Lipoprotein

Values and preferences - There is a large body of evidence supporting the potential causal association between Lp(a) and future ASCVD. The high prevalence of elevated Lp(a), the strength of association with incident and recurrent ASCVD events and the potential to improve CV risk stratification, strongly justify universal screening to identify individuals with very high levels. Identification of high levels of Lp(a) is a useful consideration for shared decision-making in subjects across all ASCVD risk categories, but especially in younger patients, particularly those who have a very strong family history of premature ASCVD. While further evidence that directly lowering Lp(a) reduces ASCVD risk is pending, the finding of high Lp(a) should alert primary care practitioners to more actively pursue an overall ASCVD event risk assessment, including careful discussion of current health behaviours, consideration of age-appropriate vascular imaging studies for detecting early evidence of subclinical atherosclerosis in select individuals (e.g. coronary artery calcium [CAC] score) and earlier introduction of statin or other lipidlowering therapy, especially in intermediate-risk individuals and/or low-risk individuals with moderate elevations of LDL-C between 3.5-5 mmol/L. In the setting of secondary prevention, the presence of high Lp(a) is strongly predictive of recurrent events, and suggests the need for intensification of LDL-lowering therapy, including use of PCSK9 inhibitors. Furthermore, preliminary evidence suggests that treatment with PCSK9 inhibitors post- ACS in patients with high Lp(a) reduces MACE independent of LDL-C lowering. When clinicians are uncertain of the implications of elevated Lp(a), consultation with a lipid specialist may be considered. • We recommend measuring Lp(a) level once in a person’s lifetime as a part of the initial lipid screening. ( Strong Recommendation; High Quality Evidence ). • For all patients in the setting of primary prevention with a Lp(a) ≥50 mg/dL (or ≥100 nmol/L), we recommend earlier and more intensive health behaviour modification counselling and management of other ASCVD risk factors ( Strong Recommendation, Expert consensus ).


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• Expanded recommendations for preventative care in women with hypertensive disorders of pregnancy • Updated recommendations for primary prevention and the importance of lipoprotein measurement, including non-HDL-C, ApoB, and Lp(a) in assessing CV risk • The role of CAC as a clinical decision-making tool for determining the need to initiate therapy • The benefit of icosapent ethyl (IPE) in patients with TG ≥1.5-5.6 mmol/L and a previous ASCVD event or diabetes and ≥1 additional risk factor • Lack of CV benefit from omega-3 fatty acids from dietary sources or over-the-counter formulations/supplements • New recommendations for non-statin therapies to reduce ASCVD events • Identification of new lipid/lipoprotein thresholds for the intensification of therapy in the management of dyslipidemia, beyond statins • Secondary prevention patients demonstrated to derive the greatest benefit with intensification with PCSK9 inhibitors are identified • Values for non-HDL-C and ApoB have been modified to accurately represent the same percentile equivalent as LDL-C for all recommended thresholds What's new?

Screening
All patients with any of the following conditions regardless of age: Consider earlier in ethnic groups at increased risk such as South Asian or Indigenous individuals

