Grades of recommendations (A-D) and levels of evidence (1-4) are defined at the end of the "Major Recommendations" field. Any aspects that the authors of the guideline considered worth highlighting as an area in which conclusive evidence was lacking, or because it addressed particularly relevant clinical aspects are marked as good practice points (GPP).
Cardiovascular Risk Assessment
Calculation of Cardiovascular Risk
B: Use tables adapted and validated for Spain's population.
C: Use the Registre Gironí del Cor (REGICOR) charts to calculate coronary risk in patients who have no coronary disease.
GPP: Do not use REGICOR charts to calculate coronary risk in patients of over age 74, in the presence of known vascular disease, familial hypercholesterolaemia, genetic dyslipidaemia, and in situations in which the total cholesterol level is >320 mg/dl or low-density lipoprotein cholesterol (LDL-c) >240 mg/dl.
GPP: Avoid reference to desirable cholesterol levels and normal lipid ranges in the results of clinical analyses, since their relevance will depend on the patients' particular circumstances, such as previous cardiovascular disease, familial hypercholesterolaemia, combined familial hyperlipidaemia, family histories of early cardiovascular death and, in the absence of these, on the patients' coronary risk.
Definition of Dyslipidaemia
GPP: Further research is needed to help to establish the nature of the association between triglycerides and coronary disease.
Screening for Dyslipidaemia
GPP: Screen the general population for a lipid profile at age 40 in men and age 45 in women to prevent coronary risk.
GPP: Repeat the calculation of coronary risk every four years using the REGICOR chart after age 40 in individuals who are at low risk in the first evaluation.
D: There is no evidence to support the assessment of coronary risk in patients over age 75.
GPP: Assess individual lipid profile in patients with a family history of early vascular disease, familial dyslipidaemia or obesity.
D: An annual lipid profile should be part of the preliminary assessment of patients with high blood pressure or diabetes.
C: To determine lipid variables such as total cholesterol and high-density lipoprotein cholesterol (HDL-c) is sufficient to estimate coronary risk.
D: Decision-making at the beginning lipid-lowering intervention requires a complete lipid profile obtained after 12-hour fasting.
D: At least two lipid profiles are required before a decision to begin a lipid lowering intervention.
D: Lipid profile determinations should not be made until 12 weeks after acute myocardial infarction and up to 8 weeks after a trauma, surgery, a bacterial or viral infection, and childbirth.
D: Ask patients to remain seated for 5 minutes prior to taking a blood sample. Avoid prolonged venal occlusion. If this is not possible, release the tourniquet one minute after tying it and try the other arm, or wait a few minutes before attempting to extract a sample again.
Ankle-Brachial Index Test
C: When considering drug therapy, the ankle/arm index should be performed on patients with a 10% to 19% coronary risk in the REGICOR chart.
Target Figures for LDL-c
GPP: Target LDL-c levels in primary prevention cannot be based on the existing evidence.
Suspected Cases of Familial Hypercholesterolaemia
GPP: Familial hypercholesterolaemia should be suspected in:
- Patients with previous cases of familial hypercholesterolaemia in first-degree relatives.
- In individuals with no previous cases of familial hypercholesterolaemia, with early cardiovascular disease and high cholesterol levels.
- Individuals >40 with total cholesterol levels above 360 mg/dl or LDL-c levels of >260 mg/dl, and in individuals 30-39 years old with total cholesterol (TC) levels of >340 or LDL >240 mg/dl.
GPP: The recommendation is to determine total cholesterol in all first-degree relatives of patients with familial hypercholesterolaemia, starting at age 10.
GPP: Individuals suspected of familial hypercholesterolaemia should undergo the MedPed test and be referred to specialist care.
C-B*: It is recommended to advise the general population and individuals who have suffered a coronary event (*) to follow the Mediterranean dietary model (diet and physical activity). Essentially, this advice should be given in infirmaries.
B: Efforts should be made to promote the daily consumption of fruit and vegetables.
C: It is recommended to advise the general population and patients who have suffered a cardiovascular disease that they should continue to consume alcohol, providing their previous alcohol consumption pattern was low or moderate.
C: The recommended level of alcohol consumption must not exceed 2 units* daily of alcohol in men and 1 unit daily in women.
GPP: Information on the benefits of alcohol must be accompanied by a clear explanation of what one unit of alcohol represents and the adverse effects of heavy drinking.
*1 unit of alcohol is equal to 1 small glass of wine, 1 beer, half a glass of brandy or one coffee with brandy. 2 units of alcohol are equal to 1 glass of wine, a glass of brandy, or one rum and Coke highball or similar.
