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Évaluation du risque cardiovasculaire en première lignePublished by: Domus MedicaLast published: 2010Cardiovasculaire risicobepaling in de eerste lijnPublished by: Domus MedicaLast published: 2020Globaal Cardiovasculair RisicobeheerPublished by: Domus MedicaLast published: 2007Gestion globale des risques cardiovasculairesPublished by: Domus MedicaLast published: 2007Évaluation du risque cardiovasculaire en première lignePublished by: Domus MedicaLast published: 2020

Several treatment options exist for hypercholesterolemia, which may be instituted individually or in combination. They include lifestyle changes to diet and exercise, medications, and dietary supplements. Rarely, experimental therapies or procedural interventions can be applied.

International guidelines have reinforced the role of pharmacologic treatment to reduce cholesterol based on the risk of cardiovascular events.[44][51]​​​[54]​​[56]​​ Despite some differences in suggested risk stratification tools and cholesterol goals, the guidelines are unanimous in recommending intensive pharmacologic treatment and, consequently, robust cholesterol reduction with statins in high-risk patients - primarily those with atherosclerotic cardiovascular disease (ASCVD) (coronary heart disease [CHD] or non-coronary forms of atherosclerotic disease, such as peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease [e.g., transient ischemic attacks, stroke of carotid origin, or >50% obstruction of a carotid artery]). However, less intensive regimens may be instituted in lower-risk patients. 

Management of patients diagnosed with familial hypercholesterolemia requires specialist consultation.

Risk stratification

The net benefit that each patient receives from preventive therapies is directly related to the baseline cardiovascular risk (i.e., those at the highest risk will derive the greatest absolute risk reductions from preventive interventions). Therefore, it is critical to perform adequate risk stratification to serve as the basis for a risk discussion and framework to decide on the intensity of preventive strategies. Individuals with clinical ASCVD have a high risk for recurrent events. Within this strata, those with recurrent major ASCVD events (symptomatic peripheral arterial disease, ischemic stroke, myocardial infarction, or recent acute coronary syndrome) are at greatest risk for repeat events.

In adult patients without previous ASCVD, risk scores may be used for risk estimation. Several are available, such as Framingham,​​​​​ ​QRISK, PROCAM,​​​​​ the Pooled Cohort Equations, and SCORE2 and SCORE2-OP. [ Cardiovascular Risk Assessment in Men (10-year, patient information, Framingham 2008) Opens in new window ] [ Cardiovascular Risk Assessment in Women (10-year, patient information, Framingham 2008) Opens in new window ] [ Cardiovascular Risk Assessment (10-year, PROCAM Score, Munster Heart Study) Opens in new window ] [ SCORE2 and SCORE2-OP Opens in new window ] QRISK risk calculator Opens in new window Pooled Cohort Equations CV Risk Calculator Opens in new window​​​​​​ Another tool, developed by the American Heart Association, the Primary Prevention Risk Assessment Tool (PREVENT) calculator, helps healthcare providers evaluate an individual's 10-year risk of developing ASCVD by considering various clinical and lifestyle factors. [ PREVENT™ online calculator Opens in new window ] ​​​[57]​ When applied to populations similar to their derivation cohort, these tools perform well. Therefore, healthcare providers should be familiar with the best risk prediction tool in their patient population.​[53][58]

When using the Pooled Cohort Equations, patients may be classified according to their predicted 10-year risk of ASCVD events (fatal and nonfatal myocardial infarction or stroke): low risk (<5%), borderline risk (5.0% to <7.5%), intermediate risk (≥7.5% to <20%), and high risk (>20%). In borderline- and intermediate-risk patients, clinical and laboratory risk-enhancing factors may be considered to decide the use of lipid-lowering therapies. These factors include: a family history of premature ASCVD (men ages <55 years, women <65 years), primary hypercholesterolemia (LDL-cholesterol ≥160 mg/dL or non-HDL-cholesterol ≥190 mg/dL), metabolic syndrome, estimated GFR 15-59 mL/min/1.73 m², chronic inflammatory conditions (psoriasis, rheumatoid arthritis, HIV/AIDS), premature menopause, preeclampsia, South Asian ancestry, elevated high-sensitivity CRP (≥2 mg/L), elevated lipoprotein(a) (>50 mg/dL or >125 nmol/L), elevated apolipoprotein B (≥130 mg/dL), or an ankle-brachial index <0.9.[44][53][59]

