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Section 2.3

Lipid Management

4th Edition
2012-2013 UPDATE
September 20, 2012
*Moderate revisions for 2012

Patients who have had an ischemic stroke or transient ischemic attack should have their serum lipid levels assessed and aggressively managed [Evidence level A].

2.3.1     Lipid assessment

  1. Fasting lipid levels (total cholesterol, total triglycerides, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol) should be measured on all patients presenting with stroke or TIA [Evidence Level C].
  2. For management of dyslipidemia in the primary prevention of cardiovascular events, including stroke, refer to the current Canadian Cardiovascular Society Dyslipidemia clinical practice guidelines.78

2.3.2     Lipid management

  1. A statin drug should be prescribed for primary prevention of cardiovascular events, including stroke, to most patients with high global cardiovascular risk [Evidence Level A].
  2. A statin drug should be considered for primary prevention of cardiovascular events, including stroke, for those patients at intermediate cardiovascular risk [Evidence Level B]. Refer to Canadian Cardiovascular Guidelines for Dyslipidemia 2012 for additional information.
  3. A statin drug should be prescribed as secondary prevention to most patients who have had an ischemic stroke or transient ischemic attack in order to achieve an LDL cholesterol of less than 2.0 mmol/L, or a 50% reduction in LDL cholesterol from baseline [Evidence Level B]
  4. Patients with ischemic stroke or transient ischemic attack should be managed with aggressive therapeutic lifestyle changes, including dietary modification, as part of a comprehensive approach to lower risk of first or recurrent stroke [Evidence Level A].49
  5. Statin therapy is not indicated for prevention of intracerebral hemorrhage. For intracerebral hemorrhage patients who have a clear concomitant indication for cholesterol lowering treatment, statin therapy should be individualized and should take into account the patient’s overall thrombotic risk as well as the possibility of increased risk of intracerebral hemorrhage on statin therapy [Evidence Level B].
  6. Statin therapy has not been well studied in certain sub-populations of stroke patients (for example, patients over 80 years of age, patients with cardioembolic stroke, arterial dissection). Decisions for prescribing should be based on current health status, comorbidities and other indicators of systemic vascular disease (such as coronary artery disease, peripheral vascular disease, and renal vascular disease)[Evidence Level C].
    Rationale

    High cholesterol and lipids in the blood are associated with a higher risk of vascular events including stroke and myocardial infarction. People who have already had an ischemic stroke or transient ischemic attack will benefit from cholesterol-lowering medications with a statin class of drug. Aggressive reduction of low-density lipoprotein cholesterol is likely to yield greater benefit than more modest reductions. A 20 to 30 percent relative risk reduction has been reported in recurrent vascular events for patients with a history of stroke without coronary artery disease who are treated with statin agents.

    The Cholesterol Treatment Trialists meta-analysis of 14 statin trials showed a dose-dependent relative reduction in cardiovascular disease with low-density lipoprotein cholesterol lowering. Every 1.0 mmol/L reduction in low-density lipoprotein cholesterol is associated with a corresponding 20 to 25 percent reduction in cardiovascular disease mortality and nonfatal myocardial infarction.77

    With the childhood obesity epidemic, dyslipidemia is becoming a growing issue in paediatric stroke cases; therefore, fasting lipid panels should be part of the assessment of paediatric stroke cases.

    Note: The current clinical trial evidence does not include enough stroke patients with atrial fibrillation or other cardioembolic sources to make specific recommendations for this patient population. The decision to use statins in this setting should be based on the patient's global cardiovascular risk. It is unclear whether statins are of benefit in patients with a combination of atrial fibrillation and stroke.

