Because PCSK9 is elevated after ACS, PCSK9 inhibitors could benefit patients with ACS, according to a review published in the Annals of Internal Medicine.
The PCSK9 inhibitors alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen) are approved for lowering of LDL in patients with familial hypercholesterolemia or clinical atherosclerotic CVD who are not at goal despite maximally tolerated statin therapy. They are not yet approved for patients with ACS.
Although most research has focused on the LDL-lowering properties of PCSK9 inhibitors, “preliminary evidence also supports other potential mechanisms that are mediated by PCSK9 antibodies in reducing [CV] events,” Eliano P. Navarese, MD, PhD, and colleagues wrote. “We posit that these findings support a rationale for the use of PSCK9 antibodies in patients with ACS and highlight the need for further investigation in this area.”
Eliano P. Navarese
Navarese, from Heinrich Heine University, Düsseldorf, Germany, and colleagues reviewed research on PCSK9’s mediated pathways, its relationship with myocardial ischemia and plaque vulnerability and the pharmacokinetics and effects of inhibition of PCSK9.
Relationship with plaque
Elevated PCSK9 levels are “associated with more severe atherosclerosis and higher rates of [CV] events that were potentially triggered by destabilization of coronary plaque,” they wrote, noting that two retrospective studies found plasma PCSK9 levels independently predicted CAD.
Pathways by which PCSK9 can affect coronary plaques include proinflammatory LDL oxidation and direct modification of plaque composition, they wrote, concluding that “these observations provide a rationale for considering PCSK9 antibodies in the early phase of ACS.”
After patients with ACS are treated with PCSK9 inhibitors, they may benefit not only from LDL reduction, but also plaque stabilization, they wrote. “In aggregate, these data suggest that the administration of PCSK9 antibodies to patients with ACS could be associated with clinical benefit that is at least similar to that seen in low- and medium-risk stable patients with [CAD],” they wrote.
Animal and in vitro studies have suggested that PCSK9 can affect oxidized LDL, which is associated with platelet activation, plaque destabilization and other adverse consequences, according to the authors.
Formal studies on the timing of administration of the drugs to patients with ACS and the effect on inflammatory and thrombosis pathways are necessary, Navarese and colleagues wrote, noting that eventually, outcome studies powered for hard endpoints will be needed.
Rigorous research required
In a related editorial, Michael S. Lauer, MD, from the NIH, wrote that, “The authors present a compelling argument for why PCSK9 inhibitors might someday find themselves sitting alongside platelet inhibitors, statins, anticoagulants and percutaneous interventions as part of the routine management of high-risk patients with [ACS].”
However, he wrote, “we cannot afford to cut corners” on research to prove this hypothesis. “As strong as hypotheses might be, rigorous science requires rigorous testing and retesting and involves thousands of people and places.” – by Erik Swain
Disclosure: Navarese reports receiving fees from Sanofi and Regeneron outside the submitted work. See the full study for a list of the other authors’ relevant financial disclosures. Lauer is an employee of the NIH.