In patients with borderline- or intermediate-risk after the use of risk scores and risk enhancers (if present), coronary artery calcium (CAC) may be used as a decision aid if it will affect the intensity of preventive strategies, particularly lipid-lowering therapies.[44][53]

Patients with clinical manifestations of or at high risk for cardiovascular disease should be treated with lipid-modifying therapies, usually a statin if not contraindicated, in addition to lifestyle modifications. In people at lower levels of risk, pharmacologic therapy is usually indicated if lifestyle changes are ineffective in the short term (3-6 months). There is evidence that statin therapy reduces cardiovascular events and mortality in people without clinical cardiovascular disease but with cardiovascular risk factors present.[60][61]​​ Moreover, there is evidence that reductions in risk are similar in men and women at comparable risk for cardiovascular disease.[62]

The Cholesterol Treatment Trialists (CTT) Collaboration has shown reduction in both mortality and cardiovascular disease by lowering low-density lipoprotein cholesterol independent of the presence of cardiovascular disease.[60] This meta-analysis evaluated the effects of statins versus placebo, more potent versus less potent, and higher versus lower dose statins for approximately 5 years. This work clearly showed the benefits of LDL lowering in the prevention of cardiovascular disease and mortality, even in subjects without overt hypercholesterolemia and solely in the presence of risk factors for cardiovascular disease. One meta-analysis from the US Preventive Services Task Force (USPSTF) confirmed the CTT results, including benefits on mortality.[61] In the current era, the cost-effectiveness of statin treatment is broadly applicable to nearly all primary and secondary risk populations.[63]

In patients with chronic inflammatory disorders, such as rheumatoid arthritis, or HIV, American Heart Association/American College of Cardiology guidelines recommend a fasting lipid profile and assessment of ASCVD risk factors before and 4-12 weeks after starting inflammatory disease-modifying therapy or antiretroviral therapy, to aid decision-making on initiating and adjusting lipid-lowering therapy.[44]

Lifestyle modification

Lifestyle changes are recommended for all patients. There is clear evidence that dietary reduction in total and saturated fat, weight loss in overweight patients, aerobic exercise, and the addition of plant stanols/sterols to the diet leads to a decrease in LDL-cholesterol (LDL-C) and an increase in HDL-cholesterol (HDL-C).​[30][64][65][66]

The implementation of dietary change can be difficult for many patients, and it may be helpful to include a dietician in the patient's care. A reduced intake of cholesterol and saturated fats should be advised, as well as increased consumption of dietary fiber, complex carbohydrates, and unsaturated fats.[14][31]​ 

One large UK study in more than 2500 patients found that with diet alone, LDL-C was lowered by 5% to 7% in 60% of patients, who also achieved a mean reduction in body weight of 1.8%.[67] A meta-analysis of 37 studies testing step I and step II diets (concentration of saturated fat <10% and <7%, respectively) showed an average 13% reduction in LDL-C. A meta-analysis of 23 controlled trials showed a 7% reduction of LDL-C with soy supplementation and 19% reduction in LDL-C with a Mediterranean diet. Diets rich in soluble fiber reduce LDL-C 2% per gram of ingested fiber per day.[68] Plant-based diets have been associated with reduction in LDL-C, total cholesterol, and apolipoprotein B.[69][70]

The effect of aerobic exercise and diet has been studied in 377 men and women with low HDL- and high LDL-C. Significant reductions in LDL were found in the diet and exercise group compared with control or diet alone.[71]

Patients with average or low cardiovascular risk can be allowed 3-6 months of lifestyle modification before considering lipid-lowering drugs.[72] However, this length of time remains controversial; two to three follow-up visits over 2-3 months should be arranged to assess motivation and adherence.

