new cholesterol guidelines 2018

The American College of Cardiology and American Heart Association task force on clinical practice guidelines included 10 other organizations for the 2018 guideline on the management of blood cholesterol. Major points:

1. In all individuals, emphasize a heart-healthy lifestyle across the life course.

-- Should be done to reduce atherosclerotic risk at all ages

-- in adults 20 to 39 years old, the assessment of lifetime risk facilitates clinician-patient risk discussion

-- in all age groups, lifestyle therapy is the primary intervention for metabolic syndrome

2. In patients with clinical ASCVD, reduce low-density lipoprotein cholesterol (LDL-C) with high-intensity statin therapy or maximally tolerated statin therapy

-- the more the LDL is reduced, the greater the subsequent risk reduction

-- the goal of a maximally tolerated statin is to lower the LDL > 50%

3. In very high-risk ASCVD, use a LDL-C threshold of 70 mg/dL (1.8 mmol/L) to consider addition of nonstatins to statin therapy. Very high-risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions.

-- It is reasonable to add ezetimibe to maximally tolerated statins when LDL remains>70 mg/dL. Consider adding PCKS9 inhibitor if LDL is still>70 mg/dL. But long-term safety (> 3 years) of PCKS9 inhibitors is uncertain and “economic value is low at mid-2018 list prices” [>$150,000 per QALY]

4. In patients with severe primary hypercholesterolemia (LDL-C level ≥190 mg/dL [≥4.9 mmol/L]), begin high-intensity statin therapy without calculating 10-year ASCVD risk.

-- If the LDL remains>100mg/dL, adding ezetimibe is reasonable; if it continues to be >100 mg/dL and the patient has multiple factors that increase the risk of atherosclerotic events, a PCSK9 may be considered.

5. In patients 40 to 75 years of age with diabetes mellitus and LDL-C ≥70 mg/dL (≥1.8 mmol/L), start moderate-intensity statin therapy without calculating 10-year ASCVD risk

-- in patients with diabetes at higher ASCVD risk, especially if multiple risk factors or 50-75 years old, it is reasonable to use a high-intensity statin to achieve an LDL reduction>50% 

6. In adults 40 to 75 years of age evaluated for primary ASCVD prevention, have a clinician–patient risk discussion before starting statin therapy.

-- Review the major risk factors (cigarette smoking, elevated blood pressure, LDL, hemoglobin A1c if indicated, 10 year ASCVD risk score) as well as what they call the ”risk-enhancing factors” noted in point 8; review the potential benefits of lifestyle and start therapies; the potential for adverse effects and drug-drug interactions; cost of statin therapy; and patient preferences/values and shared decision-making

7. In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL (≥1.8 mmol/L), at a 10-year ASCVD risk of ≥7.5%, start a moderate-intensity statin if a discussion of treatment options favors statin therapy.

-- Risk-enhancing factors should favor statin therapy.

-- Consider coronary artery calcium scores (CAC) to improve the specificity (likely benefit) for the meds (see point number 9 below) [the issue here is that those with known ASCVD have a greater absolute risk reduction with statins, though the relative risk reduction is similar in primary and secondary prevention trials]

-- general goal is to decrease LDL by >30%, but if 10-year risk is >20%, attempt to achieve a LDL reduction of >50%

8. In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), risk-enhancing factors favor initiation of statin therapy (see No. 7)

-- risk-enhancing factors: family history of premature ASCVD, persistently elevated LDL>160 mg/dL, metabolic syndrome, chronic kidney disease (eGFR 15-59 mL/min/1.73m²), history of preeclampsia or premature menopause (age<40), chronic inflammatory disorder (e.g. rheumatoid arthritis, psoriasis, chronic HIV), high risk ethnic group (e.g. South Asian), persistent elevations of triglycerides >175 mg/dL, and, if measured: apolipoprotein B>130 mg/dL, high-sensitivity CRP>2.0 mg/L, ankle brachial index<0.9, and lipoprotein (a) >50mg/dL.

