It is not wise to make predictions about the results of major clinical trials. If we were reasonably confident that we could know the answer in advance, then the trial would not be necessary.
Nevertheless, people do enjoy the thought experiment. It is human to try to see if you can solve a puzzle, even if you don't have all the pieces.
Sometimes it is possible to make an educated guess. Those of us who have been doing trials for years often see patterns in the way that a trial has been designed or executed, which might be indicative of what might be going on beneath the surface.
I have been making predictions about the results of trials for a long time. Some people think that my track record is good, but I would disagree. In truth, they are likely to only remember the times I was right. By contrast, I will distinctly remember the times I was wrong.
Not surprisingly, many people have been asking me to make a prediction about the ODYSSEY Outcomes trial, which is to be on March 10.
The is evaluating the effects of a PCSK9 inhibitor, alirocumab, on major cardiovascular events in patients with an acute coronary syndrome within the prior year. The drug lowers serum cholesterol dramatically, and some are hopeful that that effect will translate into an important reduction in the risk of major adverse cardiovascular events.
If you believe that cholesterol reduction inevitably leads to the prevention of cardiovascular death, myocardial infarction and stroke, then you would have high expectations for the ODYSSEY trial.
But cardiovascular risk reduction is complicated. There is more to the puzzle than cholesterol. Some drugs lower both cholesterol and prevent cardiovascular events, but some people think that the two effects are actually not that closely related.
Nevertheless, some have major hopes for ODYSSEY. The trial uses a somewhat more aggressive treatment strategy and has a longer follow-up period than its predecessors. So maybe the benefit will be large. Maybe the drug will even reduce cardiovascular death or all-cause mortality.
Maybe, but not likely.
For PCSK9 inhibitors, the effect on major adverse cardiovascular events has always fallen short of expectations based on cholesterol lowering. In a previous trial (FOURIER), another PCSK9 inhibitor had only a modest benefit on its primary endpoint, and it did not reduce cardiovascular death, although the magnitude of cholesterol lowering was striking.
In another trial (SPIRE), a third PCSK9 inhibitor missed on its primary endpoint entirely, despite an impressive reduction in serum cholesterol.
The ODYSSEY trial comes to the table with an intriguing feature. In order to enrich the population for cardiovascular events, the trial enrolled patients with an acute coronary syndrome within the prior year. These patients are at high risk of having a recurrence. The problem is that risk is not necessarily related to changes in cholesterol, especially the events occurring early in the trial. And in this type of trial, the analysis tends to give extra weight to early events.
Trials like ODYSSEY are often designed to stop early if the results are unbelievably impressive. The ODYSSEY trial wasn't stopped early.
And the patients in the trial did not have a very high serum LDL cholesterol even before they were enrolled in the study. In the past, it was relatively easy to show the benefits of cholesterol lowering if the participants entered the trial with a serum LDL cholesterol of >140 mg/dL or >120 mg/dL.
But it seems likely that the patients entering the ODYSSEY trial are starting out with a serum LDL <100 mg/dL or even <90 mg/dL. Is cholesterol really playing an important role at that level, especially when compared with noncholesterol factors?
I have no idea what the ODYSSEY trial will show. It is a landmark trial, and I am sure that it will reveal many interesting analyses. But my guess is that it will miss on the primary analysis of its primary endpoint.
My friends who are hoping for an impressive result shouldn't worry. No one should bet money based on my predictions of the results of a trial.
But do you think what I think?
Disclosures
Packer recently consulted for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Novo Nordisk, Relypsa, Sanofi, Takeda, and ZS Pharma. He chairs the EMPEROR Executive Committee for trials of empagliflozin for the treatment of heart failure. He was previously the co-PI of the PARADIGM-HF trial and serves on the Steering Committee of the PARAGON-HF trial, but has no financial relationship with Novartis.