Overview of guidelines for the management of dyslipidemia: EU perspectives

Figures & data

Table 1 Main actual disposable CV risk calculators and their general characteristics

	PCERC^Citation19	Frmingh^Citation35	SCORE^Citation36	QRISK2^Citation37, ^Citation38	ASSIGN^Citation39	Lloyd-Jones^Citation40	PROCAM^Citation41
CPG	2013 ACA/AHA^Citation15	ATP III^Citation14	ESC/EAS^Citation15,Citation16	NICE^Citation18	SIGN^Citation43	IAS^Citation29	ITFPCD^Citation44
Data source	7 NHLBI -funded cohort studies for US population	Prospective Framingham Heart and Offspring studies	12 pooled prospective studies from 11 European countries	QResearch electronic database	SHHEC prospective study	Framingham Heart Study participants free of CV disease	Prospective study
Population	African-American or White participants with ≥12 years of follow-up	US general population volunteers from Framingham, MA, USA	Random samples from general population, some occupational cohorts	Health records of general practice attendees	General population in Scottish MONICA and the Scottish Heart Health studies	US general population volunteers from Framingham, MA, USA	Healthy male employees in Münster (Germany)
Sample size	Whites: 9,098 ♂ 11,240 ♀ African-American: 1,647 ♂ 2,641 ♀	3,969 ♂ 4,522 ♀	117,098 ♂ 88,080 ♀	2.29 million (QRISK2)	6,540 ♂ 6,757 ♀	564 ♂ 4,362 ♀	18,460 ♂ 8,515 ♀
Age (years)	40–79	30–75	40–65	35–74	30–74	50	20–75
Calculates	Sex- and race-specific 10-year risk for fatal CHD, nonfatal MI, all stroke	Latest version: 10-year risk of CV events	10-year risk of CV mortality Version for relative risk for <40 years	10-year risk of CV events All-life CV risk version^Citation38	10-year risk of CV events	Total CV morbidity by age 80 years, from age 50 years	10-year risk of coronary and cerebral ischemic events
Included variables	Age, Tc, HDLc, SBP, DM, current smoking status	Sex, age, Tc, HDLc, SBP, smoking, DM, HTd	Sex, age, Tc or Tc/HDLc, SBP, smoking Versions for high- and low-risk countries	Sex, age, Tc/HDLc, SBP, smoking, DM, social deprivation, family history, BMI, HTd, ethnicity, comorbidity	Sex, age, Tc, HDLc, SBP, number of cigarettes, DM, social deprivation, family history of CHD	Tc, smoking, BP, DM	Age, sex, LDLc, HDLc, DM, smoking, SBP
Thresholds	+ <5% ++ 5–7.4% +++ ≥7.5%	+ <5 % ++ 5–20% +++ >20%	+ <1% ++ 1–4% +++ 5–10% ++++ >10%	+ 5% ++ 10% +++ 15% ++++ ≥20%	+ <10% ++ 10–19% +++ ≥20%	+ <15% ++ 15–29% +++ 30–44% ++++ >45%	+++ >53 (>20%)

Notes: +, low CV risk; ++, moderate CV risk; +++, high CV risk; ++++, very high CV risk. Data based on Cooney et al.⁴⁴

Abbreviations: ACA/AHA, American College of Cardiology/American Heart Association; ASSIGN, Assessing cardiovascular risk using SIGN guidelines to ASSIGN preventive treatment; ATP III, Adult Treatment Panel III; BMI, Body mass index; BP, blood pressure; CHD, coronary heart disease; DM, diabetes mellitus; ESC/EAS, European Society of Cardiology/European Atherosclerosis Society; Frmingh, Framingham score; HDLc, high-density lipoprotein cholesterol; HTd, having antihypertensive drugs; IAS, International Atherosclerosis Society; ITFPCD, International Task Force for Prevention of Coronary Disease; MI, myocardial infarction; NICE, National Institute for Health and Care Excellence; PCERC, Pooled Cohort Equations Risk Calculator; SBP, systolic blood pressure; SCORE, Systematic Coronary Risk Evaluation; SHHEC, Scottish Heart Health Extended Cohort; SIGN, Scottish Intercollegiate Guidelines Network; Tc, Total cholesterol; CV, cardiovascular; LDLc, low-density lipoprotein cholesterol; CPG, clinical practice guidelines; NHLB, National Heart, Lung, and Blood Institute; MONICA, multinational monitoring of trends and determinants in cardiovascular disease.