    System Implications
    • Coordinated dyslipidemia awareness programs at the provincial and community levels that involve community groups, primary care providers (including physicians, nurse practitioners and pharmacists), and other relevant partners.
    • Stroke prevention, including lipid level monitoring offered by primary care providers in the community as part of comprehensive patient management.
    • Increased availability and access to education programs for healthcare providers across the continuum of care on dyslipidemia diagnosis and management.
    • Continued alignment with recommendations and guidelines developed by the Canadian Cardiovascular Society Dyslipidemia group.
    Performance Measures
    1. Proportion of stroke patients prescribed lipid-lowering agents for secondary prevention of stroke, either at discharge from acute care, through a secondary prevention clinic or by primary care physician.
    2. Proportion of the population who report that they have elevated lipid levels, especially low-density lipoprotein.
    3. Proportion of stroke patients with a low-density lipoprotein cholesterol between 1.8 and 2.5 mmol/L at three months following the stroke event.
    4. Proportion of stroke patients who have lipid levels completed as part of initial comprehensive assessment.
    5. Proportion of stroke patients who have lipid levels completed as part of initial comprehensive assessment with elevated lipid levels that require and receive treatment.

    Measurement Notes

    • Performance measures 1 and 2: Data may be available through the Canadian Community Health Survey.
    • Performance measure 2: Data sources may include physician order sheets, physicians’ and nurses’ notes, discharge summaries, or copies of prescriptions given to patients.
    • Performance measure 3: Blood values should be taken from official laboratory reports where possible.
    • Prescriptions for lipid-lowering agents may be given during the inpatient stay or during a secondary prevention assessment and follow-up, either in a stroke prevention clinic or in a primary care setting. When tracking these performance rates, it is important to record the setting where this therapy was initiated.
    • Prescriptions given to a patient do not imply compliance.
    Summary of the Evidence

    The causal relationship between dyslipidemia and atherosclerosis is well documented. Screening and appropriate management of dyslipidemia by healthcare providers is imperative in both primary and secondary prevention of coronary artery disease, peripheral vascular disease and stroke.77 The 2009 update of the Canadian dyslipidemia guidelines provides a detailed description of the current recommended treatment levels and management modalities for dyslipidemia.78 They emphasize a need to balance lifestyle and risk factor modifications through behaviors change with pharmacological intervention to maximize treatment and improve outcomes for cardiovascular disease and stroke.

    Several systematic reviews of lipid-lowering therapies have affirmed the following points: (1) the relative reduction in stroke risk is on the order of 25–30 percent, (2) ischemic stroke is reduced, with little effect on hemorrhagic stroke and (3) the relative reduction in stroke events is constant irrespective of the baseline risk of stroke. The latter indicates that a greater absolute benefit may accrue from treating patients with a history of stroke or transient ischemic attack, who have a markedly higher baseline risk of recurrent cerebrovascular events.79-84

    O’Regan and collaborators conducted a comprehensive review of randomized trials evaluating statin therapy for stroke prevention.80 Data were pooled using a random-effects model, and meta-regression techniques were employed. Following a thorough search, 42 trials assessing statin therapy for all-stroke prevention (n = 121 285) were included, resulting in a pooled RR of 0.84 (95% CI 0.79–0.91). The pooled relative risk of statin therapy for all-cause mortality (n = 116 080) was 0.88 (95% CI 0.83–0.93). Each unit increase in LDL resulted in a 0.3 percent increased RR of death (p = 0.02). Seventeen trials evaluated the effect of statins on cardiovascular death (n = 57 599, RR 0.81, 95% CI 0.74–0.90), and 11 evaluated non-hemorrhagic cerebrovascular events (n = 58 604, RR 0.81, 95% CI 0.69–0.94). Eleven trials reported hemorrhagic stroke incidence (total n = 54 334, RR 0.94, 95% CI 0.68–1.30), and 21 trials reported on fatal strokes (total n = 82 278, RR 0.99, 95% CI 0.80–1.21).80 Only one trial reported on statin therapy for secondary prevention. Statin therapy provides high levels of protection for all-cause mortality and non-hemorrhagic strokes, reinforcing the need to consider prolonged statin treatment for patients at high risk of major vascular events, but a need for caution remains for patients at risk of bleeds. A large meta-analysis of various lipid-lowering therapies (including statins, fibrates, niacin, bile acid sequestrants and diet) found that only statins reduced the risk of stroke, with a risk reduction of 26 percent (95% CI 14%–36%) for secondary prevention.81 Non-statin drug therapy (with 32 550 subjects studied, of whom 73% were randomized in trials employing fibrates) was associated with a nonsignificant risk reduction of seven percent (RR 0.93, 95% CI 0.79–1.08).