Drug therapy: statins

When lifestyle changes alone are not adequate in reducing cholesterol to guideline-directed levels, drug therapy with statins is recommended as a first-line option. In patients with extremely elevated LDL-C (>190 mg/dL) and those at high cardiovascular risk, drug therapy must accompany diet​​​ and exercise as an initial therapeutic approach.​[44][48]​​[51]

The CTT Collaboration has shown that for every 39 mg/dL reduction in LDL-C, there is a relative risk reduction of 10% for all-cause mortality, 20% for deaths due to coronary heart disease, 27% for nonfatal myocardial infarction, 25% for coronary revascularization, and 21% for ischemic stroke.[60]

One expanded meta-analysis from the USPSTF and one Cochrane review confirm a reduction of all-cause mortality and major cardiovascular events.[61][73][74]​​​​​ [ Cochrane Clinical Answers logo ] ​​ The USPSTF recommends that adults ages 40-75 years who have one or more cardiovascular risk factors (i.e., dyslipidemia, diabetes, hypertension, or smoking) and an estimated 10-year cardiovascular disease risk of 10% or greater should be started on a statin. Those with 10-year risk of 7.5% to less than 10% may selectively be offered a statin.[73]​ Trial data support the use of statins in ethnically diverse intermediate-risk individuals without cardiovascular disease.[75] Higher doses are used in patients with acute coronary syndrome because of the role statins play in plaque stabilization.

Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme in cholesterol synthesis, which leads to upregulation of LDL receptors and increased LDL clearance. Reductions of LDL with statins range from 20% to 55%, depending on the type and dose of statin chosen.[76]

A moderate-intensity statin has been defined by the American College of Cardiology/American Heart Association as one that generally lowers LDL-C level by 30% to 49%, while a high-intensity statin has been defined as one that lowers LDL-C level by ≥50%.[44]

Statin therapy should be started in patients who fall into the following groups:

American College of Cardiology/American Heart Association guidelines:[44]

  • Presence of ASCVD, not at very high risk of future events: treat patients ages ≤75 years with high-intensity statin (daily dose lowers LDL-C by ≥50%) or with moderate-intensity statin (daily dose lowers LDL-C 30% to <50%) if high-intensity therapy is not tolerated; treat patients ages >75 years with moderate- or high-intensity statin.

  • Presence of ASCVD, at very high risk of future events: treat with high-intensity or maximal statin therapy. Very high risk is defined as a history of multiple major ASCVD events (recent acute coronary syndrome [within the past 12 months], myocardial infarction other than the recent acute coronary syndrome, ischemic stroke, symptomatic peripheral arterial disease [claudication with ankle brachial index <0.85, previous revascularization, or amputation]) or one major ASCVD event and multiple high-risk conditions (age ≥65 years, heterozygous family history, history of previous coronary artery bypass graft or percutaneous coronary intervention, diabetes mellitus, hypertension, chronic kidney disease, current smoking, persistently elevated LDL-C [≥100 mg/dL] despite maximally tolerated therapy, history of congestive heart failure).

  • People ages 20-75 years with primary elevations of LDL-C ≥190 mg/dL: this group is enriched with patients who have familial hypercholesterolemia and are high risk on the basis of LDL-C alone; do not estimate 10-year risk in this group; treat with a high-intensity statin or moderate-intensity statin if not a candidate for high-intensity statin therapy.

  • People ages 40-75 years with diabetes mellitus: start moderate-intensity statin in those who have an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk of <7.5% and no additional high risk factors. Start high-intensity statin in those who are at higher risk.

  • People without ASCVD or diabetes ages 40-75 years with LDL-C 70-189 mg/dL: estimate 10-year risk and if borderline risk, 5.0% to <7.5%, and risk enhancers are present, then discuss moderate-intensity statin therapy; the patient-clinician discussion should consider the potential for ASCVD risk-reduction benefits and adverse effects, drug-drug interactions, and patient preferences for treatment. Risk enhancers include: family history of premature ASCVD; persistently elevated LDL-C ≥160 mg/dL; chronic kidney disease; metabolic syndrome; conditions specific to women (e.g., preeclampsia, premature menopause); inflammatory diseases (especially rheumatoid arthritis, psoriasis, HIV); ethnicity factors (e.g., South Asian ancestry); elevated high-sensitivity CRP ≥2 mg/dL; elevated lipoprotein(a) >50 mg/dL or >125 nmol/L, elevated apolipoprotein B ≥130 mg/dL, ankle-brachial index <0.9. If intermediate risk, ≥7.5% to <20%, and risk enhancers are present, start moderate-intensity statin therapy; if uncertain can use CAC score (CAC=0: lowers risk; consider no statin unless diabetes, family history of premature CHD, smoking; CAC=1-99: favours statin, especially if age >55 years; CAC=100+ and/or ≥75th percentile: begin statin). If high risk, ≥20%, start high-intensity statin therapy.

