Should we Encourage Earlier and Broader Use of Combination Therapies in Dyslipidemia?

• The 2019 ESC guidelines for dyslipidemia include risk assessment (low, moderate, high, and very high) and treat-to-target strategy.
• Two strategies for LLT:
  • Step-by-step strategy to reach the LDL-C target: Start low–moderate statins, increase LLT intensity, add ezetimibe, and add PCSK9 inhibitor to reach the LDL-C target
  • Start with high-intensity statins + ezetimibe and add PCSK9 inhibitor to reach the LDL-C target

Real-life results of the step-by-step strategy

• EUROASPIRE V: Included patients with acute coronary artery events or interventions.
  • It was found that only 23% of women had LDL-C <1.8 mmol/L (70 mg/dL) compared to 32% of men.
  • At first prescription (discharge), 58% patients were treated with high-intensity statins.
  • During follow-up: Among the patients treated with high-intensity statins, there was a decrease in intensity (to low/moderate intensity or no LLT) in 20.8% patients vs an increase in LLT in 11.7% patients.
  • As a result, instead of an increase, there was mostly a decrease in low-intensity treatment; hence, the step-by-step approach was not efficient, and only few patients fulfilled this target.

Treat-to-target strategy linked to combination LLT

• Percent LDL-C reduction with LLT combination makes it possible to select the appropriate LLT to reach the LDL-C target, according to baseline LLT.
• Example of treat-to-target prescription in a very high-risk patient:
  • Target is <1.4 mmol/L (<55 mg/dL): Cannot be reached with high intensity alone if baseline LDL-C is >3 mmol/L (115 mg/dL) and needs additional effect of ezetimibe.
  • Target is >50% decrease in LDL-C: Cannot be reached with high-intensity statin alone; additional effect of ezetimibe is needed.

An innovative lipid-lowering approach to enhance attainment of LDL-C goals

• Real-life application in 270 randomly selected very high-risk patients:
  • Admission LDL-C: 120 ± 47 mg/dL (33% already under statins at admission).
  • Compliance with treatment algorithm was 76% despite a discharge treatment with 97% higher intensity statins plus 67% ezetimibe.
  • LDL-C target according to the recent guidelines (ESC 2019) was reached in only 46%; even with use of ezetimibe for old patients, this algorithm would have only 56% of patients at this target.
  • Hence, giving the systematic combination is much simpler and much more efficient than any algorithm.

Early combination: Evidence for high-intensity statin

• PROVE-IT trial demonstrated that high-intensity statins were much better than low-intensity statins (LDL-C during study: 62 vs 95 mg/dL: RRR = 16%).
• However, before PCI, the use of high-intensity statin is suggested instead of no or moderate-intensity statins because it is safe for MACE.

Early combination: Evidence for ezetimibe

• IMPROVE-IT: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL-C levels and improved CV outcomes.
  • Addition of ezetimibe to statin therapy in stable patients who had an ACS and had LDL-C levels within guideline recommendations further lowered the risk of CV events.

Early combination: Observational studies

• SWEDEHEART registry in post-MI patients showed larger LDL-C reduction, and more intensive statin therapy after MI was associated with a reduced hazard of all CV outcomes and all-cause mortality.
• Thus, earlier lowering of LDL-C after an MI conferred the greatest benefits.

Early combination:Timely decision for PCSK9 inhibitors

• Evidence for early PCSK9 inhibitor use:
  • PCSK9i reduces MACE and all-cause mortality immediately after MI. In ODYSSEY outcomes, PCSK9 inhibitor showed 15% RRR in MACE at 33 months.
  • In Fourier trial, few patients had recent MI and remote MI; most patients got the advantage of using PCSK9 inhibitor.