A look back at 2018: what made the news?
Commentary by EAS Scientific writer Jane K. Stock
2018 featured interesting developments in lipid and cardiovascular disease research. First up, was the second cardiovascular outcomes study with a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, which confirmed the clinical benefits and safety profile of these agents in very high-risk patients1. There were also important insights beyond low-density lipoprotein cholesterol (LDL-C), targeting triglycerides, inflammation and lipoprotein(a) [Lp(a)]. While there were a few disappointments, findings from key trials in 2018 will undoubtedly advance the personalized management of patients with dyslipidemia.
Does ODYSSEY mark the end of the PCSK9 revolution?
2018 started with presentation of topline results from ODYSSEY OUTCOMES, the cardiovascular outcomes study with alirocumab, at the American College of Cardiology Annual Scientific Sessions, which were subsequently published in November1. This trial studied 18,924 patients with a recent (within 1-12 months, median 2.6 months) acute coronary syndrome, the majority (89%) on high-intensity statin therapy, who were randomized to treatment with alirocumab (75 mg every 2 weeks) or placebo. In contrast to the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study 2, ODYSSEY OUTCOMES used a blinded titration scheme so as to ensure that patients were maintained at LDL-C levels of 25-50 mg/dL (0.65-1.3 mmol/L).
A 4-point composite primary endpoint of coronary heart disease death, myocardial infarction [MI], ischemic stroke and unstable angina requiring hospitalization was used in ODYSSEY OUTCOMES, whereas FOURIER also included coronary revascularization in the primary endpoint. Despite this difference, the benefit associated with PCSK9 inhibition, against a background of intense statin therapy, was remarkably similar in the two studies, with a 15% reduction in the primary endpoint. The ODYSSEY OUTCOMES Investigators also used a novel approach that simultaneously modelled total nonfatal cardiovascular events and fatal events over the trial trajectory. This analysis showed that alirocumab treatment avoided twice the number of nonfatal cardiovascular events or deaths compared with placebo, with 60% of the absolute benefit with alirocumab in patients with the highest LDL C levels (≥100 mg/dL or 2.6 mmol/L) 3. These findings very much align with current thinking that the absolute benefit from PCSK9 inhibition is greatest in those patients at highest absolute risk 4, a view that is consistent with recommendations for the clinical use of PCSK9 inhibition proposed by a Joint European Society of Cardiology/European Atherosclerosis Society (EAS) Task Force 5. Finally, the results from ODYSSEY OUTCOMES provide further reassurance regarding the safety of PCSK9 monoclonal antibody therapy in very high-risk patients, although longer-term data are still needed.
A major barrier to the uptake of PCSK9 inhibitors remains cost. To address this. the ODYSSEY OUTCOMES trial incorporated a health economics analysis of the study data from the US perspective 6. Based on a willingness-to-pay threshold of $100,000/ quality adjusted life year, alirocumab was cost-effective at an annual cost of $6,319. In patients with the highest baseline LDL-C levels (≥100 mg/dL or 2.6 mmol/L), cost-effectiveness was established at a higher annual price ($13,357). As with all health economics analyses, however, the results vary according to the setting and assumptions. Moreover, questions persist regarding the relevance of these study-based analyses given that the recommended clinical pathway for such very high-risk patients typically includes prior addition of ezetimibe, which was received by only 3-5% of patients in FOURIER and ODYSSEY OUTCOMES.
Despite completion of these trials, the PCSK9 story is far from over. Ongoing studies are evaluating an alternative approach to PCSK9 inhibition using inclisiran, an RNA interference therapeutic. This agent reduces synthesis of PCSK9 protein in hepatocytes, thereby reducing intracellular LDL receptor turnover, and lowering plasma LDL-C levels 7. Due to its prolonged mode of action, after initial loading doses, inclisiran is administered every 6 months as maintenance therapy. Development has continued rapidly with the launch in 2018 of a major cardiovascular outcomes study, ORION-4 in more than 15,000 patients with stable atherosclerotic cardiovascular disease (ASCVD) and LDL-C levels ≥100 mg/dL (2.6 mmol/L) 8. Of course, the results of this study are some time away, but if positive, the reduced cost of this treatment (versus monoclonal antibody therapy) and improved patient convenience of the dosing regimen are likely to be highly relevant considerations in cost utility analyses.
Despite establishing the clinical benefit associated with efficacious lowering LDL-C with a PCSK9 inhibitor beyond levels attained with statin therapy, it is also evident that very high-risk patients continue to experience cardiovascular events. This had led investigators to consider other lipoprotein targets that may contribute to this residual cardiovascular risk. Among the candidates, Lp(a) and triglycerides (a surrogate for triglyceride-rich lipoproteins and their remnants) feature strongly. Indeed, both have been the focus of previous statements from the EAS Consensus Panel 9,10.