  • People with heart failure: do not routinely initiate statin therapy in patients requiring hemodialysis or with class III or IV heart failure.

National Institute for Health and Care Excellence (UK) guidelines:[51]

  • Presence of ASCVD or secondary prevention: start high-dose atorvastatin in the absence of contraindications.For secondary prevention of CVD, the goal is to achieve LDL cholesterol <77 mg/dL (≤2.0 mmol/L), or non-HDL cholesterol 100 mg/dL (2.6 mmol/L). High-dose atorvastatin is recommended for individuals with CVD, regardless of their cholesterol level, unless any of the following conditions apply: potential drug interactions (e.g., with clarithromycin, systemic azoles, or other antifungal agents); a high risk of adverse effects (e.g., in older people, people with low muscle mass or impaired renal function); or a patient preference for a lower dose.[Evidence A][Evidence B]

  • Offer atorvastatin for the primary prevention of cardiovascular disease (CVD) to people who have a 10% or greater 10-year risk of developing CVD (estimated with QRISK3). QRISK risk calculator Opens in new window

  • Offer atorvastatin for the primary prevention of CVD to people with type 1 diabetes who are ages >40 years, have had diabetes for more than 10 years, have established nephropathy, or have other CVD risk factors.

  • Offer atorvastatin for the primary or secondary prevention of CVD to people with chronic kidney disease. Increase the dose if a >40% reduction in non-HDL-C is not achieved and estimated GFR is ≥30 mL/minute/1.73 m². Discuss the use of higher doses with a renal specialist if estimated GFR is <30 mL/minute/1.73 m².

  • Follow-up after starting statin treatment: measure total cholesterol, HDL-C and non-HDL-C in all people who have been started on high-intensity statin treatment at 3 months of treatment, and aim for a >40% reduction in non-HDL-C. If a >40% reduction in non-HDL-C is not achieved: discuss adherence and timing of dose; optimize adherence to diet and lifestyle measures; consider increasing the dose if started on less than 80 mg/day of atorvastatin, and the person is judged to be at higher risk because of comorbidities, risk score, or using clinical judgment.

International Atherosclerosis Society (IAS) recommendations:[54]

  • The IAS does not specifically prescribe “treatment goals” for atherogenic lipoproteins for different circumstances. Instead, it identifies optimal levels of atherogenic cholesterol and makes the general statement that the intensity of cholesterol-lowering therapy should be adjusted to long-term risk.

  • Most patients with ASCVD deserve maximal statin therapy when it is tolerated. The optimal LDL-C in patients with established ASCVD is <70 mg/dL(<1.8 mmol/L) (or non-HDL-C of <100 mg/dL [<2.6 mmol/L]). In many patients adjuvant treatment with other lipid-lowering medications (e.g., ezetimibe, bile acid sequestrants, fibrates) might be needed to attain recommended values. [ Cochrane Clinical Answers logo ]

  • The IAS suggests that an optimal LDL-C level for primary prevention is <100 mg/dL or non-HDL-C is <130 mg/dL. The use of statin therapy is recommended according to the lifetime risk of cardiovascular disease (from ages 50-80 years) as follows: high (≥45%), moderately high (30% to 44%), moderate (15% to 29%), and low (<15%). Most high-risk patients will require statin treatment to attain an LDL-C level of <100 mg/dL (or non-HDL-C of <130 mg/dL); therefore, the use of these drugs is recommended. Statin use should also be considered in moderately high-risk people and as optional in moderate-risk people.

  • For younger people, especially those with high LDL-C (familial hypercholesterolemia), smoking, and diabetes clinical algorithms usually underestimate risk and those risk factors must be treated. Statin treatment must be considered depending on the severity of LDL-C elevations and if other risk factors are not adequately controlled.

