PCSK9 inhibition and cardiovascular outcomes by heart failure status: a pooled analysis of SPIRE-1 and SPIRE-2

Heart failure (HF) remains a major cause of cardiovascular mortality, developing from diverse risk factors including hypertension, metabolic disease, and ischaemic heart disease, which drive microvascular changes and fibrosis.1 While proprotein convertase subtilisin/kexin type 9 (PCSK9) is well characterized for its hepatic regulation of LDL receptors, it is also expressed in the myocardium, where it modulates fibrosis and inflammation.2 Experimental models have suggested that PCSK9 promotes cardiomyocyte inflammation, apoptosis/pyroptosis, and adverse fibrotic remodelling.2,3 Clinically, elevated circulating PCSK9 levels have been correlated with poor prognosis in HF, as shown in the The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) sub-analysis,4 whereas inhibition has been shown to reduce infarct size in preclinical models.5 Conversely, global PCSK9 knockout in murine models has been shown to drive phenotypes of HF with preserved ejection fraction (HFpEF), dilated cardiomyopathy, and premature death.6 Together, these findings suggest that PCSK9 inhibition may limit inflammation and scarring after acute injury, whereas profound and sustained suppression may impair myocardial structure and function over the long term. Given that the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402) trial suggested a lack of benefit for atherosclerotic and HF events in patients with HF,7 we aimed to determine whether HF status modified the relationship between PCSK9 inhibition and clinical outcomes using pooled individual patient-level data from the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) programme.8