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The Lp(a)HORIZON trial tested one of the most genetically validated targets in medicine, but failed to meet its primary endpoint of cardiovascular event reduction in secondary prevention. While other therapeutic programs are also supported by genetic data, what was special about the Lp(a) hypothesis was that genetic estimates were used to predict the effect expected in trials, and these predictions partly informed the design of Lp(a)HORIZON. The results therefore offer a unique opportunity to ask how well estimates from genetic studies translate into clinical risk reduction. In this new piece (link in the comments), I go through the genetic evidence, the trial results, how they agree or disagree, and where this leaves the Lp(a) hypothesis.

Some take aways from what we know about HORIZONS phase 3 trial of Lp(a) lowering 1. We know very little. We only know the primary endpoint in the entire population. 2. We do not know if some subgroups may have benefited more like those with a higher baseline Lp(a). 3. Do those who were not on dual or single anti platelet therapy benefit? 4. Did efficacy vary by baseline and on treatment LDL? 5. Did efficacy vary by achieved Lp(a)? 6. We need more sophisticated analyses of the particle composition and oxidizing potential of the patient’s Lp(a) particle to assess for heterogeneity in response. 7. Were the results different in MI patients vs stroke vs PAD patients? These vascular beds behave differently in response to therapeutic interventions. 8. Were the results different in patients with single vessel disease vs multivessel disease where there were more targets for modification. 9. This was a time to first event analysis and not a time to any event analysis (a multiple event analysis). A multiple event analysis captures disease burden and may be more highly powered. 10. For those who were on dual antiplatelet therapies, once these were discontinued, was there an event reduction which would suggest optimal antiplatelet therapy may have reduced residual risk so much it could not be modified? 11. Much has been made of observational data suggesting aspirin may modify risk in patients with an elevated Lp(a). Was there an interaction with aspirin therapy ? 12. Mendelian randomization / genetics captures lifetime exposure and not several years of exposure as in this trial. Were the KM curves diverging late suggesting prolonged therapy might have been needed? 13. Were the assumptions regarding the magnitude of the potential efficacy signal too optimistic and was the trial underpowered? 14. In a trial this long patients may go missing. How good was the follow up? Was there informative censoring? 15. The results of primary prevention trials where LDL lowering and antiplatelet therapy may not have been as aggressive may still show benefit. 16. This ONE trial does not negate the potential causal role of Lp(a). The LDL and antiplatelet therapy may have reduced residual risk so much that there was very little risk to be modified. A trial Lp(a) lowering only would share more light on this question (a trial will never be done). What would happen if all patients were on Lp(a) lowering therapy. Would LDL lowering further improve outcomes? We don’t know for sure. 17. Was there an interaction with CRP, gender age risk score? 18. Obviously there are more questions than answers at this point. I raise these questions as exploratory hypotheses, to further our understanding of the biology, not to salvage a neutral trial. We all anxiously await the full recitation of results and answers to these questions as well as others. Thank you to the patients who participated.

My Lp(a) is 175. I have been waiting for this trial for years. Yesterday, Novartis released the results of HORIZON. The biggest Lp(a) outcomes trial in history. 8,323 patients. A drug built from the ground up to do one thing: lower Lp(a). The drug worked. The cardiovascular events did not change. This is the most important failed trial in cardiovascular medicine this year. Nobody is explaining why it failed. I will.