Physical Activity/Weight Loss
B: The general recommendation is aerobic-intensive exercise such as walking, running, moderately strenuous swimming for at least 30 minutes, five days per week; or strenuous activity for at least 20 minutes, three days per week.
C: In overweight or obese individuals, the recommendation is to reduce calorie intake and to increase physical activity.
D: To eat fish as a source of omega-3 acids and non-saturated fats as part of the Mediterranean diet.
A: The use of medicinal plants to lower coronary risk is not recommended.
Drug Therapy in Primary Prevention
D: 6 months of dieting and physical activity is recommended prior to beginning the lipid-lowering treatment.
A: Primary preventive measures with low to mild dose statin are recommended in patients of ages 40-75 with >20% coronary risk levels according to the REGICOR equation. Recommendations for a cardio-healthy lifestyle should be given before and/or during pharmacological treatment.
B: Treatment with low to mild statin doses in patients with coronary risks of between 10% and 19%, determined by means of the REGICOR project equation, must be made after treating other cardiovascular risk factors (obesity, high blood pressure, smoking).
B: In patients with coronary risks of between 10% and 19%, determined by means of the REGICOR project equation and the presence of other non-modifiable cardiovascular risk factors (family case histories of premature coronary death, previous cases of family hypercholesterolaemia, preclinical evidence of arteriosclerosis), starting treatment with low to mild statin doses should be considered.
GPP: Therapy should begin with low to mild dose statin in patients with isolated levels of total cholesterol higher than 320 mg/dl and/or LDL-c levels of 240 mg/dl.
GPP B(*) D(**): The recommendation for patients with a prescription for statin therapy in primary prevention and intolerance to statins is to insist on non-drug therapy and to lower the dose or change to another statin. If intolerance persists, the recommendation is to begin fibrate therapy*. Other options may be resins* and/or ezetimibe**.
GPP: In primary prevention, women of ages 40 to 75 at a 10% to 19% coronary risk according to the REGICOR equation should be intervened with preference over other cardiovascular Risk (CVR) factors before they begin lipid-lowering drug therapy.
C: Women of ages 40 to 75 at a risk of coronary disease >20% should begin statin therapy a low to mild doses.
D: Estimating the risk of coronary disease with the information afforded by cholesterol levels is not recommended in patients over age 75.
GPP: In primary prevention, the decision to begin lipid-lowering therapy with statins in patients over age 75 should be made individually and only after assessing the risks, which may be higher than the benefits for which there is no evidence.
GPP: In primary prevention, patients over age 80 previously undergoing treatment with statins, the recommendation is to assess the convenience of interrupting statin therapy on the basis of the patient's life expectancy and quality of life.
C: In diabetic patients with no cardiovascular disease, the coronary risk should be estimated to make decisions on lipid-lowering intervention. When estimating coronary risk in diabetic patients liable for primary prevention, the recommendation is to use the REGICOR project tables for coronary risk (CR).
B: In type 2 diabetic patients age 40 to 75 with a CR of >10% according to the REGICOR project's tables, the recommendation is to begin statin therapy with low to mild doses.
GPP: In diabetic patients over age 75, the recommendation should be made on an individual basis according to the patient's cardiovascular risk factors.
B: The administration of fibrates may be considered in type 2 diabetic patients with a cardiovascular risk of >10% in the REGICOR project table, who do not tolerate statins or for whom statins are contraindicated.
C: In long-term diabetics of >15 years, assess treatment with statins at low to mild dosages, irrespective of coronary risk.
Drug Therapy in Secondary Prevention
Ischaemic Heart Disease
A: In patients with ischaemic heart disease, the recommendation is to begin treatment with mild statin doses, regardless of baseline LDL-c.
B(*) D(**): In patients with ischaemic heart disease and intolerance to statin, the recommendation is to lower the doses or change to a different statin. If the intolerance persists, begin treatment with fibrates*. Other options may be nicotinic acid**, resins**, and/or ezetimibe**.
GPP: After informing the patient of the benefits and risks of treatment, the statin dosage may be increased in patients with ischaemic heart disease in whom LDL-c levels of less than 100 mg/dl have not been attained.
Acute Coronary Syndrome
A: Treatment should begin with mild statin doses in individuals discharged from hospital after acute coronary syndromes, regardless of their total cholesterol and LDL-c base levels.