RECOMMENDATION
• We recommend non-fasting lipid and lipoprotein testing can be performed in adults in whom screening is indicated as part of a comprehensive risk assessment to reduce CVD events • We recommend that for any patient with triglycerides >1.5 mmol/L, non-HDL-C or ApoB be used instead of LDL-C as the preferred lipid parameter for screening (Strong Recommendation, High-Quality Evidence).
• We suggest that for individuals with a history of triglyceride levels >4.5 mmol/L that lipid and lipoprotein levels be measured fasting (Conditional Recommendation, Low Quality Evidence).
Pratical Tip -Compared to fasting lipid values, there will be minimal change with non-HDL-C, a slight decrease in LDL-C and small increase in triglyceride concentrations when most individuals do not fast. • We recommend that CAC screening using computed tomography imaging not be undertaken for a) high risk individuals b) patients receving statin treatment: or c) most asymptomatic, low-risk adults (Strong Recommendation, Moderate Quality Evidence).
• We suggest that CAC screening might be considered for a subset of low-risk middle-aged individuals ≥40 years with a family history of premature ASCVD (men ≤55 years; women ≤65 years) in addition to identifying known genetic causes of ASCVD such as elevated Lp(a) or FH) (Weak Recommendation, Low-Quality Evidence).
Values and preferences -Patients with modifiable ASCVD risk factors should be counselled with respect to the potential merit of preventing atherosclerosis itself, the substrate for clinical ASCVD events in the long term, through comprehensive ASCVD risk factor management. As outlined elsewhere, RCTs show the ASCVD risk reduction value of statin therapy in patients with intermediate risk and additional ASCVD risk factors (eg, HOPE 3 and justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin [JUPITER] in the absence of CAC testing or any testing to identify preclinical atherosclerosis. Accordingly, the patient-physician decision often does not require CAC scoring but might be strongly influenced by these other factors, including family history of premature ASCVD, other features suggesting genetic causes of dyslipidemia, or side effects of statin therapy. In some low-to intermediate-risk subjects, it might be reasonable to withhold statin therapy for CAC = 0 AU because of a favourable intermediate-term outcome. Exceptions would include cigarette smokers, patients with diabetes, those with poorly controlled hypertension, genetic dyslipidemias such as FH or elevated Lp(a) level, and patients with strong family history of premature ASCVD events. If available, a CAC >100 AU is an indication for statin therapy regardless of FRS. For those with a CAC of 1-99 AU, individual decision-making is required because risk will not be reclassified and would remain intermediate. If a decision is made to withhold statin or lipid-modifying therapy on the basis of CAC = 0, this decision should be reevaluated during follow-up or if clinical circumstances change. CAC scoring should rarely be performed sooner than within 5 years to aid in this reevaluation. Finally, this section is restricted to application in patients who are at least 40 years of age for whom the traditional FRS assessment applies. Prevalence of calcification is a sequential aspect of the atherosclerotic process and might be absent in the early phases. Although CAC has been studied extensively for ASCVD risk prediction, the prevalence of CAC is lower in young patients compared with middle-aged and older patients and also in women vs men younger than 50 years of age.

Coronary Artery Calcium (CAC) Measurement -Recommendations
Screening Values and preferences -There is a large body of evidence supporting the potential causal association between Lp(a) and future ASCVD. The high prevalence of elevated Lp(a), the strength of association with incident and recurrent ASCVD events and the potential to improve CV risk stratification, strongly justify universal screening to identify individuals with very high levels. Identification of high levels of Lp(a) is a useful consideration for shared decision-making in subjects across all ASCVD risk categories, but especially in younger patients, particularly those who have a very strong family history of premature ASCVD. While further evidence that directly lowering Lp(a) reduces ASCVD risk is pending, the finding of high Lp(a) should alert primary care practitioners to more actively pursue an overall ASCVD event risk assessment, including careful discussion of current health behaviours, consideration of age-appropriate vascular imaging studies for detecting early evidence of subclinical atherosclerosis in select individuals (e.g. coronary artery calcium [CAC] score) and earlier introduction of statin or other lipidlowering therapy, especially in intermediate-risk individuals and/or low-risk individuals with moderate elevations of LDL-C between 3.5-5 mmol/L. In the setting of secondary prevention, the presence of high Lp(a) is strongly predictive of recurrent events, and suggests the need for intensification of LDL-lowering therapy, including use of PCSK9 inhibitors. Furthermore, preliminary evidence suggests that treatment with PCSK9 inhibitors post-ACS in patients with high Lp(a) reduces MACE independent of LDL-C lowering. When clinicians are uncertain of the implications of elevated Lp(a), consultation with a lipid specialist may be considered.
• We recommend measuring Lp(a) level once in a person's lifetime as a part of the initial lipid screening. (Strong Recommendation; High Quality Evidence).
• For all patients in the setting of primary prevention with a Lp(a) ≥50 mg/dL (or ≥100 nmol/L), we recommend earlier and more intensive health behaviour modification counselling and management of other ASCVD risk factors (Strong Recommendation, Expert consensus).

