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Confessions and Omens From the ODYSSEY Trial

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Confessions and Omens From the ODYSSEY Trial

Milton Packer assesses his predictions on the future of lipid research

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The investigators of the ODYSSEY Outcomes trial presented the results last weekend, and they spoke volumes about the role of lipids in cardiovascular risk. But not necessarily in the manner in which they intended.

As background, the ODYSSEY Outcomes trial enrolled 18,924 patients who had recently suffered an acute coronary syndrome and had increased levels of LDL cholesterol. Patients were randomized to treatment with either placebo or with alirocumab (Praluent) for at least 3 years. The PCSK9 inhibitor had a dramatic effect on serum LDL cholesterol. Most patients had a baseline LDL cholesterol >70 mg/dL despite treatment with high-intensity statins, and the drug further reduced LDL cholesterol by more than 50%.

In my post two weeks ago, I made three predictions.

First, I thought that the enrollment of patients with a recent acute coronary syndrome would lead to many early events that would not be affected by cholesterol lowering.

The actual result: the event curves for the two treatment arms did not diverge during the first year of follow-up.

Second, I thought that it would be very difficult to show the benefits of cholesterol lowering if the participants entered the trial with an LDL cholesterol that was already low.

I said: “It seems likely that the patients entering the ODYSSEY trial are starting out with a serum cholesterol <90 mg/dL. Is cholesterol really playing an important role at that level, especially when compared with non-cholesterol factors?”

The actual result: the benefit in the entire trial was driven entirely by the effect seen in 5,629 patients who started with LDL cholesterol >100 mg/dL. There was no benefit in patients with lower values for baseline LDL cholesterol.

Third, I thought the effect in patients with a LDL cholesterol >90 mg/dL would not be enough to move the trial to a positive result. I predicted that the trial would miss on its primary endpoint.

The actual result: The trial achieved its primary endpoint robustly. The effect was consistent across the components of the composite endpoint. I was wrong in this prediction. The effect in the subgroup of patients with a baseline LDL cholesterol >100 mg/dL was large enough — a 24% reduction in risk — to carry the trial to a win on the primary endpoint. The benefit was large enough to drive a nominally significant effect on all-cause mortality in the highest LDL cholesterol subgroup.

The investigators and the sponsors of the ODYSSEY trial should be congratulated. It is a wonderful trial, and something they should really be proud of. The trial confirms once again that lowering LDL cholesterol is important.

But the trial brings sad news to those who believe that lowering LDL is important if your LDL is already low, e.g., 70 mg/dL or lower.

There are many physicians in the lipid community who believe that the ideal LDL cholesterol might be zero. That a value of 50 is better than 65. That a value of 35 is better than 50. That a value of 20 is better than 35.

The ODYSSEY trial strongly suggests that those beliefs aren’t true. And that has huge implications for lipid research.

The sponsor of alirocumab says it will dramatically lower the price of alirocumab to make the drug accessible to those with a LDL cholesterol >100 mg/dL. It is really unusual for a sponsor to cut the price of a drug after a successful trial. That is a brilliant move.

But that is not good news for those who are developing new drugs to further lower LDL cholesterol. The ODYSSEY trial shows that we may have reached the limits of what we can achieve by lowering lipids.

On Oct. 18, 2017, I predicted the demise of lipid research as a means of lowering cardiovascular risk. Sadly, according to the ODYSSEY trial, that prediction may actually come true.

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.

2018-03-14T10:30:00-0400
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At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.

Medpage Today

Confessions and Omens From the ODYSSEY Trial

Milton Packer assesses his predictions on the future of lipid research

MedpageToday

  • by

The investigators of the ODYSSEY Outcomes trial presented the results last weekend, and they spoke volumes about the role of lipids in cardiovascular risk. But not necessarily in the manner in which they intended.

As background, the ODYSSEY Outcomes trial enrolled 18,924 patients who had recently suffered an acute coronary syndrome and had increased levels of LDL cholesterol. Patients were randomized to treatment with either placebo or with alirocumab (Praluent) for at least 3 years. The PCSK9 inhibitor had a dramatic effect on serum LDL cholesterol. Most patients had a baseline LDL cholesterol >70 mg/dL despite treatment with high-intensity statins, and the drug further reduced LDL cholesterol by more than 50%.

In my post two weeks ago, I made three predictions.

First, I thought that the enrollment of patients with a recent acute coronary syndrome would lead to many early events that would not be affected by cholesterol lowering.

The actual result: the event curves for the two treatment arms did not diverge during the first year of follow-up.

Second, I thought that it would be very difficult to show the benefits of cholesterol lowering if the participants entered the trial with an LDL cholesterol that was already low.

I said: "It seems likely that the patients entering the ODYSSEY trial are starting out with a serum cholesterol <90 mg/dL. Is cholesterol really playing an important role at that level, especially when compared with non-cholesterol factors?"

The actual result: the benefit in the entire trial was driven entirely by the effect seen in 5,629 patients who started with LDL cholesterol >100 mg/dL. There was no benefit in patients with lower values for baseline LDL cholesterol.

Third, I thought the effect in patients with a LDL cholesterol >90 mg/dL would not be enough to move the trial to a positive result. I predicted that the trial would miss on its primary endpoint.

The actual result: The trial achieved its primary endpoint robustly. The effect was consistent across the components of the composite endpoint. I was wrong in this prediction. The effect in the subgroup of patients with a baseline LDL cholesterol >100 mg/dL was large enough -- a 24% reduction in risk -- to carry the trial to a win on the primary endpoint. The benefit was large enough to drive a nominally significant effect on all-cause mortality in the highest LDL cholesterol subgroup.

The investigators and the sponsors of the ODYSSEY trial should be congratulated. It is a wonderful trial, and something they should really be proud of. The trial confirms once again that lowering LDL cholesterol is important.

But the trial brings sad news to those who believe that lowering LDL is important if your LDL is already low, e.g., 70 mg/dL or lower.

There are many physicians in the lipid community who believe that the ideal LDL cholesterol might be zero. That a value of 50 is better than 65. That a value of 35 is better than 50. That a value of 20 is better than 35.

The ODYSSEY trial strongly suggests that those beliefs aren't true. And that has huge implications for lipid research.

The sponsor of alirocumab says it will dramatically lower the price of alirocumab to make the drug accessible to those with a LDL cholesterol >100 mg/dL. It is really unusual for a sponsor to cut the price of a drug after a successful trial. That is a brilliant move.

But that is not good news for those who are developing new drugs to further lower LDL cholesterol. The ODYSSEY trial shows that we may have reached the limits of what we can achieve by lowering lipids.

On Oct. 18, 2017, I predicted the demise of lipid research as a means of lowering cardiovascular risk. Sadly, according to the ODYSSEY trial, that prediction may actually come true.

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.

2018-03-14T10:30:00-0400
Comments

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.



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Dr Irfanullah Khan Born: 15th July,1994 in Khagram,Dir Upper KPK Pakistan. Others names:Doctor Irfo,Peshoo Education:Pharm-D Scholar Graduated from Abasyn University Peshawar. Occupation:Clinical Pharmacist,Doctor,Entrepreneur. Home Town:Dir Upper Height: 6 feet. Website:Iukmedonline.com

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