Lifetime risk can be estimated as:[Figure caption and citation for the preceding image starts]: Risk for CVD morbidity by age 80Expert Panel on Dyslipidemia. An international atherosclerosis society position paper: global recommendations for the management of dyslipidemia: executive summary. Atherosclerosis. 2014 Feb;232(2):410-3; used with permission [Citation ends].com.bmj.content.model.Caption@1d2e4b3b[Figure caption and citation for the preceding image starts]: Lloyd-Jones/Framingham risk algorithmExpert Panel on Dyslipidemia. An international atherosclerosis society position paper: global recommendations for the management of dyslipidemia: executive summary. Atherosclerosis. 2014 Feb;232(2):410-3; used with permission [Citation ends].com.bmj.content.model.Caption@14b88793

European Society of Cardiology/European Atherosclerosis Society guidelines:[41]

  • For patients at very high cardiovascular risk (documented CVD clinical or unequivocal on imaging; diabetes mellitus with target organ damage (microalbuminuria, retinopathy, neuropathy), or at least three major risk factors, or type 1 diabetes mellitus of long duration [>20 years]; severe chronic kidney disease [GFR <30 mL/minute/1.73 m²]; a calculated SCORE level ≥10% for 10-year risk of fatal CVD), an LDL-C reduction from baseline of ≥50% and an LDL-C goal of <55 mg/dL are recommended. European Society of Cardiology SCORE risk charts Opens in new window

  • For patients at high cardiovascular risk (markedly elevated single risk factors [in particular total cholesterol >310 mg/dL or blood pressure ≥180/110 mmHg], people with diabetes mellitus who don't meet very high risk criteria and have an additional risk factor or diabetes mellitus duration ≥10 years, moderate chronic kidney disease [GFR 30-59 mL/minute/1.73 m²], a calculated SCORE between 5% and 9% for 10-year risk of fatal CVD), an LDL-C reduction from baseline of ≥50% and an LDL-C goal of <70 mg/dL are recommended. European Society of Cardiology SCORE risk charts Opens in new window

  • For people at moderate risk (young patients with diabetes mellitus [<35 years for type 1 and <50 years for type 2] with duration <10 years, without additional risk factors, SCORE level between 1% and 4% for 10-year risk of fatal CVD) an LDL-C goal <100 mg/dL should be considered. European Society of Cardiology SCORE risk charts Opens in new window

  • For people at low risk (SCORE level <1% for 10-year risk of fatal CVD) an LDL-C goal <116 mg/dL should be considered European Society of Cardiology SCORE risk charts Opens in new window

  • Recommendation for statin use: prescribe statin up to the highest recommended dose or highest tolerable dose to reach the goal.

  • While the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) dyslipidemia guidelines reference the SCORE risk assessment system, the updated SCORE2 risk assessment is recommended by the 2021 ESC guidelines on cardiovascular disease prevention.[58]​ Future lipid guideline iterations will likely update recommendations to this scoring system. 

Adverse effects of statins are uncommon but include liver enzyme elevations and myositis or rhabdomyolysis. Muscle toxicity without enzyme elevation has also been reported; this seems to be most common when some of the statins are used with drugs that inhibit cytochrome P450 3A4 (e.g., macrolide antibiotics, HIV protease inhibitors, azole antifungals, and cyclosporine). Some statins (lovastatin, simvastatin, rosuvastatin, fluvastatin) may raise digoxin levels and potentiate the effect of warfarin. Caution is advised when using statins with these drugs, and lower doses of the statin (or the interacting drug) may be required. Also, the Food and Drug Administration (FDA) now recommends that the dose of simvastatin not exceed 40 mg/day due to the increased risk of myopathy with the 80 mg/day dose. It recommends that the 80 mg/day dose only be used in patients who have been using this dose for 12 months or longer with no ill effect. For patients who do not respond to 40 mg/day, the FDA recommends changing to an alternative statin rather than increasing the dose.

Two meta-analyses, one comparing statins with placebo, and the other comparing more intensive versus less intensive statin treatment, report an increased risk of new-onset type 2 diabetes associated with statin use.[77][78]​​ Another study, which looked at 3 large trials, found a slight increased risk of developing new-onset type 2 diabetes with high-dose atorvastatin, and that baseline fasting glucose and features of the metabolic syndrome are predictive of new-onset type 2 diabetes.[79] One large trial of rosuvastatin showed that while statin therapy increased the risk of diabetes mellitus, this hazard was exceeded by the cardiovascular benefits of statins, with 134 vascular events or deaths avoided for every 54 new cases of diabetes diagnosed.[80]

In patients with chronic kidney disease, a study looking at the association of simvastatin and ezetimibe, and a meta-analysis of the main lipid-lowering trials in chronic kidney disease patients, confirmed the importance of reducing cholesterol to prevent cardiovascular disease in these populations.[81]

Adverse effects are more common in older patients, those with multiple diseases, and those on multiple drugs. In some people, changing from one statin to another or lowering the dose may ameliorate negative effects.

