Effects of early protein convertase subtilisin/kexin 9 inhibitor therapy after acute coronary syndrome

After acute coronary syndrome (ACS), early use of protein convertase subtilisin/ kexin 9 (PCSK9) inhibitors is strongly recommended to help more rapidly and aggressively prevent major adverse cardiovascular events (MACEs).

Key Takeaway

  • PCSK9 inhibitors significantly reduce MACE in post-ACS patients; this seems to occur directly by modifying plaque composition, with subsequent stabilization, and indirectly by altering lipid metabolism and platelet aggregation.
    • EVACS study: More than 90% patients receiving evolocumab achieved low-density lipoprotein cholesterol (LDL-C) <55 mg/dL target (European Society of Cardiology [ESC]/European Atherosclerosis Society [EAS] guidelines); 11% patients only receiving statins attained this target.
    • EVOPACS study: Evolocumab reduced LDL-C levels by 40.7% and helped 95.7% patients achieve LDL-C <55 mg/dL.
    • ODYSSEY Outcome trial: Alirocumab vs placebo reduced the overall MACE risk, reduced all-cause mortality risk, and caused fewer deaths for coronary heart disease (CHD).
  • PCSK9 inhibitor resistance may be related to discontinuation of concurrent lipid-lowering therapies after PCSK9 inhibitor initiation.
  • Occasionally, a limited LDL-C lowering response may be noted due to PCSK9 inhibitor hypo-responsiveness.

Why This Matters

  • Considering frequency, mortality, and costs, ACS remains one of the most relevant diseases globally. Over time, the approach for treating ACS has changed.
  • This review aims to highlight the beneficial effect of early use of PCSK9 inhibitors post-ACS in reducing LDL-C and MACE risk, which is very high in the first year and continues to stay high after the acute event.

Key Highlights

PCSK9 is implied both directly and indirectly in atherosclerotic plaque formation.

  • It acts directly via the proinflammatory oxidation of LDL-C and modification of plaque composition for an inflammatory response.
  • It acts indirectly by affecting lipid metabolism (by modulating LDLR, very LDLR, and LDLR-related protein-1 expression) and platelet aggregation.

PCSK9 inhibitors:

  • PCSK9 inhibitors reduce circulating LDL-C levels, and this effect can be potentially increased by a combination with statins.
  • The FOURIER trial demonstrated that anti-PCSK9 reduced lipoprotein (a) levels by ≈25%–30%.
  • In ORION-1 trial, a single inclisiran injection reduced mean LDL-C levels by 27.9%–41.9% after 180 days and by 28.2%–36.6% after 240 days (P <0.001). Two doses led to a mean reduction of 35.2% – 52.6% on day 180 (P <0.001).
  • Similarly, ORION-10 trial showed that inclisiran reduced LDL-C levels by 52.3% after 510 days in patients with atherosclerotic cardiovascular disease (CVD).
  • In ORION-11 trial, LDL-C levels reduced by 49.9% in patients with atherosclerotic CVD or an atherosclerotic CVD risk equivalent.

LDL-C management after ACS

  • American College of Cardiology/American Heart Association guidelines recommend initiating a more intensive lipid-lowering therapy for patients with LDL-C ≥70 mg/dL (≥1.8 mml/L).
  • ESC/EAS guidelines recommend early use of high-intensity statins and addition of ezetimibe and anti- PCSK9 antibodies in ACS patients without both LDL-C reduction ≥50% from baseline and LDL-C reduction >1.4 mmol/L (>55 mg/dL).
  • Although neither evolocumab nor alirocumab significantly reduced inflammatory markers in patients with ACS, both these PCSK9 inhibitors in combination with high-intensity statins significantly reduced LDL-C levels after 8 weeks.
  • In the EVACS trial, evolocumab helped >90% patients with ACS achieve LDL-C <55 mg/dL (according to ESC/EAS guidelines) compared with 11% patients receiving only statins.
  • In the EVOPACS study, evolocumab on top of a high-intensity statin reduced LDL-C levels by 40.7% and helped 95.7% patients achieve LDL-C <55 mg/dL.
  • In ODYSSEY Outcome study, alirocumab vs placebo reduced overall MACE risk by 15%, and reduced all-cause mortality risk and caused fewer deaths for CHD.

Pitfalls and future perspectives:

Although most patients receiving PCSK9 inhibitors attain the expected 50%–60% reduction in LDL-C, sporadically, a limited LDL-C-lowering response is noted.

  • Proposed mechanisms for such PCSK9 inhibitor hypo-responsiveness (<15% of LDL-C reduction): (1) Impaired monoclonal antibody entry into the systemic circulation and (2) physiological impairment after monoclonal antibody absorption.

The most common cause of apparent PCSK9 inhibitor resistance is related to discontinuing concurrent lipid-lowering therapies after initiating PCSK9 inhibitors.

Novel PCSK9 inhibitors that are currently under development: Inclisiran, oral small-molecule inhibitors, vaccines, and clustered regularly interspaced short palindromic repeats.

    Iannuzzo G, Gentile M, Bresciani A, Mallardo V, Di Lorenzo A, Merone P, et al. Inhibitors of protein convertase subtilisin/kexin 9 (PCSK9) and acute coronary syndrome (ACS): The state-of-the-art. J Clin Med. 2021;10(7):1510. doi:10.3390/jcm10071510. PMID:33916362.

MAT-BH-2200042/v2/Jan 2024