The much anticipated ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab trial of alirocumab was presented during the 2018 ACC 67th Scientific Sessions as a Late Breaking Trial (the study has not been published at this time; presentation slides available are here). On the heels of the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial of evolocumab and the higher risk participants from the SPIRE (Evaluation of Bococizumab in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects) trials of bocozizumab,^1,2 ODYSSEY is the third large cardiovascular outcomes trial with a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor showing important clinical benefits for patients at risk for atherosclerotic cardiovascular disease (ASCVD) events. These highly anticipated trials (along with the IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin vs Simvastatin study of ezetimibe) address a significant knowledge gap from the 2013 ACC/AHA cholesterol guidelines, when there was a lack of data supporting the routine use of non-statin drugs for low-density lipoprotein cholesterol (LDL-C) reduction with the goal of further reducing ASCVD events.³

Alirocumab and evolocumab are fully human monoclonal antibodies that inactivate the PCSK9 protein, which results in increased recycling of the LDL receptor to the surface of hepatocytes, increased removal of LDL particles from the circulation and consequently lower LDL-C levels in the bloodstream. The two medications were approved by the FDA in 2015 on the basis of safely reducing LDL-C by up to 60% in those already treated with statins.^4,5

In 2017 the first large PCSK9 inhibitor outcomes trial was published (FOURIER), which randomized patients with stable ASCVD and LDL-C ≥70 mg/dL on maximally tolerated statin therapy to receive evolocumab or placebo.¹ Evolocumab significantly reduced a composite endpoint of cardiovascular death, MI, stroke or hospitalization for unstable angina or coronary revascularization (9.8% vs 11.3% with placebo) yielding a relative risk reduction of 15% over 2.2 years and an absolute risk reduction of 1.5% (number needed to treat ~67). There were no significant differences in all-cause mortality nor significant safety concerns, except for a small increased risk of injection site reactions.

ODYSSEY Outcomes provided important confirmatory data for the PCSK9 inhibitor class while raising some interesting questions. It was an international, multicenter, double-blind trial that randomized 18,924 patients to either alirocumab every 2 weeks or placebo. The trial differed from FOURIER by including participants with a recent acute coronary syndrome (ACS) event in the last 1-12 months (median 2.6 months since index ACS) rather than the more stable ASCVD population of FOURIER.

Similar to FOURIER, participants had to have "inadequate lipid control" which was defined as an LDL-C ≥70, non-HDL-C ≥100, or apolipoprotein B ≥80 mg/dl while on a statin. A second notable difference from FOURIER was that alirocumab was titrated between 75 and 150 mg to keep the LDL-C between 25 and 50 mg/dl but above 15 mg/dl. A significant finding was an attenuation of LDL-C reduction over the course of follow-up from an early 63% LDL-C reduction to 55% reduction after 48 months based on the on-treatment analysis; FOURIER did not show a similar attenuation.

The primary outcome — a composite endpoint of nonfatal MI, ischemic stroke, unstable angina and cardiovascular disease-specific mortality — occurred in 9.5% of the patients on alirocumab and 11.1% of those on placebo, after a median follow up of 34 months. Similar to FOURIER, this translated into a statistically significant and clinically meaningful 15% relative risk reduction (RRR) with a number needed to treat of ~63. While the cardiovascular disease-specific mortality rate in the two study arms were similar, the other three components of the primary endpoint occurred significantly less often in the alirocumab group. Notably, all-cause mortality, a secondary outcome, was significantly lower with alirocumab (3.5% vs 4.1%). As seen with FOURIER, there was no safety signal with alirocumab except for local injection site reactions, most of which were categorized as mild.

While the relative risk reduction was similar across all baseline LDL-C subgroups (non-significant p-value for interaction), the presenters reported the greatest absolute benefit in the subgroup of patients with a baseline LDL-C of ≥100 mg/dl, resulting in 3.4% reduction in the primary composite endpoint and 1.7% reduction in all-cause mortality. This is a challenging result to interpret given the downward titration of alirocumab dose to 75 mg per the study protocol at low LDL-C levels, which would occur more often in those with baseline LDL-C <100 mg/dL.