-- These risk enhancing factors might favor statin therapy in those with borderline, 5-7.5% 10-yr ASCVD risk

-- diabetes-specific risk enhancers include: duration of diabetes (>10 years for type II or >20 years for type I), albuminuria, eGFR<60, retinopathy, neuropathy, ABI<0.9

9.  In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL to 189 mg/dL (≥1.8–4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5% to 19.9%, if a decision about statin therapy is uncertain, consider measuring CAC

-- if CAC is 0, treatment with a statin may be withheld or delayed, except in cigarette smokers, those with diabetes, and those with a strong family history of premature ASCVD

-- if CAC is 1-99 Agatston units, a statin is favored especially in those >55 yo

-- if CAC>100, statin therapy is indicated, unless deferred by outcome of a clinician/patient risk discussion

-- might also consider CAC in those men 55 to 84 women 60 to 80 years old with a low burden of risk factors who question whether they might benefit from statin therapy

10. Assess adherence and percentage response to LDL-C–lowering medications and lifestyle changes with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated every 3 to 12 months as needed

-- they defined the response to lifestyle and statin therapy by a percentage reduction in LDL at baseline.

-- patients at very high ASCVD risk, and LDL >70 should trigger adding a non-statin drug therapy when patients on maximal statin therapy

Commentary:

-- in terms of measurement of lipids,

    -- adults >20yo and not on lipid-lowering therapy should have either a fasting or nonfasting plasma lipid profile to effectively estimate their ASCVD risk and baseline LDL

    -- those with a triglyceride >400 mg/dL with a nonfasting profile should have a fasting one performed

    -- for those with a calculated LDL <70 mg/dL it is reasonable to have a direct LDL measured to improve its accuracy

    -- in adults >20yo with a family history of premature ASCVD or genetic hyperlipidemia, it is reasonable to measure a fasting plasma lipid profile

-- for patients aged >75yo

    -- those with clinical ASCVD, it is reasonable to initiate moderate or high-intensity statin therapy after evaluation for the potential of ASCVD risk reduction, adverse effects, and drug-drug interactions, as well as patient frailty and patient preferences

    -- for those already tolerating a high-intensity statin, it is reasonable to continue this therapy

-- in patients with heart failure with reduced ejection fraction attributable to ischemic heart disease and with life expectancy of 3-5 years, it is reasonable to consider in moderate-intensity statin [this really does not make sense to me: statins are remarkably well-tolerated and these patients are at very high risk of a recurrent atherosclerotic event]

-- triglycerides:

    -- those >20yo with moderate hypertriglyceridemia 175-499 mg/dL fasting or nonfasting, address lifestyle changes (obesity and metabolic syndrome), secondary factors (diabetes, chronic liver or kidney disease, nephrotic syndrome, hypothyroidism), and medications that increase triglycerides

    -- those 40-75yo  with moderate to severe hypertriglyceridemia and ASCVD risk of >7.5%, address above and consider starting or intensifying statins

    -- those 40-75yo with severe hypertriglyceridemia (fasting>500 mg/dL, and especially if >1000mg/dL), address the above and if triglycerides are persistently elevated, implement a very low-fat diet, avoiding refined carbohydrates and alcohol, advise consumption of omega-3 fatty acids, and if necessary to prevent acute pancreatitis, fibrate therapy [the studies show that a low glycemic-index diet is quite effective in lowering triglycerides and increasing HDL]

-- women of childbearing age who would benefit from a statin should have a reliable form of contraception, and they should stop a statin 1 to 2 months before pregnancy is attempted

-- patients who require dialysis are not recommended to start a statin [the studies have had pretty mixed results. the SHARP study found continued benefit of statins (in this case simvastatin/ezetimibe) in those migrating to dialysis. several studies, like the AURORA trial with rosuvastatin 10mg, did show some benefit in posthoc analysis in those starting statins, finding a 32% reduction in cardiac events in diabetic patients. the 4-D study found the same. Meta-analyses have come to mixed conclusions, but none found significant harm. so, though it is not even close to rock-solid, i have been prescribing statins on the basis of quite possible benefit and not a lot of harm....]

-- statin-associated adverse effects:

    --1-5% of people in RCTs have myalgias (more like 5-10% in observational studies), more frequently when older, females, those with low BMI, meds which interfere with statin metabolism, comorbidities (HIV, renal, liver, thyroid, pre-existing myopathy), Asians, excess alcohol intake, high levels of physical activity, and trauma [no mention was made of vitamin D treatment, though observational studies of suggested 90% effectiveness for those with statin-associated myopathy: see http://gmodestmedblogs.blogspot.com/2017/05/statin-myopathy-and-vitamin-d-deficiency.html  ]

    -- diabetes: more frequent adverse effects if diabetes risk factors present (BMI > 30, fasting blood sugar greater than 100, metabolic syndrome, A1c > 6%), also more common in high intensity statin therapy