Table 2 Proportion of participants of the Rotterdam study to be treated with statins applying different actual guidelines for the management of dyslipidemia criteria

Guideline	♂	♀
2013 ACC/AHA^Citation15	96.4% (95% CI, 95.4%–97.1%) n=1,825	65.8% (95% CI, 63.8%–67.7%) n=1,523
2012 ESC/EAS^Citation16,Citation17	66.1% (95% CI, 64.0%–68.3%) n=1,253	39.1% (95% CI, 37.1%–41.2%) n=906
2002 ATP III^Citation14	52.0% (95% CI, 49.8%–54.3%) n=985	35.5% (95% CI, 33.5%–37.5%) n=821

Note: Data from Kavousi et al.⁴⁷

Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; ATP, Adult Treatment Panel; CI, confidence interval; EAS, European Atherosclerosis Society; ESC, European Society of Cardiology.

Table 3 Risk factors to be considered for the assessment of final individual CV risk in addition to CV calculators based on traditional CV risk factors

Guidelines	Other CV risk factors to be considered for the estimation of individual global CV risk
2012 ESC/EAS^Citation16,Citation17	• Familial prevalence of ASCVD or of major risk factors before 55 years in ♂ and 65 years in ♀ • Low socioeconomic status, lack of social support, stress at work and in family life, depression, anxiety, hostility, and the type D personality • DM • Low HDLc or apolipoprotein A1 • Increased Tg, fibrinogen, homocysteine, apolipoprotein B, and lipoprotein(a), familial hypercholesterolemia or increased hs-CRP • Asymptomatic individuals with preclinical evidence of ASCVD (plaques or increased CIMT) • Those with impaired renal function (low estimated glomerular filtration and/or increased microalbuminuria/proteinuria) • Risk may be lower than indicated in those with very high HDLc levels or a family history of longevity
2013 ACC/AHA^Citation15	• Family history of premature ASCVD with onset <55 years of age in a first-degree male relative or <65 years of age in a first-degree female relative • Primary LDLc ≥160 mg/dL or other evidence of genetic hyperlipidemias • hs-CRP ≥2 mg/L • CAC score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity • Ankle-brachial index <0.9 • Lifetime risk of ASCVD
2014 NICE^Citation18	• Family history of premature CV disease in medical records • Familial hypercholesterolemia or other inherited disorders of lipid metabolism • Low socioeconomic status • Ethnicity • Evidence of estimated glomerular filtration rate <60 mL/min/1.73 m^2 and/or albuminuria • People with treated HIV, serious mental health problems, taking drugs that can cause dyslipidemia (antipsychotics, corticosteroids, or immunosuppressants), systemic inflammatory disorders such as systemic lupus erythematosus, on antihypertensives or lipid modifying drugs, recently stopped smoking, body mass index >40 kg/m^2 • People aged 85 years or older, particularly people who smoke or have raised blood pressure

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CIMT, carotid intima/media thickness; DM, diabetes mellitus; HDLc, high-density lipoprotein cholesterol; HIV, human immunodeficiency virus; hs-CRP, high-sensitivity C-reactive protein; Tg, triglycerides; CV, cardiovascular; LDLc, low-density lipoprotein cholesterol; ESC/EAS, European Society of Cardiology/European Atherosclerosis Society; ACC/AHA, American College of Cardiology/American Heart Association; NICE, National Institute for Health and Care Excellence.