The main difference in the results between FOURIER and ODYSSEY Outcomes was that the latter showed a statistically significant reduction all-cause mortality, which the investigators cautiously interpreted as a nominally significant result. The relative risk reduction was 15% in both trials. One would have expected the difference in all-cause mortality to have been driven by the fact that the ACS population of ODYSSEY Outcomes should have been higher risk (FOURIER had a post-ACS population of 20%) with longer follow-up. However, placebo event rates were similar in both studies, and there was no difference in cardiovascular mortality. The underlying driver for the mortality reduction is unclear and we look forward to the primary publication to address this.

The results of this landmark trial indicate that the use of alirocumab significantly reduces major adverse cardiovascular events and all-cause mortality in a recent post-ACS population that have inadequate control of lipids. In combination with the results from FOURIER, this trial pushes the boundaries of what was previously considered as an optimal LDL-C level; it suggests that further decreasing LDL-C cuts the residual risk of ASCVD in high-risk patients. Therefore, it further reinforces the "lower is better" hypothesis with LDL-C.

However, there are some important caveats. Even though almost 90% of patients were on high-intensity atorvastatin or rosuvastatin (compared with ~70% in FOURIER), only 3% of patients were on ezetimibe. Given that the baseline LDL-C was 87 mg/dl, it is safe to assume that if more participants had been on ezetimibe, many of them would have been ineligible for the trial (92.5% of patients qualified based on LDL-C levels ≥ 70 mg/dl). A higher proportion of ezetimibe use, a much less expensive lipid lowering therapy, hypothetically could have attenuated the clinical benefits observed with alirocumab.

One important question that has arisen is whether there might be a point of diminishing return once the LDL-C is below a certain level. The Cholesterol Treatment Trialists' Collaboration (CTT) meta-analysis modeled the expected average cardiovascular risk reduction per 1 mmol/L (~40 mg/dl) LDL-C reduction.⁶ In ODYSSEY Outcomes, the LDL-C was reduced by 1.23 mmol/L after 1 year, which based on the CTT model would translate into a 24% RRR in major vascular events, but only a 15% RRR was observed. This lower than expected risk reduction may be due to the shorter duration of the study at ~2.5 years rather than the median 5-year follow-up in the CTT analyses. Indeed, CTT has shown less benefit in the first year of LDL-C lowering.

Another important consideration is the slight attenuation in the reduction of LDL-C during the duration of this trial. According to the investigators the trend upward in LDL-C in the treatment arm is not due to neutralizing antibodies as was seen with bococizumab, a murine-derived "humanized" antibody to PCSK9 that is no longer in development due to the incidence of neutralizing antibodies over time.⁷ Alirocumab differs since it is a fully human antibody and prior studies suggest low levels of neutralizing antibodies, albeit not for longer than 78 weeks of follow-up time.⁸ The incidence of neutralizing antibodies in ODYSSEY Outcomes has not been reported thus far and will be an important consideration for the primary publication.

There are a few other potential explanations for the attenuation in LDL-C reduction over the study period. Since the study protocol called for a reduction in dose for those achieving LDL-C <15 mg/dL on two consecutive occasions, this likely increased the average LDL-C in the treatment arm over time. Also, since this was a post ACS population, it is possible that the proportion of relatively statin naïve participants was higher than that of FOURIER and those who may have developed intolerance could have decreased their statin doses preferentially in the treatment group as their LDL-C levels would have been lower. Finally, the results of FOURIER and the FDA approval of PCSK9-inhibitors may have impacted treatment in the placebo arm, though overall, LDL-C levels did increase over time in this arm.

Importantly, PCSK9 inhibitors continue to be very expensive medications and cost/availability will continue to be a barrier to the use of this medication. Regeneron and Sanofi — the developers of alirocumab and sponsors of the ODYSSEY Outcomes trial — announced plans to renegotiate their contracts with insurers by offering rebates and discounts of up to 69% in exchange for insurers to ease restrictions and expand their coverage of the medicine to more patients.

