The systematic review of randomized controlled trials of PCSK9 antibodies challenges their “efficacy breakthrough” and the “lower, the better” theory

Abstract

Background: A Cochrane review with meta-analysis showed controversial results about the efficacy of PCSK9 antibodies in the prevention of cardiovascular diseases. This review gives the opportunity to test the relationship between LDL-C levels and cardiovascular events.

Methods: The authors analyzed the relationship between the calculated LDL-C lowering and the risk of all-cause mortality, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, any adverse event, cardiovascular events and cardiovascular disease mortality.

Results: No beneficial relationship was found between LDL-C lowering and cardiovascular events explored by meta-regression; instead, there was a trend toward harm. For any of the other outcomes there was no significant association between LDL-C lowering and risk. Furthermore, the authors calculated the efficacy that would be expected through the LDL-C lowering showed in the meta-analysis, considering widely accepted predictions. These were respected only for stroke, while the observed efficacy on other cardiovascular events was significantly lower than the expected, and no significant result was observed at all for fatal outcomes. A separate meta-analysis of trials recruiting familial hypercholesterolemia patients have showed a tendency to harm for almost all outcomes.

Conclusions: The relationship between LDL-C lowering and cardiovascular events has not showed any significant association (and even a tendency toward harm), challenging the “lower the better” theory. A separate meta-analysis of trials recruiting familial hypercholesterolemia patients has showed a tendency to harm for all outcomes with PCSK9 antibodies. Therefore, at the moment, the data available from randomized trials does not clearly support the use of these antibodies.

Keywords:

• PCSK9
• LDL-C lowering
• clinical atherosclerotic cardiovascular disease
• CVD
• LDL-C target
• statins
• ezetimibe

Transparency

Declaration of funding

This review was not funded.

Author contributions: A.B. dealt with statistical processing and has written the manuscript. He is the guarantor. A.S. supported the statistical elaborations. A.D. contributed to the ideation, and has revised the manuscript and its editing. The authors agree with the final approval of the version to be published and agree to be accountable for all aspects of the work.

Declaration of financial/other relationships

A.B., A.S. and A.D. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. The views expressed by AD are his own and do not necessarily represent those of his organization.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgements

The authors thank Dr. Donatella Sghedoni and Dr. Alessandro Schivalocchi for support in scientific and linguistic corrections of the manuscript.