Beyond LDL-C: a revival for triglycerides
Over the last 5 years there has been a resurgence of interest in the role of triglyceride-rich lipoproteins and their remnants in ASCVD, largely driven by genetic studies using a Mendelian randomization design, a type of ‘natural’ randomized trial. Insights from the Copenhagen studies demonstrated a causal association between elevated triglyceride-rich lipoproteins and remnant cholesterol and risk for ischemic heart disease, as well as all-cause mortality, which was independent of plasma levels of high-density lipoprotein cholesterol 11-13. Studies which investigated the impact of mutations in genes encoding various proteins influencing lipoprotein lipase function, notably APOA5, APOC3, and ANGPTL3, provided further support for a causal association for elevated triglyceride-rich lipoproteins and ASCVD 14-17. However, definitive evidence that lowering triglycerides reduces cardiovascular events has been elusive.
With this background, the results from REDUCE-IT (Reduction of Cardiovascular Events With EPA – Intervention Trial), using a high-dose (4 g) purified form of the omega-3 oil, eicosapentaenoic acid (EPA), provided much food for thought 18. The trial randomized 8,179 patients with raised triglycerides (median at baseline 216 mg/dL or 2.44 mmol/L) with either cardiovascular disease (70%) or diabetes and one additional risk factor (30%). After a median follow-up of 4.9 years, treatment with high-dose EPA led to significant reductions in the primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization and unstable angina (by 25%), MI (by 31%), stroke (by 28%), as well as a 20% reduction in cardiovascular death. The magnitude of triglyceride-lowering observed with this dose of EPA (18.3% versus an increase of 2.2% in the placebo group) would not, however, have led to this magnitude of benefit, leading the authors to speculate about other mechanism(s), given the known profile of pleiotropic effects with this agent 19. Additionally, some have suggested that effects of the placebo (a mineral oil) in raising LDL-C (by 10.2% versus 3.1% in the EPA group) and C-reactive protein (by 32% at 2 years versus a 14% decrease in the EPA group) may have contributed to the greater than expected cardiovascular benefit seen in this trial. Irrespective of these ongoing discussions, REDUCE-IT is a landmark trial for the field. Further insights may be expected in late 2019 when STRENGTH (Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia) [Clinical Trials Number NCT02104817] – a trial using a mixed formulation of EPA and docosahexaenoic acid – reports.
Time to test the ‘lipoprotein(a) hypothesis’
2018 also set the stage for testing the Lp(a) hypothesis, i.e. whether specific lowering of elevated Lp(a) is associated with reduction in cardiovascular events. Over the last decade, epidemiologic and genetic studies have established elevated Lp(a) as a cardiovascular risk factor, and supported a causal role for Lp(a) in ASCVD 20. Most recently, there is novel information linking elevated Lp(a) with increased mortality risk. This increase in risk was explained by carriage of variants encoding a low number of LPA kringle-IV type 2 repeats, as the effect was greater than that explained by cholesterol content 21.
Until recently, testing the Lp(a) hypothesis has been problematic due to the lack of specific treatments. The advent of antisense oligonucleotides targeting apolipoprotein(a) [apo(a)] have shown promise; in particular, an antisense oligonucleotide conjugated with an N-acetylgalactosamine (GalNAc3) moiety has shown improved specificity and potency, resulting in an increase in the safety margin, highly relevant for a treatment administered on a long-term basis. In late 2018, results were reported from a phase IIB trial with this novel agent in patients with pre-existing cardiovascular disease and baseline Lp(a) levels ≥60 mg/dL (~≥150 nmol/L). After a screening period of up to 4 weeks, patients were randomized to treatment with this agent (20, 40 or 60 mg every 4 weeks, 20 mg every 2 weeks or 20 mg every week). or placebo, administered by subcutaneous injection, for 6-12 months, followed by a follow-up period of 16 weeks. The study showed dose-related reductions in Lp(a) ranging from 35% to 72% when given every 2 to 4 weeks, increasing to 80% when given weekly. With the weekly regimen, nearly all patients attained an Lp(a) level <50 mg/dL 22. Importantly, this treatment was not associated with concerns regarding platelet counts, liver or renal function, which has plagued other innovative antisense therapies.
The stage is now set for the next step, a definitive cardiovascular outcomes study to test the Lp(a) hypothesis. However, elucidation of the pathophysiological mechanisms by which Lp(a) contributes to cardiovascular risk, remains elusive and the focus of further research.
Residual inflammatory risk: ups and downs
Factors other than lipids and lipoproteins may contribute to residual cardiovascular risk. A role for ‘residual inflammatory risk’ was established by the proof-of-concept Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) using canakinumab, which inhibits inflammation by neutralizing interleukin-1β. The reduction in cardiovascular events with canakinumab was independent of changes in lipids or blood pressure, and greatest in individuals with the largest reductions in C-reactive protein and interleukin-6 23-25.
