ISCHEMIC STROKE / PREVENTION
Dyslipidemia
Created 20/02/2023, last revision 27/03/2023
Definition of dyslipidemia
Definition of dyslipidemia- the previously used term hyperlipidemia is now being replaced by the broader term dyslipoproteinemia or dyslipidemia (DLP), which better reflects the fact that pathology may not be limited to elevated blood fat levels
- metabolic disease with increased concentration of:
- total cholesterol (>5 mmol/l) and/or
- LDL-cholesterol (>3 mmol/l) and/or
- Lp(a) (risk value >430 nmol/L)
- triacylglycerols (TAG > 2 mmol/L)
- there may be a concomitant decrease (<1 mmol/L) or increase (>1.6 mmol/L) in HDL cholesterol
- the cause: increased synthesis and/or decreased catabolism of lipids
- the most serious clinical consequence of prolonged dyslipidemia is the premature manifestation of atherosclerotic cardiovascular disease (ASCVD), especially CAD, PAD, and stroke (mainly TOAST type 1 or 3)
- deposition of LDL-C and apolipoprotein B (ApoB) within the arterial wall is the key initiating event in atherogenesis
- another important risk factor for atherogenesis is lipoprotein (a) – Lp(a) (risk value > 430 nmol/L)
- structural similarity to plasminogen causes competition for its activator, impaired fibrinolysis occurs together with the development of endothelial dysfunction
Notes on dyslipidemia therapy
- treatment with reduces stroke risk and mortality by ~21-26%
- meta-analysis of 42 studies (n=121,285) – RR 0.84
- SPARCL (atorvastatin) – RR 0.85/5 years, Heart Protection Study (HPS) (simvastatin), ASCOTT-LLA (simvastatin), JUPITER (rosuvastatin)
- the effect of statin treatment is directly related to the extent of LDL-c reduction (a 10% decrease in LDL-c reduces the risk of stroke by 13.2%)
- according to the data analysis of the SPARCL trial, a 39 mg/dl (1 mmol/l) reduction in LDL led to a 20% reduction in stroke risk [Amarenco, 2020]
- there is no lower limit for LDL-C values, or ‘J’-curve effect
- effective in stroke prevention in patients with manifest cardiovascular disease (CVD), after a TIA/stroke, but also in people with increased overall CV risk without a history of CVD
- the effect is also in patients with other than pure atherosclerotic etiology ⇒ treatment should be started ASAP after the stroke
- intensive therapy does not increase the risk of hemorrhagic stroke according to meta-analyses [Masson, 2021]
- randomized trials have shown a further reduction in ASCVD risk by adding ezetimibe and anti-PCSK9 antibodies to statins (which correlates with a decrease in LDL-C)
- with no lower limit of effect or J curve effect
- fibrates or ethyl-icosapent can be added to the medication when triglyceridemia is significant
- the clinical effect of HDL-raising drugs (niacin, CETP inhibitors) has not yet been demonstrated [Keene, 2014]
→ hypolipidemics
→ statin intolerance
SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels)
- 80 mg atorvastatin vs placebo were randomly assigned to 4731 patients with a history of stroke or TIA within one to six months before study entry
- statin treatment achieved a mean LDL-C level of 1.9 mmol/l (73mg/dL)
- mean LDL on placebo was 3.3 mmol/l (129 mg/dL)
- a median follow-up of 4.9 years
- fatal/nonfatal stroke 11.2% vs 13.1% (ARR/5 let 2.2%, RRR 15%)
- the 5-year absolute reduction in the risk of major cardiovascular events was 3.5%
- the SPARCL trial clearly documented the beneficial effect of high-dose statin therapy in secondary stroke prevention
- comparison of intensive and conservative hypolipidemic intervention in patients after stroke (within previous 3 months) or TIA ((within previous 15 days)
- n= 2860 (1463 each group), median follow-up 3.5 years
- mean baseline LDL cholesterol was 135 mg/dL (3.5 mmol/L)
- target LDL
- lower-target LDL: < 70 mg/dL (1.8 mmol/L)
- higher-target LDL: 90-110 mg/dL (2.3-2.8 mmol/L)
- intensive treatment (mean LDL 1.8 mmol) vs conservative treatment (mean LDL 2.4 mmol/l)
- the composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes
- combined endpoint 8.5% (lower target) vs. 10.9% (22% decrease of RR in the intensively treated group; comparable risk of hemorrhage)
Classification
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Epidemiology
- frequency of major congenital DLP in the population approx 2% of the adult population
- lipid metabolism disorder is present in > 50% of the population
- inappropriate diet, obesity, lack of physical activity, and smoking are involved
- inappropriate diet, obesity, lack of physical activity, and smoking are involved
Clinical presentation
- long latent period
- less severe symptoms (at an older age or in severe (mostly congenital) forms):
- xanthelasma (yellow bump on or near your eyelid skin)
- arcus lipoides cornae
- tendon and skin xanthomas
- xanthelasma (yellow bump on or near your eyelid skin)
- atherosclerotic cardiovascular disease (ASCVD):
- ischemic stroke (IS)
- Coronary Artery Disease (CAD)