Soon after the results of ODYSSEY Outcomes, the Institute for Clinical and Economic Review (ICER) performed cost-effectiveness analyses to establish value-based price benchmarks for alirocumab.⁹ ICER came up with two value-based price estimates. One calculation estimated that a cost of $2,300-$3,400 per year would be cost-effective if used to treat all patients who meet trial eligibility criteria. A second calculation estimated that alirocumab at a cost of $4,500-$8,000 per year would still be cost-effective if used in the patients with LDL-C ≥100 mg/dl, with a slightly better relative risk reduction. This higher cost generated some controversy in cardiology social media circles, since strictly speaking the relative risk should not vary based on LDL-C entry level given a non-significant interaction based on LDL-C baseline levels. This is further complicated by the study protocol allowing for changes in dose based on achieved LDL-C levels. Regardless, the list prices for alirocumab and evolocumab are substantially more than the annual price of ezetimibe, even accounting for the three times greater LDL-C lowering efficacy.

After taking into account these considerations, what is clear is that ODYSSEY Outcomes represents a step forward in improving the residual risk of ASCVD in high-risk patients. Lowering LDL-C further than achieved by statins by PCSK9 inhibition has modest benefits, but in whom should we use this novel class? The answer is less well delineated.

In 2017, an expert consensus decision panel (ECDP) recommended that the first non-statin agent that may be considered in patients with recent ACS and LDL-C ≥70 mg/dl should be ezetimibe given its low cost, ease of use and known-long-term safety profile.¹⁰ The ECDP added that further factors that should favor ezetimibe over PCSK9 inhibitors are a need of <25% LDL-C lowering or in patients with recent ACS <3 months, heart failure, hypertension, age >75 years, diabetes, stroke, coronary artery bypass graft, peripheral arterial disease, smoking and chronic kidney disease stage 3 or worse. However, the ECDP concluded that if patients with clinical ASCVD and comorbidities require >25% lowering of LDL-C, a PCSK9 inhibitor may be preferred as the initial non-statin agent. This set of recommendations was published in 2017 after FOURIER but prior to ODYSSEY Outcomes. It is unlikely that the needle has moved much after the results of ODYSSEY Outcomes were made available, in large part because of the cost of the PCSK9 inhibitors.

The addition of PCSK9 inhibitors should be strongly considered on a case-by-case basis via a two-way clinician-patient discussion of cost, net ASCVD risk-reduction benefit and patient preferences. In our practice, among our secondary prevention group, we will continue to prioritize high intensity statins with ezetimibe for added lowering, along with lifestyle, while adding PCSK9 inhibition in the minority who still have LDL-C ≥70 mg/dL.

References

1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
2. Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med 2017;376:1527-39.
3. 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. J Am Coll Cardiol 2014;63:2889-934.
4. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.
5. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.
6. Cholesterol Treatment Trialists' Collaboration, Baigent C, Blackwell L. et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data for 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.
7. Ridker PM, Tardif JC, Amarenco P, et al. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N Engl J Med 2017;376:1517-26.
8. Roth EM, Goldberg AC, Catapano AL, et al. Antidrug antibodies in patients treated with alirocumab. N Engl J Med 2017;376:1589-90.
9. Institute for Clinical and Economic Review. Alirocumab for High Cholesterol – Preliminary New Evidence Update. March 10, 2018. (Accessed June 24, 2018) https://icer-review.org/wp-content/uploads/2018/03/Alirocumab-Preliminary-New-Evidence-Update_03102018.pdf
10. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 focused update of the 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 Expert Consensus Decision Pathways. J Am Coll Cardiol 2017;70:1785-1822.

Keywords: Acute Coronary Syndrome, Angina, Unstable, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Apolipoproteins B, Brain Ischemia, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Cost-Benefit Analysis, Double-Blind Method, Antibodies, Monoclonal, Hepatocytes, Hospitalization, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids, Outcome Assessment, Health Care, Receptors, LDL, Risk, Risk Factors, Risk Reduction Behavior, Simvastatin, Stroke, Subtilisins, Dyslipidemias

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