As canakinumab is a costly treatment, the Cardiovascular Inflammation Reduction Trial (CIRT) investigated an alternative approach to inhibiting inflammation using an inexpensive, widely available treatment, low-dose methotrexate, in patients with stable ASCVD. However, this trial was stopped after a median follow-up of 2.3 years, due to lack of efficacy. Methotrexate did not reduce inflammatory mediators (interleukin-1β, interleukin-6 and C-reactive protein) compared with the placebo group, and as a consequence, there was no reduction in the primary endpoint, a composite of nonfatal MI, nonfatal stroke or cardiovascular death 26. The failure of CIRT may be attributed to patient selection; in CANTOS, patients were screened for high residual inflammatory risk whereas this was not performed in CIRT. Additionally, treatment with low-dose methotrexate in CIRT was associated with elevation in liver enzymes, as well as a higher incidence of non-basal cell skin cancers.
These highlighted trials from 2018 provide important insights into the management of very high-risk patients. The totality of data from ODYSSEY OUTCOMES and FOURIER has established the clinical benefit derived from efficacious lowering of LDL-C levels with PCSK9 inhibition beyond guideline-recommended goals. Other trials also inform the management of patients with well controlled LDL-C levels who remain at very high risk. Notably, REDUCE-IT is a landmark trial in patients with elevated triglycerides, although it is also likely that effects beyond triglyceride-lowering contribute to the clinical benefit observed. Finally, the failure of CIRT reinforces the importance of patient selection in these trials, highly pertinent to the concept of personalized cardiovascular medicine.
1. Schwartz GG, Steg PG, Szarek M et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097-107.
2. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical oOutcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
3. Szarek M, White HD, Schwartz GG et al. Alirocumab reduces total nonfatal cardiovascular and fatal events in the ODYSSEY OUTCOMES Trial. J Am Coll Cardiol 2018 Oct 27. doi: 10.1016/j.jacc.2018.10.039. [Epub ahead of print]
4. Annemans L, Packard CJ, Briggs A, Ray KK. ‘Highest risk-highest benefit’ strategy: a pragmatic, cost-effective approach to targeting use of PCSK9 inhibitor therapies. Eur Heart J 2018;39:2546-50.
5. Landmesser U, Chapman MJ, Stock JK et al. 2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia. Eur Heart J 2018;39:1131-43.
6. Bhatt DL et al. Cost-effectiveness of alirocumab based on evidence from a large multinational outcome trial: The ODYSSEY OUTCOMES Economics Study. Latebreaker, American Heart Association Scientific Sessions, Saturday 10th November, 2018. Abstract 19490.
7. Nishikido T, Ray KK. Inclisiran for the treatment of dyslipidemia. Expert Opin Investig Drugs 2018;27:287-94.
8. ORION-4. http://www.orion4trial.org
9. Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.
10. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
11. Varbo A, Benn M, Tybjærg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013;61:427–36.
12. Thomsen M, Varbo A, Tybjærg-Hansen A, Nordestgaard BG. Low nonfasting triglycerides and reduced all-cause mortality: a mendelian randomization study. Clin Chem 2014;60:737–46.
13. Varbo A, Freiberg JJ, Nordestgaard BG. Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90000 individuals from the general population. Clin Chem 2015;61:533–43.
14. Nilsson SK, Heeren J, Olivecrona G, Merkel M. Apolipoprotein A-V; a potent triglyceride reducer. Atherosclerosis 2011;219:15-21.
15. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32–41.
16. Crosby J, Peloso GM, Auer PL et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371:22–31.
17. Stitziel NO et al; PROMIS and Myocardial Infarction Genetics Consortium Investigators. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol 2017;69:2054-2063.
18. Bhatt DL, Steg PG, Miller M et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
19. Davidson MH. Omega-3 fatty acids: new insights into the pharmacology and biology of docosahexaenoic acid, docosapentaenoic acid, and eicosapentaenoic acid. Curr Opin Lipidol 2013;24:467-74.
20. Tsimikas S. A test in context: Lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol 2017;69:692-711.
21. Langsted A, Kamstrup PR, Nordestgaard BG. High lipoprotein(a) and high risk of mortality. Eur Heart J 2019 Jan 4. doi: 10.1093/eurheartj/ehy902. [Epub ahead of print]
22. Tsimikas S et al. Safety and efficacy of AKCEA-APO(a)-LRx to lower lLipoprotein(a) levels in patients with established cardiovascular disease: a Phase 2 dose-ranging trial. Abstract 19497, 2018 American Heart Association Scientific Sessions, 10-12 November, Chicago, USA.
23. Ridker PM, Everett BM, Thuren T et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31
24. Ridker PM, MacFadyen JG, Everett BM et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 2018;391:319-28.
25. Ridker PM, Libby P, MacFadyen JG et al. Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J 2018; doi:10.1093/eurheartj/ehy310
26. Ridker PM, Everett BM, Pradhan A et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med 2018 Nov 10. doi: 10.1056/NEJMoa1809798. [Epub ahead of print]