Older studies have suggested that aggressive lipid lowering may have adverse effects on the brain, leading to cognitive impairment, dementia, and hemorrhagic stroke. However, a review of current evidence and scientific statement by the American Heart Association concludes that there is no association. The risk of hemorrhagic stroke with lipid-lowering treatment among patients with a history of hemorrhagic stroke is noted as not being robust and requiring further study.[82]

Data from some of the earliest statin trials have emerged documenting the long-term safety and efficacy of statin therapy. In the West of Scotland Coronary Prevention Study primary prevention trial, statin therapy led to a substantial reduction in cardiovascular disease outcomes in two decades without new safety concerns.[83] Similarly favorable findings were documented regarding the effectiveness of statin therapy in 16-year follow-up of the Long-term Intervention with Pravastatin in Ischemic Disease trial, a secondary prevention trial.[84] Regarding long-term safety there was no impact of statins on cancer or noncardiovascular mortality during long-term follow-up.

Drug therapy: nonstatin options

Statins are a very safe class of drugs. However, many patients do not achieve adequate LDL-C lowering and up to 10% of people are intolerant, especially where muscular symptoms are concerned.[85] There is no consensus regarding treatment of patients intolerant to statins. Changing from one statin to another or reducing dose/intensity may improve tolerance. In addition, alternate-day dose therapy, either with or without daily ezetimibe, has been proposed for these patients. One systematic review of every other day administration of statins suggests that when more potent statins such as atorvastatin and rosuvastatin are used, similar LDL-C reductions to every-day treatment are attained.[85] However, tolerance was not adequately evaluated in most of these studies. In addition, studies are hindered by the small numbers of subjects and short-term follow-ups. Finally, alternate-day therapy may lead to either missed or extra doses.

Complete statin intolerance is rare; however, for these patients, a trial of nonstatin LDL-C lowering drugs may be considered as an alternative to statins, with referral to a lipid specialist.[41][56]

For patients who do not achieve adequate LDL-C lowering on maximally tolerated statin therapy, addition of nonstatin therapies may be considered.[41][44][56]

1. Ezetimibe

  • Impairs dietary and biliary cholesterol absorption at the intestinal brush border by interaction with specific receptors and, in contrast to bile acid sequestrants, results in systemic exposure.

  • Can also be used alone or in addition to statin therapy and lifestyle changes. Effective for lipid lowering in patients with mild-to-moderate elevations of LDL-C; however, with an average of 20% LDL-C lowering it may not be sufficient for patients in need of greater LDL-C lowering. If used alone, LDL reductions of 15% to 20% have been reported.[86] In conjunction with simvastatin, LDL was lowered an additional 14% above the effect achieved with simvastatin alone.[87]

  • The IMPROVE-IT trial showed that ezetimibe plus simvastatin reduced the relative and absolute risks of major cardiovascular events in high-risk coronary heart disease individuals in comparison with simvastatin alone.[88] The benefit of ezetimibe is proportional to its LDL-C-lowering ability.[89]

  • The EWTOPIA 75 trial, which randomized patients ages 75 years or older without ASCVD to ezetimibe versus placebo, showed a significant reduction in cardiovascular events and coronary revascularization in the ezetimibe arm compared with placebo.[90]

2. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (monoclonal antibodies)

  • PCSK9 binds LDL receptors, facilitating their degradation. When in excess, PCSK9 is a cause of familial hypercholesterolemia. Loss-of-function mutations are associated with lower LDL-C levels and a reduced risk of cardiovascular events.[91]

  • Human monoclonal antibodies directed against PCSK9 (e.g., evolocumab and alirocumab) provide three times the effect of ezetimibe (60% LDL-C lowering).

