PCSK9 inhibition and cardiovascular outcomes by heart failure status: a pooled analysis of SPIRE-1 and SPIRE-2
A Razaghizad, J Ni, T Huynh, J P Ferreira, A SharmaAbstract
Background/Introduction
Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) produce substantial low-density lipoprotein (LDL) cholesterol lowering, but the effects of PCSK9 inhibition on heart failure (HF) outcomes and potential heterogeneity by baseline HF status remain uncertain.
Purpose
To evaluate lipid effects and clinical outcomes of PCSK9 inhibition in participants with versus without baseline HF using data from SPIRE-1 and SPIRE-2.
Methods
We conducted a pooled analysis of two randomised, double-blind, placebo-controlled cardiovascular outcome trials of bococizumab (150 mg subcutaneously every 2 weeks) versus placebo in patients at high cardiovascular risk; both trials were stopped early to due the development of antidrug antibodies. Baseline HF was defined by investigator report. Lipid and biomarker changes were assessed at 14 weeks. Clinical outcomes included 3-point major adverse cardiovascular events (MACE; cardiovascular death, non-fatal myocardial infarction, or non-fatal ischaemic stroke), the composite of cardiovascular death or hospitalisation for HF (HHF), all-cause death, and cardiovascular death. Hazard ratios (HRs) were estimated using Cox proportional hazards models, and heterogeneity by baseline HF status was assessed using treatment-by-subgroup interaction testing.
Results
Among 27,438 participants, 3,652 (13.3%) had baseline HF. At 14 weeks, LDL-cholesterol reduction was similar in HF versus non-HF participants (−61% vs −63%), and median LDL cholesterol remained lower than placebo through 32 weeks in both subgroups (Figure 1a). 3-point MACE event rates (bococizumab vs placebo) were 5.09 vs 5.60 per 100 person-years in HF (77 vs 83 events; HR 0.92, 95% CI 0.68–1.26) and 2.24 vs 2.62 in non-HF (216 vs 252; HR 0.85, 95% CI 0.71–1.02; Pinteraction=0.64). Cardiovascular death or HHF event rates were 4.28 vs 5.53 per 100 person-years in HF (65 vs 82; HR 0.77, 95% CI 0.56–1.07) and 0.79 vs 0.65 in non-HF (77 vs 63; HR 1.21, 95% CI 0.86–1.68; Pinteraction=0.06; Figure 1B). Cardiovascular death event rates were 1.68 vs 1.71 per 100 person-years in HF (26 vs 26; HR 1.01, 95% CI 0.58–1.74) and 0.40 vs 0.39 in non-HF (39 vs 38; HR 1.00, 95% CI 0.64–1.56; Pinteraction=0.98). All-cause death event rates were 2.27 vs 2.44 per 100 person-years in HF (35 vs 37; HR 0.95, 95% CI 0.60–1.52) and 0.86 vs 0.81 in non-HF (84 vs 79; HR 1.05, 95% CI 0.77–1.43; Pinteraction=0.70).
Conclusion(s)
In SPIRE-1 and SPIRE-2, bococizumab produced substantial and similar lipid lowering in participants with and without baseline HF. No significant interaction was found by HF status on cardiovascular outcomes or mortality. Further studies are required to ascertain whether the efficacy and safety of PCSK9 inhibitors in HF populations.LDL cholesterol over timeFor image description, please refer to the figure legend and surrounding text.CV death or HF hospitalisationFor image description, please refer to the figure legend and surrounding text.