B: In patients with ischaemic ictus of atherothrombotic origin and no ischaemic heart disease, treatment should begin with mild statin doses and recommendations on lifestyle. Begin treatment with statins regardless of baseline LDL-c.
GPP: In patients with a prior ictus in whom LDL-c levels of less than 100 mg/dl have not been attained, the statin dose may be increased after informing the patient of the benefits and risks of treatment.
Peripheral Arterial Disease
B: Mild dose statin is recommended in patients with peripheral arterial disease and related comorbidity.
Therapy for Hypertriglyceridaemia
D: When triglyceride levels fall below 500 mg/dl, clinical decision-making should consider the patient's global risk of cardiovascular disease.
D: The first measures to recommend in patients whose triglyceride levels exceed 200 mg/dl are to lose weight, eat fewer fats, increase physical activity and drink less alcohol or stop altogether.
D: Treatment with fibrates is recommended when triglycerides levels remain higher than 500 mg/dl despite changes in lifestyle.
D: Omega-3 fatty acids may be used as a treatment for hypertriglyceridaemia, in conjunction with fibrates.
Treatment in Patients with Isolated Low HDL-c
A: Aerobic exercise on a regular basis, weight loss if obesity exists, and to quit smoking are recommended to increase HDL-c levels.
GPP: Drug therapy for isolated HDL-c levels is not recommended without taking coronary risk according to the REGICOR chart into account.
GPP: The risk of early coronary disease is higher in hereditary forms of mixed hyperlipidaemia. Therefore, a family history of early cardiovascular disease and lipid disorders should be made before beginning treatment. If such cases exist, the patients should be considered as a high cardiovascular risk.
GPP: In primary care, the coronary risk in patients with mixed hyperlipidaemia and no family history should be calculated according to the REGICOR equation. The main purpose of treatment should be to lower coronary risk.
Combined Drug Therapy Indications
GPP: In patients who require a combination of two drugs, statins and low doses of ion-exchange resins may be combined, or ezetimibe can be used in the event of intolerance to the former.
D: Fenofibrates are recommended when a combination of statins and fibrates is required.
GPP: Consider combined treatment in:
- Familial hypercholesterolaemia where adequate control is not secured with a drug.
- Circumstantially, in patients with mixed hyperlipidaemia of family origin.
Adverse Effects of Drug Therapy
D: Discontinuing treatment with fibrates should be considered if a sustained increase in creatinine levels occurs.
D: Gemfibrozil should be the first choice in patients with renal insufficiency who require treatment with fibrates.
D: Avoid resins in patients with constipation or intestinal disorders.
D: If the patient is taking any other medication concurrently with ion exchange resins, administer the other medication one to four hours after administering the resins.
Initial Assessment and Monitoring of Patients on Drug Therapy
Preliminary Analytical Test Assessment
D: Two lipid profiles are recommended before beginning drug therapy. After drug therapy, one control after an 8-12 week interval is recommended, followed by annual coronary risk assessment in primary care. After adequate control is attained, an annual analysis in secondary prevention is recommended.
D: The glutamic-oxaloacetic transaminase (GOT)/glutamic-pyruvic transaminase (GPT) levels should be determined before beginning treatment with statins or fibrates. If the levels are high, the guideline developers recommend investigating the cause before treatment commences.
B: The creatine phosphokinase (CPK) does not need to be determined before beginning treatment with statins or fibrates in patients with no symptoms.
D: In patients who are starting treatment with statins or fibrates, CPK levels should be determined before beginning treatment in patients who refer unexplainable muscle symptoms and in patients with a high risk of muscle toxicity (patients who are elderly or have a liver disorder, and in the event of potentially myotoxic pharmacological combinations).
D: Starting treatment with statins is not recommended when the CPK level is 5 times higher than the upper limit of normality.
D: GOT, GPT and creatinine levels should be tested, and the presence of cholelithiasis assessed before starting treatment with fibrates.
Regularity of Analytical Tests in Drug Therapy Follow-ups
D: A determination of transaminase 8-12 weeks after commencing treatment with statins is recommended.
D: An annual transaminase determination in patients in treatment with statins is recommended. Statins dosages should be lowered in cases where the transaminase is more than three times higher than normal, and treatment should be discontinued if the high levels persist.
D: Patients should be informed that treatment might be accompanied by muscle symptoms and of the need to request medical advice with their onset.
D: A creatine phosphokinase (CPK) determination should be requested if muscle symptoms appear. Discontinue treatment with statins in cases where CPK is 10 times higher than the upper limit of normality.