  • PCSK9 inhibitors significantly reduce LDL-C by approximately 50% to 60% and result in greater LDL-C goal achievement when added to statins in a variety of populations, including those with heterozygous familial hypercholesterolemia.[92]

  • The FOURIER and ODYSSEY OUTCOMES trials assessing evolocumab and alirocumab, respectively, have shown that PCSK9 inhibition reduces cardiovascular events in individuals with high risk for cardiovascular disease.[93][94][95][96]

  • In FOURIER (n = 27,564; patients with previous manifestation of ASCVD) the addition of evolocumab to statin therapy compared with statin therapy alone resulted in a 15% relative risk reduction in major cardiovascular events and a 20% relative risk reduction in the combined secondary end point of myocardial infarction, stroke, and mortality. Baseline median LDL-C was 90 mg/dL and was reduced to a median 30 mg/dL with evolocumab. To prevent one clinical event of the primary and secondary end points, 66 and 50 individuals, respectively, would need to be treated for 2 years. Evolocumab use in the trial led to a 20% to 25% relative risk reduction in total myocardial infarctions, strokes, and coronary revascularizations during the study period.[97] A pre-established analysis found a direct continuous association of LDL-C lowering with reduction in cardiovascular events with benefits up to LDL-C of 10 mg/dL and with the greatest benefits in those individuals who attained LDL-C <20 mg/dL.[98] Evolocumab was well tolerated, there were no significant differences between groups in adverse events (including new-onset diabetes and neurocognitive events), except for injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).

  • In the FOURIER open-label extension, 6635 patients from the FOURIER study received evolocumab and were followed up for a median of 5 years (with some, therefore, receiving evolocumab for more than 8 years in total). The extension study found that patients originally randomized to evolocumab in the parent FOURIER trial had a lower risk of cardiovascular events, compared with those originally randomized to placebo, and rates of adverse events were persistently low.[99][100]

  • A reanalysis of the mortality data from the original FOURIER trial, using regulatory documents to address discrepancies and restore complete mortality data, reported that the mortality benefit of evolocumab may be less significant than initially reported.[101]​ This reanalysis has sparked controversy. Critics argue that the reanalysis of the FOURIER study is fundamentally flawed due to its use of incomplete data and a post hoc, unblinded process. They assert that the original FOURIER trial followed a rigorous, prespecified, blinded event adjudication process by experienced cardiologists and neurologists, consistent with FDA definitions and regulatory standards. They emphasize that the original trial's methodology and results were robust and that the reanalysis improperly reclassified deaths, leading to an erroneous conclusion about the efficacy of evolocumab.​​[101]​​

  • EBBINGHAUS, a substudy of FOURIER, found no association of evolocumab treatment with neurocognitive adverse events tested objectively using the Cambridge Neuropsychological Test Automated Battery (CANTAB).[102] Further analysis of the FOURIER trial data found that evolocumab reduced low-density lipoprotein cholesterol levels by 50% or more in 90.5% of patients and by 30% or more in 99.8% of patients.[103]

  • In ODYSSEY OUTCOMES, one multicenter, double-blind, randomized controlled trial of 18,924 patients, alirocumab reduced the risk of recurrent ischemic cardiovascular events (including all-cause mortality and myocardial infarction) compared with placebo in patients who had a previous acute coronary syndrome and were receiving high-intensity statin therapy.[95][96][104][105]

  • In one meta-analysis of 11 randomized trials comparing PCSK9 inhibitors with placebo, including 38,235 individuals treated for at least 48 weeks, PCSK9 inhibitors decreased myocardial infarction by 27% and stroke events by 19%, without a significant difference in cardiovascular mortality. Importantly, however, the study population included both secondary prevention patients with previous vascular events and individuals with familial hypercholesterolemia but no prior cardiovascular events. The heterogeneity of baseline risk limits the interpretation of these findings.[106] ​One Cochrane review assessing the efficacy and safety of PCSK9 inhibitors for the prevention of cardiovascular disease found that both alirocumab and evolocumab decreased the risk of cardiovascular disease when added to other LDL‐C‐lowering medications (e.g., statins or ezetimibe) and there is a strong evidence base for PCSK9 inhibitors in people who might not be eligible for other lipid‐lowering drugs or those who cannot meet lipid goals on other therapies. There are limited data on the benefits of PCSK9 inhibitors compared with other therapies, and limited evidence on potential safety issues.[107] [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] ​​

  • In the US, alirocumab is approved as an adjunct to diet, alone, or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia) to reduce LDL-C; as an adjunct to other LDL-lowering therapies in patients with homozygous familial hypercholesterolemia to reduce LDL-C; and to reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease.