Table 4 Classification of statins depending on their theoretical capacity to reduce LDLc plasmatic levels

Guideline	Low intensity	Medium intensity	High intensity
2013 ACC/AHA	<30%	30%–49%	≥50%
2010 CCT meta-analysis^Citation50, ^Citation51	LDLc reduction Fl 20–40, Lo 20, Pr 10–20, Si 10, Pi 1	LDLc reduction Fl 40 bid, Fl XL 80, Pr 40–80, Lo 40, Si 20–40, At 10–20, Ro 5–10, Pi 2–4	LDLc reduction At –80, Ro 20–40
2012 ESC/EAS	20%–30%	30%–40%	>40%
2010 Weng et al meta-analysis^Citation72 and Mukhtar et al^Citation73	LDLc reduction Fl 40, Pr 20–40, Lo 10–20, Si 10	LDLc reduction Fl 80, Lo 40–80, Si 20, At 10, Pi 1	LDLc reduction At 40, Ro 40, Pi 2–4
2014 NICE^Citation18	20%–30%	31%–40%	>40%
2003 Law et al meta-analysis^Citation74	LDLc reduction Pr 40, Fl 40, Pr 20, Fl 20, Pr 10, Si 10	LDLc reduction Si 40, Si 20, At 10, Ro 5	LDLc reduction Si 80, At 40–80, Ro 20–40, Ro 10–20

Note: The number after the abbreviation indicates the daily dose in mg.

Abbreviations: At, Atorvastatin; CCT, Cholesterol Treatment Trialists’ Collaboration; Fl, Fluvastatin; Lo, Lovastatin; Pi, Pitavastatin; Pr, Pravastatin; Ro, Rosuvastatin; Si, Simvastatin; CV, cardiovascular; LDLc, low-density lipoprotein cholesterol; XL, extended release.

Table 5 Gaps to be solved in the future according to the European and the American clinical practice guidelines on dyslipidemia

ACC/AHA 2013^Citation14	ESC/EAS 2012^Citation16, ^Citation17	NICE 2012^Citation18
General aspects
Outcomes of RCTs to evaluate alternative treatment strategies for ASCVD risk reduction. These RCTs may compare titration to specific cholesterol or apolipoprotein goals versus fixed-dose statin therapy in high-risk patients. Outcomes of RCTs of new lipid-modifying agents to determine the incremental ASCVD event-reduction benefits when added to evidence-based statin therapy. RCTs to determine whether submaximal statin doses, combined with nonstatin therapies, reduce ASCVD risk in statin-intolerant patients.	There are no recent RCTs of a total risk approach to risk assessment; nor risk management. Current systems of grading evidence give most weight to RCTs, but many lifestyle measures are less amenable to such assessment than are drug treatments, which therefore tend to receive a higher grade. While the GRADE^Citation33 system attempts to address this issue, more debate is needed. A systematic comparison of current international guidelines is needed to define areas of agreement and the reasons for discrepancies.	What is the comparative effectiveness of age alone and other routinely available risk factors versus formal structured multifactorial risk assessment for identifying people at high risk of developing CVD disease? When evaluating cost-effectiveness for statin therapy in reducing CVD, is prediction improved by the use of a complete meta-analysis dataset based on individual patient outcomes rather than published outcomes data from individual trials? What is the clinical effectiveness and rate of adverse events of statin therapy using atorvastatin 20 mg per day compared with atorvastatin 40 mg per day and atorvastatin 80 mg per day in people without established CVD?
Specific aspects
Outcomes of RCTs to evaluate statins or the primary prevention of ASCVD in adults >75 years of age. Evaluation of the incidence, pathophysiology, clinical course, and clinical outcomes of new-onset diabetes associated with statin therapy.	The young, women, older people, and ethnic minorities continue to be underrepresented in clinical trials.	What is the effectiveness of statin therapy in older people? What is the effectiveness of statins or other treatments that lower low-density lipoprotein-cholesterol in people with type 1 diabetes?

Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; EAS, European Atherosclerosis Society; ESC, European Society of Cardiology; NICE, National Institute for Health and Care Excellence; RCT, randomized clinical trial; CVD, cardio vascular disease; ESC/EAS, European Society of Cardiology.

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