Large interpersonal variation in estimated benefit from PCSK9 inhibition in CAD patients

Estimated individual lifetime benefit from PCSK9 inhibition in statin-treated patients with coronary artery disease

Literature - Kaasenbrood L, Ray KK, Boekholdt SM, et al. - Heart 2018; published online ahead of print

Introduction and methods

Patients with coronary artery disease (CAD) are at high risk for recurrent CV events, particularly if they have high LDL-c levels, despite high-dose statin therapy [1].

The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial showed that the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab attenuate the LDL-c-induced residual CV risk. It is, however, not clear which patients should be treated with this effective but costly therapy [2,3].

This study evaluated the individual benefit of PCSK9 inhibition in patients with stable CAD on high-dose statin therapy. The individual benefit was estimated from a lifetime perspective and expressed in terms of gain in life expectancy free of (recurrent) stroke or MI, in patients originating from the Treating to New Targets (TNT) trial [4,5].

The measures of individual benefit from PCSK9 inhibition in addition to high dose statins was estimated based on:

  • individual relative risk reduction, derived from large clinical trial data [6] and dependent on an individual’s LDL-c level
  • individual CV disease prognosis, based on two competing risk models [7,8] that were derived from patient data in the TNT trial

Main results

  • The study population (N=4853) was characterized by a high interpersonal variation in estimated benefit from PCSK9 inhibition.
  • The median estimated lifetime benefit from initiating PCSK9 inhibition was 5 months (IQR: 2–8) and ranged from <6 months in 61% of the patients to >12 months in 10% of the patients.
  • Patients aged 40–60 years with a high risk factor burden had the highest estimated benefit, particularly if LDL-c levels were >1.8 mmol/L (>70 mg/dL).


The potential incremental benefit of PCSK9 inhibition varies a lot among patients with stable CAD on high-dose statin treatment, ranging from a few months to more than a year gain in life expectancy free of recurrent stroke or MI. Highest benefit is expected in younger patients with a high risk factor burden and high LDL-c levels. Individualized estimated treatment benefit may contribute to targeted treatment and shared decision making on whether or not initiating PCSK9 inhibition in statin-treated patients with stable CAD.


1. Mora S, Wenger NK, Demicco DA, et al. Determinants of residual risk in secondary prevention patients treated with high- versus low-dose statin therapy: the Treating to New Targets (TNT) study. Circulation 2012;125:1979–87.

2. 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.

3. Simoons ML, Deckers JW. Intensive LDL lowering therapy for prevention of recurrent cardiovascular events: a word of caution. Eur Heart J 2016;37:520–3.

4. L aRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425–35.

5. Waters DD, Guyton JR, Herrington DM, et al. Treating to New Targets (TNT) Study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol 2004;93:154–8.

6. 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;366:1267–78.

7. Wilson PW, D’Agostino R, Bhatt DL, et al. An international model to predict recurrent cardiovascular disease. Am J Med 2012;125:695–703.

8. Hippisley-Cox J, Coupland C, Robson J, et al. Derivation, validation, and evaluation of a new QRISK model to estimate lifetime risk of cardiovascular disease: cohort study using QResearch database. BMJ 2010;341:c6624.

Find this article online at Heart

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