  • In the US, evolocumab is approved as an adjunct to diet, alone, or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia) to reduce LDL-C; as an adjunct to diet and other LDL-lowering therapies in patients with homozygous familial hypercholesterolemia who require additional lowering of LDL-C; and to reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease.

3. Bile acid sequestrants

  • Effective in patients with mild-to-moderate elevations of LDL-cholesterol.

  • Bile acid sequestrants such as cholestyramine and colesevelam can be used as adjuvant therapies to statins and ezetimibe in cases of severe hypercholesterolemia, in patients with high risk of coronary heart disease, when LDL-C goals are not attained, and generally in familial hypercholesterolemia patients. Ezetimibe blocks about 50% of cholesterol absorption, and bile acid sequestrants can work on the remaining cholesterol in the intestinal lumen. There is evidence that both colesevelam and cholestyramine potentiate the lowering effect of ezetimibe on cholesterol levels. Also, in sitosterolemia (a rare condition), bile acid sequestrants can be added to ezetimibe to reduce phytosterol and cholesterol levels.

  • Bile acid sequestrants work by binding bile acids in the intestine and preventing their reabsorption. Through this process, about 90% of bile acids are extracted. The loss of cholesterol-rich bile acids leads to a lowering of intrahepatic cholesterol and an upregulation of LDL receptors. Increased receptor density in the liver results in further reduction of blood cholesterol. LDL reductions ranging from 10% to 24% can be achieved depending upon the dose used.[108]

  • Most adverse effects are related to the gastrointestinal tract and include nausea, bloating, cramping, and increased hepatic transaminases. For many patients these adverse effects are very limiting.

  • The absorption of other drugs can be significantly impaired. Take other drugs 1 hour before or 4 hours after bile acid sequestrants.

  • Formally contraindicated in patients with triglycerides >500 mg/dL.

The threshold for considering additional nonstatin therapy varies depending on risk. If target LDL-C lowering is not achieved with maximally tolerated statin therapy, additional nonstatin therapies may be considered, such as ezetimibe and/or a PCSK9 inhibitor (monoclonal antibody).[41][44][56]​​​​ Newer nonstatin therapies (e.g., bempedoic acid, inclisiran) are also approved; they may not yet be included in guidelines and you should consult your local protocols.[56]​ See Emerging treatments for more information.  

The decision to add nonstatin therapies should be shared between patient and clinician after a discussion on risks, benefits, and patient preferences. Lifestyle modifications should be optimized, in addition to reviewing adherence to statins.[56]

Treatment of older patients

There is controversy in the literature whether older patients should be treated with lipid-modifying therapy. As compared with younger patients, older individuals are at an increased risk of ASCVD. However, cholesterol loses its impact as a risk factor in older patients and there is no consensus whether statins should be prescribed to asymptomatic older patients with hypercholesterolemia. The PROSPER study that evaluated the effects of pravastatin treatment in subjects ages 70-82 years found that in primary prevention, statin treatment was effective only in those subjects with HDL-C 45 mg/dL, where a relative 33% reduction was found.[109] One meta-analysis of 8 studies enrolling 24,674 primary prevention subjects ages >65 years (42.7% females; mean age 73.0 ± 2.9 years; mean follow-up 3.5 ± 1.5 years) showed that statins, compared with placebo, reduced the risk of myocardial infarction by 39.4% (relative risk: 0.606, 95% CI 0.434 to 0.847; p = 0.003) and the risk of stroke by 23.8% (relative risk: 0.762, 95% CI 0.626 to 0.926; p = 0.006).[110] However, there was no mortality benefit. 

Large cohort data have shown an increase in major adverse cardiovascular events in adults ages 75 years or older deprescribed from statins, compared with those continuing statins in both primary and secondary prevention cohorts.[111]

​One meta-analysis from the CTT collaboration showed a similar relative reduction in the risk of ASCVD events per mmol/L reduction in LDL-C with statin therapy in individuals over the age of 75 years old, as compared with younger patients.[112]

Therefore, both ESC/EAS and American College of Cardiology/American Heart Association guidelines recommend statin therapy for patients over the age of 75 years old with a prior ASCVD event. In primary prevention, guidelines recommend considering statin therapy in this age group. The guidelines also highlight the need for increased awareness for adverse events in this population, particularly in the presence of comorbidities, impaired renal or liver function, and polypharmacy.​[41][44]

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