Issue 43 / 4 November 2019

THE Australian targets for LDL cholesterol (LDL-C) for patients at high risk of cardiovascular events should be lower, and both doctors and patients need to strive to achieve them.

There is no longer an “LDL-C hypothesis”. Mendelian randomisation studies have confirmed the critical role of LDL-C in atherosclerotic plaque formation and related subsequent cardiovascular events. Lowering LDL-C reduces cardiovascular events. The effect is greatest in patients with established atherosclerotic cardiovascular disease (ASCVD), with a 1 mmol/L reduction in LDL-C producing a 20% reduction in cardiovascular events.

In Australia, various guidelines suggest a target of 1.8 mmol/L for LDL-C in patients with ASCVD. This number is based on the PROVE-IT trial that demonstrated reduced death, myocardial infarction or stroke in patients treated with 80 mg of atorvastatin compared with 40mg of pravastatin. However, in the trial it was recognised that over 30% of patients will not reach LDL-C of 1.8 mmol/L with high intensity statins alone and will therefore need another agent, usually ezetimibe. Many studies in Australia and overseas demonstrate that in the real world less than 50% will reach this target due to a number of reasons, including not being prescribed appropriate therapy and perceived side effects.

Recent trials suggest the more appropriate target for LDL-C is 1.4 mmol/L. The IMPROVE-IT trial, which compared the addition of ezetimibe with simvastatin in patients after an acute coronary syndrome (ACS), demonstrated a benefit of reducing LDL-C from 1.8 mmol/L to 1.4 mmol/L, particularly in high risk subgroups, such as patients with diabetes.

The ODYSSEY OUTCOMES study, also in patients after ACS, randomised patients with an LDL-C level above 1.8 mmol/L taking high intensity statin (atorvastatin 40 mg or 80 mg, rosuvastatin 20 mg or 40 mg) to the PCSK9 inhibitor, alirocumab or placebo. PCSK9 inhibitors will produce approximately a further 50% reduction in LDL-C. In this study, if the LDL-C fell below 0.5 mmol/L, the dose was reduced so the mean LDL-C on treatment was 1.4 mmo/L compared with 2.4 mmol/L on placebo. There was a significant reduction in cardiovascular events including death, myocardial infarction and stroke, and in patients with an initial high LDL-C (> 2.6 mmol/L) there was a reduction in all cause death.

In the FOURIER trial, with the PCSK9 inhibitor evolocumab there was no dose reduction no matter how low the LDL-C went, and the mean LDL-C was 0.79 mmol/L. This trial also demonstrated significant reductions of cardiovascular events and, importantly, no evidence of harm even at very low levels of LDL-C. So far, there has been no evidence of harm, only benefit, as LDL-C goes down.

The European Society of Cardiology has recognised these new data and, in their guidelines released in August 2019, produced two new treatment targets for those patients they define as very high risk, which includes all patients with ASCVD. The general target should be 1.4 mmol/L, and for patients who have recurrent events within 2 years, the target should be 1.0 mmol/L. The evidence is so strong that I believe the Australian guidelines for patients who have had an ACS should be changed to match the Europeans guidelines.

To meet these targets many patients will require not only high intensity statin and ezetimibe but additional therapies. The therapy currently available is the PCSK9 inhibitors. These will further reduce cholesterol by 50% in patients taking a statin and ezetimibe. But these drugs are very expensive and are only available on the Pharmaceutical Benefit Scheme (PBS) in Australia for patients with familial hypercholesterolaemia. However, new agents are in the pipeline.

Patients who are high risk and have a high residual LDL-C should be screened for familial hypercholesterolaemia using the Dutch Lipid Score, as they may be eligible for PBS reimbursement for PCSK9 inhibitors.

Patients without familial hypercholesterolemia who have had an ACS and have residual LDL-C greater than 2.6 mmol/L taking high intensity statin and ezetimibe should be considered for treatment but currently would need to fund the treatment themselves. The European guidelines recommend these patients be treated with a PCSK9 inhibitor. Other groups that will benefit most from PCSK9 inhibitors are patients with recurrent events after coronary bypass surgery, patients with peripheral vascular disease, patients with diabetes, and those with an elevated LP(a).

In summary, lowering LDL-C reduces major cardiac events including death, myocardial infarction and stroke. The lower the LDL-C the better. There has been no evidence of harm even at levels below 0.5 mmol/L. The new target for patients after an ACS, or otherwise at very high risk, should be 1.4 mmol/L. To achieve this, most patients will require a combination of high intensity statin and ezetimibe and some will require additional treatment with a PCSK9 inhibitor.