    -- others are all considered rare, including rhabdomyolysis (CK>10x ULN with renal injury), myositis/myopathy (CK elevated), statin-associated autoimmune myopathy

    -- Japanese, Chinese, Malay, and Asian Indians, have  higher rosuvastatin levels, and the FDA recommend starting at 5 mg with caution on uptitration. Japanese patients may be sensitive to statin dosing, with fewer ASCVD events on lower-intensity statin therapy

--the updated ASCVD Risk Estimator Plus is at http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/

so, this new recommendation does, I think reasonably, move more back into targeting LDL thresholds. A few points on this:

    -- it is really unclear exactly what the LDL targets should be. It certainly makes sense that the higher the atherosclerotic risk, the lower the target should be. I was personally impressed by the study showing that the lower the LDL, the better (see http://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html ). However, it should be noted that this study reflects just an association of low LDL with low atherosclerotic risk, so one cannot attribute causality since this was not a randomized controlled trial. But it is pretty clear that patients tolerate very low LDL levels. I do have many patients on statins alone who do achieve very low LDL levels, in the 40 mg/dL range, and I am now much more comfortable with those numbers after the study came out.

    -- If a higher LDL target is reasonable, I also do find that in some patients even moderate-intensity statins sometimes achieve quite low LDL levels. I therefore do not automatically use their categorization of moderate- vs high-intensity statins. (High-intensity statins include atorvastatin 40 or 80 mg, rosuvastatin 20 or 40 mg). Additionally, even within the high-intensity statins, I personally have found (as been reflected in the literature) that rosuvastatin 40 mg significantly more potent than atorvastatin 40-80 mg. So, I try changing to rosuvastatin 40mg before even considering adding a 2^nd agent

    -- based on the Treating to New Targets trial (see cad TNT with hdl nejm 2007 in dropbox, or n engl j med 2007: 357;13), i think there is a role of HDL in the LDL target, though medication manipulation specifically to increase HDL, eg with CETP inhibitors (which ??create a dysfunctional HDL??) have not shown benefit.  this TNT trial, which compared atorvastatin 10mg (a moderate-intensity statin) vs 80mg (a high-intensity statin), found that it was the achieved LDL that was associated with clinical cardiovascular events (ie, dose of atorvastatin did not really matter, whether moderate- or high-intensity), andthat the number of clinical events was pretty much the same with an achieved LDL >100 but HDL >55 as with an achieved LDL of <70 but HDL <38. so, i do throw the HDL level into my decision as to how low the LDL target should be (eg, a higher risk person with an LDL of 80 but a very high HDL might be fine.  but a similar person with LDL 70 and low HDL might benefit from intensified therapy).

    --a compilation of many older studies showed a linear association between the achieved LDL and clinical cardiovascular events. this was reinforced by a more recent Korean study (see http://gmodestmedblogs.blogspot.com/2017/03/treating-ldl-to-target-more-evidence.html  )

-- one concern which I have voiced before is that studies have shown that statins work so well that patients often ease up on their lifestyle changes. I personally think it is very important to reinforce the lifestyle changes even if the patient has a superb statin-created LDL, since there are a multitude of positive effects achieved through a healthy lifestyle, which are above and beyond the relatively limited scope of the heart and blood vessels (e.g. cancer risk, cognitive health, etc., etc., as noted in many prior blogs including a recent one on the benefits of a Mediterranean diet for knee osteoarthritis with comments on other benefits: see http://gmodestmedblogs.blogspot.com/2018/11/mediterranean-diet-decreases-knee-oa.html . 

-- based on a few studies, I do include a sub-diabetes threshold A1c as a cardiovascular risk factor (a 23% increased risk in those with an A1c of 5.5-6 and a 78% increase with A1c 6-6.5), which i would include in their risk-enhancing category (see http://gmodestmedblogs.blogspot.com/2018/09/improved-a1c-control-was-associated.html , which includes a reference on that)

for the multitude of articles let loose at the AHA convention:

https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000624  has the 78 page executive summary of the guideline on the management of blood cholesterol

https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000625 has the 120 page guideline on management of blood cholesterol

https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000626 has the 32 page systematic review for the guidelines

https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000638 has the 38 page special report on the risk assessment tools to guide decision-making

https://newsroom.heart.org/news/updated-cholesterol-guidelines-offer-more-personalized-risk-assessment-additional-treatment-options-for-people-at-the-highest-risk has the Am Heart Assn/Am College of Cardiol news release on these new guidelines

geoff

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