LDL (Apo B containing Lipoprotein) target confirmed for modification of Atherosclerotic Vascular Disease – FOURIER data presented

Low lp-28density lipoprotein (LDL) and the other atherogenic lipoproteins (VLDL; IDL and Lipoprotein”a”) the Apo B containing lipoproteins are the cornerstone of the pathophysiology of atherosclerotic vascular disease (ASCVD).  The continued debate as well-established modifiable risk factors for cardiovascular disease, is how low to drive these lipoproteins in the prevention and management of ASCVD.

Monoclonal antibodies that inhibit proprotein convertase subtilisin–kexin type 9 (PCSK9) have emerged as a new class of drugs that effectively lower Apo B containing lipoproteins.  See my post PCSK9 story continues to intrigue and tantalise….posted on March 19, 2015

PCSK9

Published in NEJM and announced at the 2017 American Heart Association meeting 17 March was the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk).  This was a dedicated cardiovascular outcomes trial that tested the clinical efficacy and safety of evolocumab when added to high-intensity or moderate-intensity statin therapy in patients with clinically evident atherosclerotic cardiovascular disease.

The FOURIER trial was a randomized, double-blind, placebo-controlled, multinational clinical trial in which 27 564 patients at 1242 sites in 49 countries underwent randomization.  Patients were eligible for participation in the trial if they were between 40 and 85 years of age and had clinically evident atherosclerotic cardiovascular disease (ASCVD), defined as a history of myocardial infarction, non-hemorrhagic stroke, or symptomatic peripheral artery disease, as well as additional characteristics that placed them at higher cardiovascular risk.  Patients had to have a fasting LDL cholesterol level of 70 mg per deciliter (1.8 mmol per liter) or higher or a non–high-density lipoprotein (HDL) cholesterol level of 100 mg per deciliter (2.6 mmol per liter) or higher while they were taking an optimized regimen of lipid-lowering therapy, which was defined as preferably a high-intensity statin but must have been at least Atorvastatin at a dose of 20 mg daily or its equivalent, with or without ezetimibe.

Eligible patients were randomly assigned in a 1:1 ratio to receive subcutaneous injections of evolocumab (either 140 mg every 2 weeks or 420 mg every month, according to patient preference) or matching placebo.

The primary efficacy end point was major cardiovascular events, defined as the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke.

When added to statin therapy, the PCSK9 inhibitor evolocumab lowered LDL cholesterol levels by 59% from baseline levels as compared with placebo, from a median of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter). This effect was sustained without evidence of attenuation.

Fourier LDL reduction

In this dedicated cardiovascular outcomes trial, the addition of evolocumab to statin therapy significantly reduced the risk of cardiovascular events, with a 15% reduction in the risk of the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization and a 20% reduction in the risk of the more clinically serious key secondary end point of cardiovascular death, myocardial infarction, or stroke.

The data from this trial provide insight into the benefit of decreasing Apo B containing lipoproteins to median levels lower than those in previous trials.  These observations align well with the effects of evolocumab and aggressive LDL reduction on coronary atherosclerotic plaque volume in the Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) trial.  See my post Atherosclerotic plaque regression with intense Apo B lipoprotein lowering posted on November 17, 2016

Optimal risk reduction

Blessings Cardiologydoc

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5 thoughts on “LDL (Apo B containing Lipoprotein) target confirmed for modification of Atherosclerotic Vascular Disease – FOURIER data presented

  1. IIRC median LDL-C was in the mid 90s before and reduced accordingly by the PCSK9 inhibitor. Wouldn’t you agree that given this starting point the event reduction of only 15% is extremely(!) disappointing? I’m not even talking about cost issues here, it’s the surprising lack of clinical response given this massive LDL reduction. Heck that’s not even significantly better than the notoriously impotent ezetimibe which was tested in IMPROVE-IT under very similar starting conditions. I’m really not too sure what to make of this.

  2. Hi Dolph

    Your comment is valid about a 15% relative risk reduction for the primary end points and 20% relative risk reduction for the secondary end points translates into small absolute risk reduction. BUT you have to look a little deeper as a preventive cardiologist as to the LIFETIME benefit having ridiculously low Apo B levels. Remember these trials are VERY short and are testing the hypothesis that “lower is better” in terms of Apo B.

    FOURIER proved this hypothesis and if you look at the commentaries of all LDL lowering trials the number needed to treat (NNT) gets smaller every year you maintain a low Apo B. FOURIER follows exactly what JUPITER demonstrated that the NNT by 3-4 years is very low (~ 20) compared to 70 after one year. The point I’m making is the TARGET for preventing atherosclerotic vascular disease is still the Apo B lipoproteins.

    This trial pretty much confirms that for every i mmol/l LDL reduction you impart a 22% relative risk reduction and over you lifetime this will translate into very meaningful absolute risk reduction.

    You also have to understand that the FOURIER patients were on a moderate dose of potent statins and some also on Ezetimibe with a VERY low annual morbidity and mortality so a 15-20% reduction in events on top of this actually is impressive?

    Regards
    Cardiologydoc

  3. I absolutely don’t question that every reduction in risk is to be welcomed and an important advance. You also know that I’m very keen on lifetime Apo B control.
    Yet shouldn’t the risk reduction have been larger even at that short time frame given the extremely potent lipid reduction? As far as I remember background therapy is a rather unimportant factor in calculating the expected risk reduction given a drug induced reduction in Apo B? I don’t question the utility of PCSK 9 inhibitors, especially in FH, yet I feel a bit unimpressed when comparing these results to JUPITER just for example? I hope I’m wrong…

  4. I have been following the discussion from the AHA meeting last week and your concerns are EXACTLY the concerns of everyone. The prohibitive cost for the small absolute risk reduction is voiced by all. Until AMGEN drastically reduce the cost of Evolocumab to less than US 400 per month no-one will ever use these drugs as cost-effective studies for the US health care system seen to benchmark this figure. If the drug ever reaches our health system (South Africa) I can tell you any cost above US 100 will hard pressed to be covered by our funders……..

  5. That probably will take some time at least… As far as I understood the biochemistry of PCSK 9 a small molecule drug to inhibit it seems to be out of the question. It’s a pity.

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