- Peripheral Arterial Disease (PAD)
Diagnostic evaluation
Indication for testing
- in adults > 18 years of age, test total cholesterol every 5 years (primary prevention)
- complete lipid spectrum should be tested:
- in adults >18 years of age who have elevated total cholesterol concentrations
- in patients with manifest CVD (CAD, stroke, PAD)
- the effect of therapy is also seen in patients without a clear atherosclerotic stroke etiology
- in people without CVD (primary prevention) with additional risk factors (QRISK calculator):
- type 1 and type 2 diabetes mellitus
- evidence of subclinical atherosclerosis (IMT, ABI)
- arterial hypertension
- abdominal obesity
- clinical signs of DLP (xantelasma, xanthomas, arcus lipoides corneae)
- CHRI
- positive family history of premature clinical manifestation of atherosclerosis (first-degree relatives in men < 55 years, in women < 65 years)
- repeat lipid spectrum testing in 4-8 weeks if DLP is newly detected in primary prevention
- during this period, maintain a normal lifestyle (no change in diet or weight reduction)
- if the result of two consecutive lipid tests is significantly different in any of the parameters, perform a third critical test
- exclude from screening patients for whom treatment would not be indicated (e.g. for life-limiting disease)
Further evaluation of a patient diagnosed with hyperlipidemia
- family history (manifestation of ACVD in relatives)
- general physical examination, BMI, BP + pulse, ECG
- look for signs of DLP – xanthelasma, tendon or skin xanthomas, arcus corneae
- exclude murmur over large arteries
- basic metabolic panel to rule out the most common causes of secondary DLP
- glycemia, TSH, creatinine, AST, ALT, GMT, urine chemistry
- → diagnosis of diabetes
- investigations targeting possible subclinical atherosclerosis
- stress ECG
- neurosonology (Doppler ultrasound) including IMT measurement
- arterial (carotid and/or femoral) plaque burden on arterial ultrasonography should be considered as a risk modifier in individuals at low or moderate risk
- echocardiography
- ABI (ankle-brachial index)
- Coronary Artery Calcium (CAC) Scoring
- CAC score assessment with CT should be considered as a risk modifier in the CV risk assessment of asymptomatic individuals at low or moderate risk
- determine 10-year overall cardiovascular risk (in primary prevention)
- the Ankle-Brachial Pressure Index (ABPI) is a quick, non-invasive way to check peripheral artery disease (PAD)
- the disease occurs when narrowed arteries reduce the blood flow to the limbs
- an abnormal ABPI may be an independent predictor of mortality, as it reflects the burden of atherosclerosis
- it is a ratio of the blood pressure at the ankle to the blood pressure in the upper arm (brachial BP)
- the patient must be in the supine position, without the head or any extremities dangling over the edge of the table
- the brachial BP is measured in both arms, and the higher value is used
- a low ABPI index indicates narrowing or occlusion of peripheral arteries in the legs
ankle BP
ABPI = ———————————
brachial BP
| Interpretation of ABPI | ||
| > 1.3 | abnormal (vessel hardening due to calcifications) | |
| 1-1.2 | normal | |
| 0.9-0.99 |
acceptable |
|
| 0.8-0.89 | mild PAD |
|
| 0.8 – 0.5 | moderate PAD | |
| < 0.5 | severe PAD | |
Therapeutic target levels
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Management
Lifestyle modifications
- smoking – quit smoking, no exposure to tobacco or cigarette smoke in any form
- alcohol – reduce alcohol consumption
- modest consumption in those who take alcohol may be continued (up to 30 g/day for men, up to 20 g/day for women)
- body weight – target BMI 20-25 kg/m2, and waist circumference <94 cm (men) and <80 cm (women)
- blood pressure – keep < 140/90 mm Hg (in most patients target 130/80 mmHg, if tolerated)
- physical activity – at least 3.57 h moderately vigorous physical activity per week or 30-60 min most days
- stress reduction
- healthy diet
- reduce total fat (saturated and trans) – replace with mono- or polyunsaturated fats
- reduce total amount of dietary carbohydrates and replace them with unsaturated fats
- increased intake of wholegrain products, vegetables, fruit, and fish
- increased dietary fibre intake
- reduce salt intake to 5-6 g/d (up to 2.4 or 1.5 g/d in secondary prevention)
- reduce total fat (saturated and trans) – replace with mono- or polyunsaturated fats
- avoid/reduce drugs that promote sodium and water retention (NSAF, sympathomimetics, corticosteroids in susceptible women, or oral contraceptives)
- maintaining normoglycemia – HbA1c <7% (<53 mmol/mol) → diabetes
- lipids:
- TAG <1.7 mmol/L (<150 mg/dL) indicates lower risk and higher levels indicate a need to look for other risk factors
- ApoB secondary goals are <65, 80, and 100 mg/dL for very-high-, high-, and moderate-risk people, respectively
Pharmacotherapy
→ hypolipidemic drugs