D: GOT and GPT values should be determined 8-12 weeks after treatment with fibrates commences and annually thereafter.
D: Routine seric creatinine determinations are not necessary during therapy.
D: Plasma creatinine levels should be determined in patients under treatment with fibrates who take other drugs as well, such as metformin and statins. Therapy should be discontinued if a creatinine increase greater than 1.4 mg/dl in women and 1.5 mg/dl in men is found.
D: Patients should be informed that treatment might be accompanied by muscle symptoms and of the need to request medical advice with their onset. Discontinue treatment with fibrates in cases where CPK is 10 times higher than the upper limit of normality.
GPP: Referral to a lipid unit or second-level care is recommended in the event of:
- Suspected cases of familial hypercholesterolaemia
- Severe genetic hyperlipidaemia with abnormally high lipid profiles (total cholesterol [TC]> 400 or LDL-c >260 mg/dl or triglycerides [TG] >1000 mg/dl)
- The need to add a third drug
- The onset of adverse effects that require specialised intervention
Hypercholesterolaemia in Children
A: Population screening for cholesterol in children and adolescents is not recommended.
GPP: Cholesterol screening is recommended after the age of 10 in children with a first-degree relative with single-gene familiar hypercholesterolaemia.
Non-Drug Therapy: Physical Activity
D: A Mediterranean diet, physical activity and adequate weight control are recommended for children with hypercholesterolaemia and no family record of single-gene dyslipidaemia.
Levels of Evidence
Scottish Intercollegiate Guidelines Network (SIGN) Levels of Evidence for Intervention Studies
1++ High quality meta-analyses, systematic reviews of controlled clinical trials or high quality clinical trials with a very low risk of bias.
1+ Well conducted meta-analyses, systematic reviews of clinical trials or well conducted clinical trials with very low risk of bias.
1- Meta-analyses, systematic reviews of clinical trials or clinical trials with a high risk of bias.
2++ High quality systematic reviews of cohort and case-control studies. Cohort and case-control studies with a very low risk of bias and with a high probability of establishing a causal relationship.
2+ Well-conducted cohort and case-control studies with a low risk of bias and a moderate probability of establishing a causal relationship.
2- Cohort and case-control studies with a high risk of bias and with a significant risk of establishing a non-causal relationship.
3 Non-analytic studies, e.g., case reports and series of cases.
4 Expert opinion.
Levels of Evidence for Diagnostic Studies*
Ia Systematic review (with uniformity) of Level 1a studies
Ib Level 1b studies
II Level 2c studies; systematic reviews of Level 2 studies
III Level 3d studies; systematic reviews of Level 2 studies
IV Consensus, expert reports or opinions and/or clinical experience without explicit critical appraisal; or based on physiology, bench research or "first principles".
a Uniformity means that there is very little or no variation in the directions and degrees of results between the individual studies included in the systematic review.
b Level 1 studies:
- Studies that compare the test blindly with a certified benchmark (gold standard) and in which a sample of patients reflects the population on whom the test would be applied.
c Level 2 studies:
- Studies that deal with a small number of people (the patient sample does not represent the population on whom the test would be applied)
- Studies that use a poor benchmark standard (where "test" is included in the "benchmark", or where the "tests" have an impact on the "benchmark")
- The comparison between the test and the benchmark is not blind
- Case-control studies
d Level 3 studies: Studies that present at least two or three of the features included in Level 2
Grades of Recommendation
Scottish Intercollegiate Guidelines Network (SIGN) Grades of Recommendation for Intervention Studies
A At least one meta-analysis, systematic review or clinical trial rated as 1++, directly applicable to the guideline's target population; or a body of evidence consisting of studies rated as 1+ and showing considerable consistency with each other.
B A body of evidence including studies rated as 2++, directly applicable to the guideline's target population, and showing considerable consistency with each other; or evidence extrapolated from studies rated as 1++ or 1+.
C A body of evidence including studies rated as 2+, directly applicable to the guideline's target population, and showing considerable consistency with each other; or evidence extrapolated from studies rated as 2++.
D Evidence level 3 or 4; or evidence extrapolated from studies rated as 2+.
GPP Consensus of the editorial team.
Grades of Recommendation for Diagnostic Studies*
A Level of evidence Ia or Ib studies
B Level of evidence II studies
C Level of evidence III studies
D Level of evidence IV studies
*Adapted from The Oxford Centre for Evidence-based Medicine Levels of Evidence and the Centre for Reviews and Dissemination Report Number 4 (2001).