Between January 2019 and August 2020, 1000 patients were included, one of whom withdrew consent: 707 (70.7%) with NSTEMI and 292 (29.2%) with STEMI. Mean (SD) age was 67 (± 10) years, 23% were women, 74% had a history of ASCVD and 45% of T2DM. At baseline, 380 patients (38%) had LDL-C ≤ 1.8 mmol/l. Medication use at baseline is shown in Tab. 2. Among patients with established ASCVD, 85% were using any lipid-lowering treatment at baseline, and 43% were on target for LDL‑C. In patients with T2DM only, 50% were using any lipid-lowering treatment and 23% had LDL-C ≤ 1.8 mmol/l.

The stepwise lipid-lowering treatment protocol was correctly applied in 915 (92%) patients (per-protocol) (See Box S3 and Fig. S1 in the Electronic Supplementary Material for detailed results per step).

The primary outcome was reached in 89% (CI: 87–91) of the patients in the per-protocol group, and 84% (CI: 81–86) in the intention-to-treat group. At baseline, 38% (CI: 35–41) of patients were on target. As a cumulative result of treatment with HIST (Step 1), HIST plus ezetimibe (Step 2) and HIST plus ezetimibe plus PCSK9i (Step 3), target LDL‑C was met in 71% (CI: 68–74), 89% (CI: 87–91) and 95% (CI: 94–96) in the per-protocol group (denominator at successive steps: n = 976, n = 938 and n = 915) and 69% (CI: 67–72), 84% (CI: 81–86) and 87% (CI: 85–89) in the intention-to-treat group (n = 999), respectively. The results (Tab. 3) are visualised in Fig. 2.

The prevalence of reaching LDL-C ≤ 1.8 mmol/l in the consecutive steps. Cumulative prevalence of patients achieving LDL-C ≤ 1.8 mmol/l from baseline through Step 1 (high-intensity statin), Step 2 (addition of ezetimibe—primary outcome), to Step 3 (addition of alirocumab). This figure visually depicts Tab. 3 data for the LDL‑C target of 1.8 mmol/l

Of the 618 patients with baseline LDL-C > 1.8 mmol/l, HIST was initiated or statin was titrated to a higher dose in 553 (89%). As a result of Step 1 an additional 314 patients reached target LDL‑C after a median (IQR) of 35 (29–45) days. A total of 694 patients had reached target LDL‑C after Step 1, corresponding with 71% (CI: 68–74) of the per-protocol group and 69% (CI: 67–72) of the intention-to-treat group (Tab. 3). Tab. S2 of the Electronic Supplementary Material shows the prescribed type and dosage of statins.

After ezetimibe was added in 234 of 282 (83%) patients who had not reached target LDL‑C after Step 1, an additional 142 patients achieved target LDL‑C after a median (IQR) of 35 (29–46) days. Cumulatively, corresponding to the primary outcome, after Steps 1 + 2, 836 (84%, CI: 81–86) patients reached target LDL‑C (Tab. 3).

Patients remaining off-target after Steps 1 and 2 (n = 102) were eligible to receive PCSK9i. In 40 patients alirocumab was added on top of statin and/or ezetimibe, after which the target LDL‑C was met in an additional 34 patients. Prescribed dosages can be found in Box S1 in the Electronic Supplementary Material. In 39 patients with LDL-C ≤ 2.6 mmol/l PCSK9i therapy was not initiated because of the physician’s or patient’s preference. Overall, after completing Steps 1 + 2 + 3, target LDL‑C was reached in 870 patients, corresponding to 95% (CI: 94–96) of the per-protocol group and 87% (CI: 85–89) of the intention-to-treat group. The median (IQR) time to complete all three steps was 45 (32–77) days. The distribution of LDL‑C at baseline and after the final step is shown in Fig. 3. Even though medication adjustments were aimed at achieving an LDL-C ≤ 1.8 mmol/l, 43% of patients reached an LDL-C ≤ 1.4 mmol/l. The number of patients reaching LDL-C ≤ 1.4 mmol/l after each successive step is shown in Tab. 3.

Low-density lipoprotein-cholesterol distribution at baseline and final visit. LDL‑C distribution at baseline and final visit. At the final visit: 4% had LDL-C > 2.6 mmol/l; 9% were between 1.8–2.6 mmol/L; 44% were between 1.4–1.8 mmol/l; and 43% achieved LDL-C ≤ 1.4 mmol/l. The treatment aimed for an LDL‑C level of ≤ 1.8 mmol/l

Overall, despite an LDL-C > 1.8 mmol/l, the protocol was not followed in 122 patients (12%): 22 patients were not prescribed HIST (Step 1), 38 patients were not prescribed ezetimibe (Step 2) and 62 patients were not prescribed PCSK9i (Step 3). The reasons for protocol deviation in the first two steps were study burden as perceived by the patient (n = 25), unknown reasons (n = 18), statin-related symptoms (n = 4), physician discretion (n = 4), deceased (n = 4), missing LDL‑C and non-HDL values (n = 1). The reasons for protocol deviation in Step 3 were not fulfilling reimbursement criteria due to ezetimibe intolerance in 7 patients; 16 patients with LDL-C ≥ 2.6 mmol/l did not receive PCSK9i due to patients’ and/or physicians’ choice. A detailed overview is shown in Tab. S3 of the Electronic Supplementary Material.

At baseline, 78 patients (7.8%) reported a history of statin intolerance; 55 of them had tried ≤ 2 statins before inclusion. Among those 55 patients, 51 (93%) tolerated a rechallenge with a third statin during Step 1 (HIST). Twenty-three patients with a documented history of intolerance to ≥ 3 statins were treated with ezetimibe instead of being rechallenged with statins. In the 553 patients without a history of statin intolerance, 46 (8%) patients developed muscle complaints, causing 12 patients (2%) to cease statin therapy. For ezetimibe, 12 (4%) patients reported side effects during the study.