This session highlights the place of combination therapies for the management of dyslipidemia in the current guidelines and evaluates the advantages of combination therapy to achieve LDL-C goals as per current guidelines.
- Step-by-step approach requires an optimization of LLT during follow-up that is not observed in real life.
- Early systematic combination therapy:
- Corresponds to a treat-to-target strategy in line with ESC guidelines.
- Is easier to apply in practice than any algorithm.
- Is supported by scientific evidence (PROVE IT and IMPROVE-IT studies)
- Provides the largest decrease in LDL-C with clinical benefits in observational studies.
- Enables early decision on introducing PCSK9 inhibitors.
- 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.
ACS, acute coronary syndrome; CV, cardiovascular; ESC, European Society of Cardiology; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; MACE, major adverse cardiovascular events; MI, myocardial infarction; PCI, percutaneous coronary intervention; PCSK9i, proprotein convertase subtilisin/kexin-9 inhibitor; RRR, relative risk reduction.
- Schiele F. Should we encourage earlier and broader use of combination therapies in dyslipidemia? Presented at the European Society of Cardiology (ESC) conference on August 28, 2021.
- De Backer G, Jankowski P, Kotseva K, Mirrakhimov E, Reiner Ž, Rydén L, et al. Management of dyslipidaemia in patients with coronary heart disease: Results from the ESC-EORP EUROASPIRE V survey in 27 countries. Atherosclerosis. 2019;285:135–146. doi:10.1016/j.atherosclerosis.2019.03.014.
- Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes [published correction appears in N Engl J Med. 2006;354(7):778]. N Engl J Med. 2004;350(15):1495–1504. doi:10.1056/NEJMoa040583.
- Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–2397. doi:10.1056/NEJMoa1410489.