Lipids Update! Get up close and personal with ASCVD prevention and lipid management guidelines, including changes in the 2018 update, with our discussion with Dr. Erin Michos @erinmichos, preventive cardiologist and associate professor of medicine at the Johns Hopkins University Hospital! We review the background on the ASCVD risk calculator, basics of primary and secondary prevention, statins benefits and misconceptions, appropriate follow up, cool things to look out for in the future, the deal with medications like aspirin and icosapent ethyl, among many other things! If that wasn’t enough, Dr. Michos also goes over great ways to counsel patients on healthy living and when that darn statin is giving you the “muscle aches”!
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Producers: Christopher Chiu MD FACP FAAP; Jasneet Devgun DO; Justin Berk MD MPH MBA; Beth Garbitelli
Writers: Jasneet Devgun DO; Justin Berk MD MPH MBA
Infographic: Beth “Garbs” Garbitelli
Cover Art: Kate Grant MBChB DipGUMed
Hosts: Christopher Chiu MD FACP FAAP; Matthew Watto MD FACP; Paul Williams MD FACP
Editors: Emi Okamoto MD (written materials); Clair Morgan of Nodderly.com (audio)
Guest: Erin Michos MD MHS
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Atherosclerotic cardiovascular disease, or ASCVD, is defined by atherosclerotic disease such as myocardial infarction (MI), stroke, and sometimes peripheral artery disease. More specifically, this means both fatal and non-fatal MI and stroke when talking about the well-known ASCVD risk calculator.
The ASCVD risk calculator that we all know so well is one of many cardiovascular disease calculators out there, but this one is specifically recommended by the guidelines since 2013 for its use (Goff, 2013). It’s a pooled cohort equation derived from several large studies by the National Heart, Lung, and Blood Institute (NHLBI) in which the endpoints were “hard” cardiovascular endpoints, namely fatal and non-fatal MI and stroke. The calculator, which includes race, sex, presence of specific comorbidites, and other risk factors to estimate 10-year risk of these “hard” endpoints.
Kashlak Pearl: Whose risk should be assessed with this calculator? Anyone who is between the ages of 40 and 75 years-old who doesn’t have diabetes and has an LDL between 70 and 189. You got that?
The guideline recommendations in 2013 encouraged widespread use of the calculator for assessing ASCVD risk and, therefore, treatment strategy with statins. But many realized that the calculator is not necessarily perfect, as it does not take into account lots of other risk enhancing factors (more below) that would put someone at a much higher risk for clinical ASCVD than what this calculator would predict. Per Dr. Michos, the 2018 update is much more personalized, and making the decision to start a statin, especially in primary prevention, is much more a patient-centered endeavor (Grundy, 2018). There is also more information in the literature on those who are “borderline” or “intermediate” risk to make a more nuanced recommendation for those who fall into these categories too.
Dr. Michos emphasized the great importance in “primordial” prevention! This means that we start as early as possible in preventing ASCVD risk. She specifically noted that it’s not necessarily the magnitude of LDL burden but the duration of exposure that really determines ASCVD risk. Diet and exercise modification cannot be stressed enough! A life on this foundation is key for preventing ASCVD, and should be the cornerstone of our discussions with our patients at every step of the way.
A diet rich in fruits, vegetables, polyunsaturated fats, lean meats and plant-based proteins, plant phytosterols, and fiber can all potentially decrease LDL by 30 – 40 mg/dL! Avoid saturated fats, refined carbs and sweets, and red meat (Grundy, 2018). Patients should engage in moderate-to-vigorous intensity aerobic exercise about 3-4 x per week for 40 minutes each session.
We now have 4 ASCVD risk categories per the 2018 update. These are according to the patient’s 10-year ASCVD risk:
For patients in the “intermediate” risk category, start a moderate-intensity statin based on discussion with the patient and particularly with the presence of risk-enhancing factors (class I recommendation).
For patients in the “borderline” risk category, consider a moderate-intensity statin based on patient discussion and the presence of risk-enhancing factors (class IIb recommendation).
Patients with diabetes mellitus and age between 40 and 75 years require at least a moderate-intensity statin (class I) or high-intensity statin (class IIa with additional risk factors) regardless of ASCVD risk.
Patients with LDL > 190 mg/dL also require a high-intensity statin regardless of ASCVD risk (class I).