    The Heart Protection Study contributed a substantial amount of information about the role of statin therapy in persons at high risk of serious vascular events.82 This study randomized 20,536 patients with a total serum cholesterol of > 3.4 mmol/L to simvastatin or placebo for a mean duration of five years. The inclusion criteria were any of the following: coronary artery disease, cerebrovascular disease, peripheral vascular disease, diabetes or patients over 65 years with hypertension. The study showed that simvastatin 40 mg once daily rapidly produced a definite and substantial reduction in ischemic stroke (relative risk reduction 25 percent; 95% CI 15%– 44%), irrespective of the patient’s age, sex or blood lipid concentrations when treatment was initiated.82 It also demonstrated that statin therapy reduced the risk of major vascular events among people who have previously had a stroke or other cerebrovascular event, even if they did not already have manifest coronary disease. In addition, there was a highly significant reduction in the simvastatin arm in the frequency of carotid endarterectomy and angioplasty. These benefits were evident in every subgroup tested: patients who had or did not have coronary artery disease; those with cerebrovascular disease, peripheral vascular disease or diabetes; men or women; those over or under 75 years at entry; and those whose LDL cholesterol was over or under 2.6 mmol/L. Treatment benefits were independent of the baseline cholesterol level. The results of the Heart Protection Study imply that the initiation of statin therapy should be based more on the assessment of a patient’s absolute risk of cardiovascular disease, rather than just the baseline LDL cholesterol concentration.

    The Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial (SPARCL) randomly assigned 4731 patients who had had a stroke or transient ischemic attack within one to six months before study entry, had LDL levels of 2.6 to 4.9 mmol/L and had no known coronary artery disease to double-blind treatment with atorvastatin 80 mg once daily or placebo.83 The mean LDL level during the trial was 1.9 mmol/L among patients receiving atorvastatin and 3.3 mmol/L in the placebo group. The 5-year absolute reduction in risk of any stroke was 2.2 percent; relative risk reduction of 16%, adjusted hazard ratio (HR) 0.84 (95% CI 0.71–0.99; p = 0.03). The reduction in ischemic stroke (HR 0.78, 95% CI 0.66–0.94) should be weighed against the statistically significant increase in hemorrhagic stroke (HR 1.66, 95% CI 1.08 – 2.55). The five-year absolute reduction in risk of major cardiovascular events was 3.5 percent (HR 0.80, 95% CI 0.69–0.92; p = 0.002). The statistically significant increase in hemorrhagic stroke, not seen in other statin trials, remains unexplained.83

    In the second Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL2) study, atorvastatin 80 mg/day reduced the risk of stroke in patients with recent stroke or transient ischemic attack.84 This overall benefit included an increase in the numbers of treated patients having hemorrhagic stroke (n = 55 for active treatment v. n = 33 for placebo), prompting investigators to further explore the relationships between hemorrhage risk and treatment, baseline patient characteristics, most recent blood pressure and most recent LDL cholesterol levels before the hemorrhage. Of 4731 patients, two percent had hemorrhagic strokes as entry events.85 In addition to atorvastatin treatment (HR 1.68, 95% CI 1.09–2.59; p = 0.02), Cox multivariable regression showed that hemorrhagic stroke risk was higher in those having a hemorrhagic stroke as the entry event (HR 5.65, 95% CI 2.82– 11.30; p < 0.001), in men (HR 1.79, 95% CI 1.13–2.84; p = 0.01) and with age (10-yr increments, HR 1.42, 95% CI 1.16– 1.74; p < 0.001). There were no statistical interactions between these factors and treatment. Multivariable analyses also found that having stage 2 (JNC-7) hypertension at the last study visit before a hemorrhagic stroke increased risk (HR 6.19, 95% CI 1.47–26.11; p = 0.01), but there was no effect of most recent LDL cholesterol level in those treated with atorvastatin.