Lipoprotein (a) Measurement -Recommendation
Secondary Testing

RECOMMENDATIONS
• We recommend that a cardiovascular risk assessment be completed every 5 years for men and women age 40 to 75 using the modified FRS or CLEM to guide therapy to reduce major CV events. A risk assessment may also be completed whenever a patient's expected risk status changes (Strong Recommendation, High Quality Evidence).
• We recommend sharing the results of the risk assessment with the patient to support shared decision making and improve the likelihood that patients will reach lipid targets (Strong Recommendation, High Quality Evidence).
Pratical Tip -While there is good evidence to support the use of statins in secondary prevention in patients over the age of 75 years for some outcomes, a mortality benefit has not been demonstrated. In addition, the evidence for statin use in primary prevention is lacking in this population, mainly because they have not been extensively studied. For robust elderly patients believed to be at higher risk, a discussion about the importance of statin therapy in overall management should be undertaken as these patients are often at high risk because a CVD event has important consequences for morbidity.

RECOMMENDATIONS
Values and preferences -If the preference is to engage in early prevention and long-term risk reduction, in subjects <50 years the absolute risk of events is lower but studies suggest that statins will result in a relative risk reduction similar to those ≥50 years. The statin/ezetimibe combination recommendation is based on the SHARP study which utilized 20 mg of simvastatin and 10 mg of ezetimibe.
• We suggest that lipid-lowering therapy not be initiated in adults with dialysis-dependent CKD (Conditional Recommendation, Moderate Quality Evidence).
Values and preferences -In younger individuals who may become eligible for kidney transplantation or with a longer life expectancy, statin or statin/ezetemibe combination therapy may be desirable although high-quality studies have not been done in this population.
• We suggest that lipid-lowering therapy be continued in adults already receiving it at the time of dialysis initiation (Conditional Recommendation, Low Quality Evidence).
• We suggest the use of statin therapy in adults with kidney transplantation (Conditional Recommendation, Moderate Quality Evidence).
Values and preferences -This recommendation reflects that fact that a substantial number of patients in SHARP transitioned to dialysis during the study and there was no heterogeneity of results for the population as a whole. The evidence is of low quality overall and there is substantial debate about best practice in this situation.

Primary Prevention †
We recommend use of highintensity statin therapy in addition to appropriate health behaviour modifications as initial therapy for all eligible patients to prevent CVD. For patients who do not tolerate a high-intensity statins, we recommend the maximally tolerated statin dose.

Potential Adverse Effects of Statins
• We recommend that despite concerns about a variety of possible adverse effects, all purported statin-associated symptoms should be evaluated systematically, incorporating observation during cessation, re-initiation (same or different statin, same or lower potency, same or decreased frequency of dosing) to identify a tolerated, statin-based therapy for chronic use (Strong Recommendation, Low Quality Evidence).
• We recommend that vitamins, minerals, or supplements for symptoms of myalgia perceived to be statin-associated not be used (Strong Recommendation, Low Quality Evidence).

RECOMMENDATIONS
Values and preferences -Always confirm that there is an indication for statin use which, if present, would suggest that benefits, clearly communicated to the patient, far outweigh the potential occurrence of any of the many side effects purported to be associated with statin use. Assess patient features that might limit dosage or preclude use of statins (e.g. potential drug-drug interactions) and always emphasize dietary, weight and exercise interventions to facilitate achievement of lipid goals and other benefits of comprehensive, CV prevention.
• We recommend intensification of lipid-lowering therapy with a PCSK9 inhibitor (evolocumab or alirocumab)-with or without the additional use of ezetimibe -for secondary CV prevention patients shown to derive the largest benefit from PCSK9 inhibitor therapy in whom LDL-C remains ≥1.8 mmol/L (or non-HDL-C ≥2.4 mmol/L or ApoB ≥0.7 g/L) while receiving the maximally tolerated statin dose (Strong Recommendation, Moderate-Quality Evidence).
• We recommend intensification of lipid-lowering therapy with ezetimibe and/or PCSK9 inhibitor therapy for all secondary prevention CVD patients in whom LDL-C remains ≥1.8 mmol/L (or non-HDL-C ≥2.4 mmol/L or ApoB ≥0.7 g/L) while receiving the maximally tolerated statin dose. (Strong Recommendation; High-Quality Evidence). If ezetimibe is used initially and LDL-C remains ≥1.8 mmol/L (or nonHDL-C ≥2.4 mmol/L or ApoB ≥0.7 g/L) PCSK9 inhibitor therapy is recommended (Strong Recommendation, High-Quality Evidence).

