Low-density lipoprotein cholesterol goal attainment with "inclisiran first" versus usual care in patients with atherosclerotic cardiovascular disease

Abstract Background Rapid and sustained attainment of guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals is critical for patients with atherosclerotic cardiovascular disease (ASCVD). In VICTORION-INITIATE, inclisiran administered twice-yearly by a healthcare professional earlier in the treatment pathway allowed more patients with ASCVD to achieve and sustain LDL-C goals vs current usual care (UC). Purpose To evaluate cumulative LDL-C exposure in the overall population and LDL-C goal attainment and safety in subgroups of participants (type of ASCVD, timing of ASCVD event, and history of statin intolerance) who received an "inclisiran first" implementation strategy (IF; adding inclisiran immediately on failure to achieve LDL-C <70 mg/dL [1.8 mmol/L] with maximally tolerated statins) compared with UC. Methods VICTORION-INITIATE was a 330-day, prospective, pragmatically designed trial that randomised participants 1:1 (stratified by insurance status) to IF (open-label inclisiran 284 mg at Days 0, 90 and 270 plus UC) or UC alone (lipid management directed by treating physician’s discretion). The study took place at 45 sites across 20 states in the USA. Treating physicians had access to LDL-C measurements and were encouraged to intensify treatment per clinical practice guidelines. This prespecified subgroup analysis evaluated LDL-C goal attainment by timing of the most recent ASCVD event (<1 year/≥1 year prior to consent), ASCVD subtype (coronary heart disease [CHD], peripheral arterial disease [PAD], and cerebrovascular disease [CVD]) and statin intolerance status. Cumulative LDL-C exposure over time in the overall population and safety by subgroup were also evaluated. Results Of 450 patients randomised to IF or UC, 11.1% and 84.2% had an ASCVD event <1 year or ≥1 year prior to consent, respectively; 91.8%, 18.2% and 14.7% had a history of CHD, CVD or PAD, and 25.8% were statin intolerant. Cumulative exposure to LDL-C to Day 330 was lower in patients treated with IF vs UC (mean time-adjusted LDL-C: 42.4 mg/dL vs 90.7 mg/dL, Figure). Significantly more patients who received IF achieved LDL-C goals of <70 mg/dL and <55 mg/dL at Day 330 vs UC, irrespective of subgroup (Table). Across subgroups, the incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs were similar between IF and UC (IF: 52.6−71.2%, UC: 46.2−66.0% and IF: 10.7−28.3%, UC: 11.4−22.2%, respectively). Conclusions Participants with ASCVD and LDL-C >70 mg/dL who received IF had lower cumulative LDL-C exposure over the study period than those treated with UC. IF resulted in rapid and sustained achievement of LDL-C goals regardless of ASCVD subtype, event timing and statin intolerance. The safety profile of IF was consistent across the subgroups analysed.