Professor Philip Aylward was Australian lead investigator and member of the international steering committee for the Odyssey trial. He is a member of Sanofi and Amgen Advisory Boards and has received speaker fees from Sanofi and Amgen. He is a clinical cardiologist and a Professor of Medicine at Flinders University in Adelaide, Southern Adelaide Local Health Network, and the South Australian Health and Medical Research Institute. 

 

The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.

8 thoughts on “Time to lower LDL cholesterol targets after cardiac events

  1. Dr Christopher Hammersley says:

    Dear Professor:

    Thanks for bringing this to our collective attention. I understand the good that could result if there were a real significant benefit.

    FOURIER
    Benefit of LDL-C lowering with evolocumab on cardiovascular outcomes by age & sex: an analysis of the FOURIER trial.
    P S Sever, I Gouni-Berthold, A Keech, R Giugliano, T Pedersen, S Wasserman, K Im, M Sabatine, M O’Donoghue, FOURIER Trial

    European Heart Journal, Volume 39, Issue suppl_1, August 2018, ehy566.5002, https://doi.org/10.1093/eurheartj/ehy566.5002
    Published: 28 August 2018:

    https://academic.oup.com/eurheartj/article/39/suppl_1/ehy566.5002/5081219 …… [Copy -> Paste link in browser)

    Question: What do you mean “significant reductions of cardiovascular events”?

    It is noteworthy that most publications reporting this study in 2017 and 2018 trumpeted about the ‘ocumab’ *efficacy* in lowering LDL if you take enough, BUT are almost silent on efficacy in reducing ASCV events. They focus on the reduction in calculated *risk* (a theoretical mathematical statement) but omit stating actual outcomes. This worries me; it reads like new product ‘hoohaa’ … “Looks like it really will work!! Yay!” This will sustain sales until proven otherwise, and given the cost of the drug, it is a statement friendly to the manufacturer, who may turn out to be the main beneficiary.

    Journalistically, the reporters should have included caveats re no proven clinically efficacy in those who don’t have a Familial Hyperlipidaemia, i.e the great majority of the population.

    Yes, there was reduction in cardiovascular events in FOURIER over 2.2 years median follow up, but it was not at all impressive.
    The above EHJ paper suggests it was 1.78% – 2.69% *absolute reduction* in MI, stroke and CV deaths in either sex.
    And at the end, in the last line above Conclusions …”there were no differences between those reported on evolocumab and placebo.” [What!?]

    Given the extreme reductions in exposure to an *alleged key disease causing agent* needed to achieve this, the benefit was minor at most.
    I think this should better provoke questions, rather than to be taken as a sentinel result.

    In case I missed it, are you able to point to evidence of significant absolute reduction in adverse atherosclerotic events?

  2. Anonymous says:

    there is no comment about age limits, my work as a GP involves nursing home patients, many in their 80s and 90s,
    what is the evidence for this group of patients? How much benefit is their for them given longstanding heart disease or dementia

  3. Richard Lyle says:

    Living in the dark ages mate.

  4. Ruth Taylor says:

    What difference does LDL particle size make? Has this been researched?

  5. Geoffrey Stone says:

    Far to many people rely upon statins to reduce LDL-C where change of life style is far more effective. There is no mention in this study of the impact of sdLDL in penetrating the intima lining and causing CVD events. The whole study appears to be a marketing drive by the drug manufacturers without giving sufferers options of change of lifestyle.

    See Dr Paul Mason, Dave Feldman, Rhonda Patrick and Thomas Dayspring on LDL and the misinformation from the pharmaceutical industry.

  6. Anonymous says:

    This is just a marketing puff piece!
    I think the comments above have done a much better job of analysing the real world evidence. But let’s not let evidence get in the way of big pharma profits….

  7. Anonymous says:

    I second Ruth Taylor’s question. Not a doctor, but this does read as a “take these drugs if you don’t want to die from an LDL-C – related event” advertisement. Why is there still so little investigation into the role of LDL particle size (which can be influenced by diet) in CVD? I have high LDL and my GP wanted to put me on statins without even checking to see if I have any signs of CVD. There’s no acknowledgement that you can have high LDL and yet not have CVD. Cheers

  8. Graham Lovell says:

    I am able in South Australia to easily access CT Coronary Calcium scoring.

    For the vast majority of my Primary Prevention of Cardiovascular Events,which is what we as GPs are
    the key responsible Medical Practitioners,
    This is clearly a much more accurate tool for separating out Low risk, and high risk patients.

    It also shows evidence for being the best motivator for patients to address and comply with risk factor reduction
    , far better than poorly evidenced lipid profiles followed by adding a statin.

    Secondary Prevention as per this article by Dr Aylward is largely Cardiologist driven, and my aim as a GP is to try and engage these patients in optimal lifestyle changes looking much more holistically than just a calculated LDL-C.

    Secondary Prevention gives us a much more motivated average patient to look at optimal diet, weight reduction etc.

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