The LEASH Trial: Rationale and Study Design for Early Rosuvastatin-Ezetimibe Combination Compared with Stepwise Rosuvastatin in High/Very-High Cardiovascular Risk.

Introduction Contemporary guidelines recommend early achievement of stringent LDL-C goals in patients at high cardiovascular risk. The LEASH trial evaluates upfront rosuvastatin/ezetimibe combination therapy with a stepwise intensification strategy in treatment-naïve patients. Material and methods LEASH is an international, prospective, multicentre, randomized, open-label trial. Treatment-naïve adults aged <70 years are randomized 1:1 within country and risk strata. Arm 1 starts with rosuvastatin 20 mg/day with protocol-directed stepwise escalation; Arm 2 starts with rosuvastatin/ezetimibe 20/10 mg/day (SPC) with subsequent intensification. Treatment is reassessed at 4, 8, and 12 weeks. The primary endpoint is proportion of patients achieving complete LDL-C goal at week 12, defined as ≥50% reduction from baseline plus LDL-C<1.8 mmol/L (<70 mg/dl) for high-risk or <1.4 mmol/L (<55 mg/dl) for very-high-risk patients. Secondary endpoints include early goal attainment at week 4 and 8, lipoproteins changes, adherence, between-arm differences, and safety. Results The LEASH trial is the first RCT to evaluate the early (4–12 weeks) efficacy and safety of an upfront SPC (rosuvastatin/ezetimibe) for LDL‑C reduction and goal attainment in high and very‑high cardiovascular risk patients. The results will inform not just whether combination therapy is effective in this population, but - critically - whether earlier initiation shortens the time to LDL‑C goal attainment and, consequently, reduces the risk of first and subsequent cardiovascular events. Conclusions LEASH will assess whether upfront statin/ezetimibe combination therapy differs from conventional stepwise statin‑based lipid‑lowering intensification in early LDL‑C reduction and goal achievement. Therapy adherence and safety differences between the approaches will also be assessed.