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Will the PCSK9 inhibitor trials change guidelines and practice?

Statins are the indisputable backbone of lipid-lowering therapy for prevention of atherosclerotic cardiovascular disease (ASCVD), with add-on ezetimibe proven to provide further benefit in high-risk patients.1 Yet it is clear that even with optimally tolerated statin therapy, a high residual cardiovascular risk persists. In ODYSSEY Outcomes, for example, nearly 6% of patients in the placebo arm continued to experience major cardiovascular events at 1 year despite intensive statin therapy (with or without ezetimibe), and by 4 years, the event rate approached 15%.2 Event rates may be even higher in those patients who do not tolerate statin therapy. Data from the US Getting to an imprOved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) registry show that among patients with ASCVD and LDL cholesterol levels > 70 mg/dl or 1.8 mmol/L, most are not receiving high intensity statin therapy at baseline, and of those on PCSK9 inhibitor therapy, more than two-thirds are not taking a statin.3

PCSK9 inhibitors are known to reduce LDL cholesterol by more than 50% on top of statin therapy and thus offer the potential for reducing this high residual cardiovascular risk. We now have two cardiovascular outcomes studies with PCSK9 monoclonal antibody therapy in nearly 50,000 high-risk patients, showing significant benefit on cardiovascular outcomes, and in ODYSSEY Outcomes, a significant benefit on all-cause mortality, as well as a trend for improvement in cardiovascular death.2,4  Importantly, there is the suggestion from ODYSSEY Outcomes that clinical benefit is maximised in patients at highest risk, as defined by LDL cholesterol levels ≥100 mg/dL (1.8 mmol/l) at baseline. Furthermore, the accumulated data show that PCSK9 monoclonal antibody therapy is safe and well tolerated, with potential concerns about detrimental effects on cognitive function and ischaemic stroke, for example, not borne out by the results.

Thus, the totality of evidence reinforces the European Society of Cardiology/European Atherosclerosis Society Task Force guidance for the clinical use of PCSK9 inhibitors,5 as discussed by the Task Force Chair Professor Ulf Landmesser (Charité - Universitätsmedizin Berlin (CBF), and Institute of Health (BIH), Berlin, Germany).

Will these data change LDL cholesterol goals for high-risk patients recommended by guidelines? In FOURIER, there was no lower LDL cholesterol threshold for benefit.6 In ODYSSEY Outcomes, this issue is complicated by the use of a titration strategy which aimed to maintain patients within the LDL cholesterol target range of 25-50 mg/dL (0.65-1.29 mmol/L), given concerns at the time of study design of the safety of very low LDL cholesterol levels. Professor Stephen Nicholls (South Australian Health and Medical Research Institute, Adelaide, Australia) discusses the potential impact on guideline recommendations for LDL cholesterol goal.

Yet while the findings from both FOURIER and ODYSSEY Outcomes offer the prospect of attainment of guideline-recommended LDL cholesterol goal in all secondary prevention patients, ultimately it is cost that will determine the uptake of PCSK9 inhibitor therapy. In the Canadian PRACTICAL study, more than two-thirds of high-risk patients did not initiate this treatment due to cost.7 Against this, however, we need to weigh the societal cost of management of major cardiovascular events, such as myocardial infarction and stroke, which could potentially be avoided by the appropriate use of PCSK9 inhibition. Professor Kausik Ray (Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK) discusses issues relating to the cost of PCSK9 inhibition.

The culmination of PCSK9 inhibitor development, within 15 years of discovery of this protein, offers the tantalising prospect of attaining LDL cholesterol goal in all high-risk patients. Will ODYSSEY Outcomes and FOURIER provide the impetus for changing guidelines and routine practice?

Or will it all come down to cost? 


  1. Cannon CP, Blazing MA, Giugliano RP et al; IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-2397. PUBMED
  2. 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.
  3. Cannon CP, de Lemos J, Rosenson R et al. Getting to an imprOved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD): A Registry of High Cardiovascular Risk Patients in the United States. Poster presentation, 67th Scientific Sessions of the American College of Cardiology, 10th March, 2018. Abstract 1129-415.
  4. Sabatine MS, Giugliano RP, Keech AC et al; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-1722. PUBMED
  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 2017 Oct 16. doi: 10.1093/eurheartj/ehx549. [Epub ahead of print] PUBMED
  6. Giugliano RP, Pedersen TR, Park JG, et al; FOURIER Investigators. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017; 390(10106):1962-1971 PUBMED
  7. Pandey A, Bajaj H, Garg V et al. - PCSK9 Inhibition: Real World Application and Challenges to Achieve Unmet Cholesterol Targets in Canadian Atherosclerotic Heart Disease, the PRACTICAL Study. Poster presentation, 67th Scientific Sessions of the American College of Cardiology, 10th March, 2018. Abstract 1129-403.

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