What are these risk-enhancing factors specifically? (Grundy, 2018)
Dr. Michos usually checks lipoprotein (Lp) (a) in anyone who has a very strong family or personal history of premature CAD. Lp(a) is genetically-inherited and is worth it to check once in such patients. There might be some targeted therapies for this in the future!
She also checks an apolipoprotein B (apoB) level when she is getting close to the appropriate LDL goal. The Friedewald equation which estimates LDL levels is imperfect, and atherogenic particles are important to check to see if you need to escalate therapy.
A more accurate way to risk-stratify your patients is with coronary artery calcium (CAC) scoring, which can be particularly insightful for statin decisions in borderline or intermediate risk patients. It is a far superior marker in refining risk compared to the biomarkers themselves. It has a very strong negative predictive value with the CAC score is zero, which is equivalent to 0.1% per year risk of ASCVD. According to the MESA study (Bertoni, 2016), diabetics with a CAC score of zero had similar event rate as those without diabetes.
The guidelines highlight some select groups of people that CAC scoring could benefit (Grundy, 2018):
Secondary prevention is prevention of further ASCVD after a clinical event (like myocardial infarction, stroke, peripheral arterial or coronary revascularization) has occurred, and is a little less complicated. The two main groups in secondary prevention are “high risk” ASCVD and “stable” ASCVD. These people always get a high intensity statin right off the bat (unless the patient is > 75 years-old in which case it is a IIa recommendation to start moderate or high intensity statin).
It is about LDL goals for these people: do they achieve LDL < 70 mg/dL on a high intensity statin? If yes, then that’s awesome! If not, then we have to start thinking about adherence conversations and other medications.
When thinking of additional medications to add to a statin for further lipid lowering events, think no further than ezetimibe and PCSK9 inhibitors! The IMPROVE-IT, as well as ODYSSEY and FOURIER trials really showed us the added benefits of ezetimibe and PCSK9 inhibitors, respectively. IMPROVE-IT showed that the addition of ezetimibe to moderate-intensity statin reduced cardiovascular mortality, major cardiovascular events overall, and ischemic stroke (Cannon, 2015). Moreover, PCSK9 inhibitors showed benefit when added to high intensity statin in patients with known coronary disease or familial hypercholesterolemia in the ODYSSEY trial (Robinson, 2015). There was a 62% reduction in LDL in these patients with no increase in cardiovascular events, and a post-hoc analysis showed a 2% absolute risk reduction in major cardiovascular events (MACE). The FOURIER trial also showed 1.5% absolute reduction in MACE when added to a high intensity statin with LDL above 70 mg/dL (Sabatine, 2017).
Patients deemed as being in the “high risk” ASCVD group are those with the following:
These patients at “high risk” of future events require maximum-tolerated high intensity statin (Class I indication). It is a class IIa recommendation to add on ezetimibe if LDL > 70 mg/dL while already on a high intensity statin. A PCSK9 inhibitor can be considered either after trying a high intensity statin and ezetimibe and the LDL is still > 70 mg/dL (class I), or one can consider it after “clinically judged maximal LDL-lowering therapy” (class IIa).
Patients who have established coronary disease but do not meet any of the “high risk” categories listed above fall into this group. If the patient is > 75 years old, as noted above, it is a class IIb recommendation to start either a moderate or high intensity statin. If the patient is < 75 years old, they get a high intensity statin with a goal of LDL < 70 mg/dL, or moderate intensity statin if they cannot tolerate it (Class I). If the LDL does not drop below 70 mg/dL…you guessed it! Add ezetimibe!
The earliest you should recheck a lipid panel after starting a statin is at 4-12 weeks (1-3 months). Afterwards, you can check anywhere from 3 to 13 months depending on the patient and their situation.
You goals are going to depend on the ASCVD risk category of your patient in primary prevention. For those in the “intermediate” category, an LDL reduction of 30-49% is appropriate. In those at high risk, however, require a reduction of LDL by > 50%. Anyone who does not meet these goals can be considered for step up in therapy.
For our secondary prevention group, you know the magic number: get that LDL < 70 mg/dL!
Is there a difference between, say for example, atorvastatin 80 mg and 40 mg? Well, yes there is! Expect to see a 50-60% reduction of LDL with atorvastatin 80 mg, and 40-52% reduction with the 40 mg.
There is no floor for LDL! The lower you can go, the better. There is no such thing as an LDL that is “too low”.
“Side-effect” or “intolerance”? I think not! The guidelines recommend avoiding these terms and calling the patients’ symptoms “statin-associated muscle symptoms”. This helps to encourage reframing and redefining their symptoms without dismissing them.