Clinically evident ASCVD and any of the following
• We recommend that fibrates not be combined with statin therapy for CVD event prevention in patients who have achieved LDL-C targets (Strong Recommendation, High Quality Evidence).
• We recommend that niacin not be combined with statin therapy for CVD prevention in patients who have achieved LDL-C targets (Strong Recommendation, High Quality Evidence).
• We recommend the use of a PCSK9 inhibitor (alirocumab or evolocumab) to lower LDL-C level in patients with heterozygous FH without clinical ASCVD whose LDL-C remains above the target (ie, LDL-C ≥2.5 mmol/L or <50% reduction from baseline; or ApoB ≥0.85 mg/dL or non-HDL-C ≥3.2 mmol/L) despite maximally tolerated statin therapy with or without ezetimibe therapy (Strong Recommendation, High-Quality Evidence).
• We recommend the use of a PCSK9 inhibitor (alirocumab or evolocumab) for patients with heterozygous FH and ASCVD whose LDL-C remains above the threshold ≥1.8 mmol/L (or ApoB ≥0.7 mg/dL or non-HDL-C ≥2.4 mmol/L) despite maximally tolerated statin therapy, with or without ezetimibe (Strong Recommendation, High-Quality Evidence).
• We recommend the use of icosapent ethyl (IPE) to decrease the risk of CV events in patients with ASCVD, or with diabetes and ≥1 CVD risk factors, who have an elevated fasting triglyceride level of 1.5-5.6 mmol/L despite treatment with maximally tolerated statin therapy (Strong Recommendation, High-Quality Evidence).
• We suggest that bile acid sequestrants be considered for LDL-C lowering in high risk patients whose levels remain above target despite statin treatment +/-ezetimibe therapy (Conditional Recommendation, Low Quality Evidence).

Bile Acid Sequestrants (BAS)
†Reduce dose or avoid in renal impairment. † ‡Should not be used in combination with a statin because of the potential increased risk for rhabdomyolysis.

Management
Values and preferences -Adherence is one of the most important determinants for attaining the benefits of any diet. Individuals should choose the dietary pattern that best fits with their values and preferences, allowing them to achieve the greatest adherence over the long term.
We continue to recommend a Mediterranean dietary pattern, which has evidence of CV outcome benefit in systematic reviews and meta-analyses. Values and preferences -Although there is no apparent overall CVD event risk benefit, patients may choose to use these supplements for other indications including the management of high triglycerides, for which very high doses are required (4 g/day), and for which fibrates are generally more effective. Individuals should be aware that, in addition to marine sources, there are different preparations of long chain omega-3 PUFAs high in DHA and EPA acid from algal and yeast sources, both of which are suitable for vegans. There is also alpha-linolenic acid (ALA) from plant sources that do not contain DHA or EPA including flax seeds, chia seeds, and some oils such as canola and soybean oil, which have little or no effect on triglycerides.
• We do not recommend the use of over-the-counter omega-3 polyunsaturated fatty acids supplements (marketed as natural health products in Canada) to reduce CVD risk (Strong Recommendation; High-Quality Evidence).

Treatment: Health Behaviour Modifications
If LDL-C >2.0 mmol/L or ApoB >0.8 g/L or non-HDL-C >2.6 mmol/L on maximally tolerated statin dose Discuss add-on therapy with patient:

Monitor
• response to statin Rx • response to add-on lipid-lowering Rx • health behaviour changes ‡ Statin indicated conditions consists of all documented ASCVD conditions, as well as other high-risk primary prevention conditions in the absence of ACSVD, such as most patients with diabetes, those with chronic kidney disease and those with a LDL-C ≥5.0 mmol/L. † Calculate risk using the Framingham Risk Score (FRS) -refer to the iCCS available on the App Store or on Google Play * Screening should be repeated every 5 years for men and women aged 40 to 75 years using the modified FRS or CLEM to guide therapy to reduce major CV events. A risk assessment might also be completed whenever a patient's expected risk status changes. ¶ studies have evaluated the efficacy of BAS for the prevention of ASCVD, but results have been inconclusive.