients with lower values for baseline LDL cholesterol.”

With all due respect to Dr. Packer and others who hold this opinion, I view this conclusion as premature for several reasons. The test for heterogeneity (treatment by subgroup interaction) across baseline LDL-C categories was not significant at an alpha of 5%, showing a p-value of 0.09.  Moreover, the study was not designed with sufficient statistical power to reliably differentiate effects across baseline LDL-C categories. This lack of statistical power for tests of heterogeneity of treatment effects argues for caution in the clinical application of such findings, even when the test for heterogeneity is pre-specified and/or when it does reach statistical significance.

Sir Richard Peto, the eminent biostatistician and epidemiologist from the University of Oxford has quipped that only one thing is worse than doing subgroup analyses for a clinical trial, and that is believing the results! To demonstrate the potential unreliability, Peto reported on a set of subgroup analyses from the Second International Study of Infarct Survival (ISIS-2).12  In the trial overall, the survival advantage produced by aspirin for patients with suspected myocardial infarction was 23%, which was highly statistically significant (p < 0.000001).13 ISIS-2 patients were divided into 12 subgroups according to their astrological sign, and the treatment effect of aspirin compared with placebo was calculated in each subgroup. The results ranged from no apparent effect of aspirin in two subgroups (Libra and Gemini) to aspirin being associated with a halving of the mortality in another (Capricorn).

Results from subgroup analyses are useful for generating hypotheses to test prospectively, but should not, in most cases, be applied as the sole basis for clinical practice decisions without replication in other trials, and, ideally, prospective testing in one or more trials designed for the purpose of evaluating possible differences across subgroups in clinical response.  Regarding the results for the subgroup with baseline LDL-C <100 mg/dL in ODYSSEY Outcomes, it should be noted that the authors of the paper from the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial with the other approved PCSK9 inhibitor agent, evolocumab, report the following:6

“The benefits were also consistent across quartiles of baseline LDL cholesterol levels, from patients in the top quartile, who had a median LDL cholesterol level of 126 mg per deciliter (interquartile range, 116 to 143) (3.3 mmol per liter [interquartile range, 3.0 to 3.7]) at baseline, down to those in the lowest quartile, who had a median LDL cholesterol level of 74 mg per deciliter (interquartile range, 69 to 77) (1.9 mmol per liter [interquartile range, 1.8 to 2.0]) at baseline.”

Results from other trials such as the Improved Reduction of Outcomes: Vytorin Efficacy International Trial4 (IMPROVE-IT; statin plus ezetimibe) and the HPS3/TIMI55 Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification5 (REVEAL; statin plus anacetrapib) have shown benefits with atherogenic cholesterol lowering that are generally consistent with the results observed in statin trials based on the Cholesterol Treatment Trialists’ (CTT) analyses,14 i.e., a HR of 0.78 (22% reduction) per mmol/L (38.7 mg/dL) reduction in LDL-C, despite average baseline LDL-C levels below 100 mg/dL (~94 mg/dL in IMPROVE-IT and 61 mg/dL in HPS2/TIMI55-REVEAL).  Notably, in both IMPROVE-IT and HPS3/TIMI55-REVEAL, the placebo and active treatment group Kaplan-Meier curves did not clearly separate for the first 2.0 to 2.5 years. In a prior study with evacetrapib [Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE)], no CVD event benefit (or harm) was observed over a median follow-up period of 2.2 years, despite modest lowering of LDL-C.15  The median follow-up period for both of the PCSK9 inhibitor trials (FOURIER, 2.2 years and ODYSSEY Outcomes, 2.8 years) was short compared with those from most trials of statins, which had median follow-up periods that averaged roughly 5 years.14 In fact, the FOURIER investigators reported that:

“… in FOURIER, the magnitude of the risk reduction with regard to the key secondary end point appeared to grow over time, from 16% during the first year to 25% beyond 12 months, which suggests that the translation of reductions in LDL cholesterol levels into cardiovascular clinical benefit requires time.”