Although there is a high concern for major side effects amongst popular thought, the risk of severe muscle injury or rhabdomyolysis from a statin is < 0.1%, and the risk of drug-induced liver injury is 1 in 100,000 (Cholesterol Treatment Trialists, 2010, Thapar 2013)! Additionally, there is no evidence for certain side-effects, namely cataracts and cognitive decline per large randomized trials. There are lots of safety data out there, which is helpful in your discussions with your patients.
Many patients will tell us they have myalgias after the initiation of a statin, and many will defer taking it altogether due to concerns for severe muscle damage as a side-effect. In fact, only up to 10% of patients will develop Myalgias without CK elevation; Myalgies with CK elevation, rhabdomyolysis and statin associated autoimmune myopathy are RARE (Grundy, 2018, see Table 11)! Some studies have shown that patients with previous statin intolerance were able to tolerate statins when rechallenged, up to 72.5% (Warner 2013).
Start by discussing the benefits. We know that for every 1 mmol/L, or 39 mg/dL of LDL reduction, the relative risk reduction of cardiovascular events is 22% (Silverman, 2016). There is also even a 10% reduction in mortality! Moreover, those who have higher risk reap even more benefit. Share the data with the patient; numbers are tangible and meaningful.
Now hone in on the personal benefits. After sharing the science above, personalize it. Show them what these numbers mean to your patients, especially with their specific ASCVD risk.
Statin-associated muscle symptoms can be a big concern for patients when starting or restarting a statin. It’s all about building trust and working with your patient. For the statin-naive, discuss the numbers and personalize it, as well as possible. For instance, utilizing CAC scoring if relevant can help further this discussion in a positive way. For those who have already experienced SAMS, avoid dismissing them and discuss re-introducing the statin. Dr. Michos recommends to start low and go slow. We can start at a low dose statin and slowly work your way up. Chances are, your patient will not have those SAMs anymore (see evidence from randomized trials above). For the most reluctant patients, Dr. Michos will do rosuvastatin 5 mg every other day with ezetimibe. Keep in mind, simvastatin and lovastatin tend to have more SAMS. Pravastatin tends to be less effective.
A few recent trials (ASPREE, ASCEND, and ARRIVE) raised concerns for bleeding with less benefit in preventing first cardiovascular event. Because of this, it is now a class IIb recommendation for primary prevention in select individuals with higher cardiovascular risk and low risk for bleeding, and a class III indication in adults over the age of 70. In fact, the ASPREE trial showed a statistically significant increase in major hemorrhage events in the elderly with aspirin (McNeil, 2018). The ARRIVE trial did show benefit in major vascular events in diabetics specifically, but at the expense of an increase in major bleeding (Gaziano, 2018). Consider your population prior to prescribing rather than routinely using aspirin for primary prevention.
Often we think of fibrates when triglycerides are through the roof, however, Dr. Michos points out that first line is lifestyle modification, and if the triglycerides are persistently > 500 mg/dL, the next step is always a statin! Start a fibrate when the triglycerides are > 1000 mg/dL to avoid pancreatitis.
Icosapent ethyl is a highly purified eicosapentaenoic acid ethyl ester. Dr. Michos notes that it may not derive its benefit by lowering triglycerides, but probably through antithrombotic and antiinflammatory effects. The REDUCE-IT trial took patients with known coronary disease, diabetes with an additional risk factor, already on a statin with residual hypertriglyceridemia (135-499 mg/dL), and assessed if icosapent ethyl reduces cardiovascular events in these patients (Bhatt, 2019). Icosapent ethyl, when added to pre-existing statin, reduced events by 25%! It in fact it just received FDA approval, which should help with current prior-authorization and insurance issues.
A side note for everyone: icosapent ethyl and fish oil are NOT the same! Many over the counter fish oil supplements have been found to have some extra ingredients that would not be conducive to cardiovascular health, like hidden saturated fats!
This is truly an exciting field with lots more to look forward to. Look out for the following medications soon:
Listeners will feel comfortable managing both primary and secondary prevention for ASCVD among different patient scenarios.
After listening to this episode listeners will…
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Dr Erin Michos reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.
Michos E, Devgun J, Garbitelli B, Chiu C, Berk J, Williams PK, Watto MF. “#191 Lipids Update with Erin Michos MD”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list. January 20, 2020.
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