Findings from studies of genetic variants that alter atherogenic cholesterol levels suggest that the benefits of maintaining lower levels may not be fully apparent after only a few years of intervention. The prototypical example of this is one of the findings that led to the development of the PCSK9 inhibitor class of lipid-altering agents. Cohen et al.16 reported that a nonsense loss-of-function mutation in the PCSK9 gene was associated with a 38 mg/dL (0.98 mmol/L) lower average level of LDL-C, and a missense mutation was associated with a 21 mg/dL (0.54 mmol/L) reduction in LDL-C. Based on the CTT relationship, the predicted reductions in CVD event risk would have been roughly 22% and 13%, respectively. However, the observed reductions in CVD (CHD and stroke) incidence were approximately 50% and 37%, respectively (estimated from data presented in the paper). The reductions in risk were most evident for CHD, where HRs were 0.11 (89% reduction) and 0.50 (50% reduction) for those with the nonsense and missense mutations, respectively. These results, and those from many other studies of lipid-altering genetic variants, suggest a greater CVD event risk reduction than would be predicted from the effects of statin and other lipid-altering therapies on risk.17 A likely explanation is that genetic variants produce differences that are maintained over decades, rather just a few years duration, as is the case in randomized, controlled intervention trials. 

Thus, there are reasons to believe that “lower is probably better” for atherogenic cholesterol levels with regard to CVD event reduction in high-risk patients, even if the baseline level of LDL-C is less than 100 mg/dL. Atherosclerosis is a disease that develops and progresses over decades. Thus, it seems possible, and indeed, likely, that benefits will be observed with therapy to further reduce atherogenic cholesterol among those with LDL-C less than 100 mg/dL over follow-up periods longer than the 2- to 3-year median durations in the ODYSSEY Outcomes and FOURIER trials. At present, this is a hypothesis that remains to be verified with additional clinical research. Given that the subgroup with baseline LDL-C <100 mg/dL who received placebo in the ODYSSEY Outcomes trial experienced an event rate above 3% per year, substantial residual risk is present in such patients. Dr. Packer ended his commentary by saying “The ODYSSEY trial shows that we may have reached the limits of what we can achieve by lowering lipids.” My view is that the potential for aggressive atherogenic cholesterol reduction to lower CVD event risk in those with recent ACS (and other high-risk patients) has not been fully evaluated. Accordingly, efforts to understand the effects of atherogenic cholesterol lowering in high-risk patients with LDL-C levels <100 mg/dL should remain an important priority.

References:

  1. Schwartz GG, Szarek M, Bhatt DL, et al. The ODYSSEY OUTCOMES trial: topline results. Alirocumab in patients after acute coronary syndrome. Presented at ACC.18 67th Annual Scientific Session & Expo. Acc.18 Joint ACC/JACC Late-breaking clinical trials. Accessed at https://accscientificsession.acc.org/features/2018/03/video-sanofi-regeneron on March 15, 2018.
  2. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285(13):1711-1718.
  3. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495-1504.
  4. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397.
  5. HPS3/TIMI55-REVEAL Collaborative Group, Bowman L, Hopewell JC, et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 2017;377(13):1217-1227.
  6. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722.
  7. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-1499.
  8. Robinson JG, Rosenson RS, Farnier M, et al. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials. J Am Coll Cardiol. 2017;69(5):471-482.
  9. 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;168(5):682-689.
  10. Institute for Clinical and Economic Review, 2018. Alirocumab for treatment of high cholesterol: effectiveness and value. Preliminary New Evidence Update. March 10, 2018. Accessed at https://icer-review.org/wp-content/uploads/2018/03/Alirocumab-Preliminary-New-Evidence-Update_03102018.pdf on March 23, 2018.
  11. Packer, M. Confessions and omens from the ODYSSEY Trial - Milton Packer assesses his predictions in the future of lipid research. MEDPAGE TODAY, March 14, 2018. Accessed at https://www.medpagetoday.com/blogs/revolutionandrevelation/71755 on March 23, 2018.
  12. Peto R. Current misconception 3: that subgroup-specific trial mortality results often provide a good basis for individualising patient care. Br J Cancer. 2011;104:1057-1058.
  13. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2(8607):349-360.
  14. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267-1278.
  15. Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017;376(20):1933-1942.
  16. Cohen JC, Boerwinkle E, Mosley TH, Jr., et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272.

17.       Ference BA. Mendelian randomization studies: using naturally randomized genetic data to fill evidence gaps. Curr Opin