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Secondary Prevention Of Stroke

4. Lipid Management

7th Edition – 2020 UPDATED


Recommendations

Note: For detailed management of dyslipidemia, refer to current Canadian Cardiovascular Society guidelines on this topic. www.ccs.ca/guidelines

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

4.1 Lipid Assessment
  1. Lipid levels, including total cholesterol, triglycerides, low-density lipoprotein [LDL] cholesterol, and high-density lipoprotein [HDL] cholesterol, should be measured in patients presenting with ischemic stroke or transient ischemic attack [Evidence Level B]. 

Note: Refer to Table 1A for more information on laboratory tests.

4.2 Lipid Management
  1. Individuals with ischemic stroke or transient ischemic attack should be managed with aggressive lifestyle changes to lower lipid levels, including dietary modification and exercise, as part of a comprehensive approach to lower risk of recurrent stroke and other vascular events unless contraindicated [ Evidence Level B].   Refer to Prevention of Stroke Module, Section 2 for Lifestyle Management recommendations.

  2. Statin pharmacotherapy should be prescribed for secondary prevention of stroke in individuals who have had a non-cardioembolic ischemic stroke or transient ischemic attack, [Evidence Level A]. Refer to the current Canadian Cardiovascular Society Dyslipidemia guidelines for additional information on lipid management. 

    1. A target LDL cholesterol level of < 1.8 mmol/L is recommended [Evidence Level B].

  3. Statin therapy should not be initiated for secondary prevention of intracerebral hemorrhage [Evidence Level C]. Refer to CSBPR Management of Intracerebral Hemorrhage module for additional information on stroke prevention strategies in that population.

  4. Add-on therapies for LDL-Lowering (NEW 2020).

    1. For individuals with ischemic stroke and atherosclerotic cardiovascular disease with an LDL > 1.8 mmol/L in spite of maximal tolerated statin therapy, ezetimibe may be considered for additional LDL lowering [Evidence Level B].  

    2. For individuals with concomitant atherosclerotic cardiovascular disease where target LDL level is not achievable, consider referral to a health professional with expertise in metabolic and lipid management, or stroke expertise for consideration of adding PCSK9 inhibitor [Evidence Level A].

  5. Add-on therapies for hypertriglyceridemia (NEW 2020) For ischemic stroke patients with established atherosclerotic cardiovascular disease or diabetes plus additional vascular risk factors, who have elevated serum triglyceride levels (≥1.5 mmol/L) despite statin therapy, icosapent ethyl 2 g bid may be considered to decrease the risk of vascular events [Level of Evidence B]. 

4.3 Statin Intolerance (new 2020)
  1. For patients with an intolerance to statins (including persistent myalgias, persistent significant liver enzyme abnormalities or rarely, myopathy or rhabdomyolysis), the indication for statin therapy should be confirmed and in general, systematic evaluation of the contribution of statins to the patient’s symptoms should be considered (including temporary statin cessation with observation of symptoms, dose-adjustment, use of alternate agents) [Evidence Level C] 

Note: For diagnosis and management of dyslipidemia in the primary prevention of cardiovascular events, including stroke, refer to the current Canadian Cardiovascular Society Dyslipidemia guidelines.

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 16 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 with and NNT of 30 reported by the Treat to Target trial (2020).

People who have experienced stroke report a wide range of approaches to the way their lipids are managed; some are referred to and followed by a lipid specialist and others by their family doctor, whereas others have reported never had their lipids discussed (SPoS CCRP, 2019).  An individualized approach to lipid management is necessary to help people be successful in reaching their appropriate lipid targets. Our Community Review Panel emphasize the importance of a comprehensive approach to lipid management that includes education on medications, diet, exercise, weight management and clear information on what their target lipid level should be, their prescribed medication regime, and potential side effects and how the side effects can be managed.  

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 +-
  1. 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.
  2. Stroke prevention, including lipid level monitoring and education, offered by primary care providers in the community as part of comprehensive patient management.
  3. Increased availability and access to education programs on dyslipidemia diagnosis and management for healthcare providers across the continuum of care.
  4. Continued alignment with recommendations and guidelines developed by the Canadian Cardiovascular Society Dyslipidemia group.
  5. Universal and equitable access to cost-effective medicines for all people in Canada, regardless of geography, age, or ability to pay.
Performance Measures +-
  1. Proportion of stroke patients who have lipid levels completed as part of initial comprehensive assessment
  2. Proportion of the population who report that they have elevated lipid levels, especially low-density lipoprotein.
  3. 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 provider (includes MD and NP).

Measurement Notes

  • Performance measures 1 and 2: Data may be available through the Canadian Community Health Survey.
  • Performance measure 2: Blood values should be taken from official laboratory reports where possible
  • Performance measure 3: Data sources may include physician order sheets, physicians’ and nurses’ notes, discharge summaries, or copies of prescriptions given to patients.
  • 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 +-

Lipid Management Evidence Tables and Reference List

Given the well-documented causal relationship between dyslipidemia and the development of atherosclerosis, appropriate management is important for both primary and secondary prevention of stroke. To maximize treatment and improve outcomes for cardiovascular disease, current strategies emphasize the need to balance lifestyle and risk factor modifications through behaviors change with pharmacological intervention. 

Evidence from several systematic reviews has demonstrated a significant reduction in overall risk of ischemic stroke and other vascular events associated with lipid-lowering therapies. In one of the more recent Cholesterol Treatment Trialists (CTT) publications (Fulcher et al. 2015), 27 RCTS (n=186,854) were included, in which the treatment aim was solely the reduction of LDL cholesterol and was continued for at least two years. Treatment contrasts included statin vs. placebo and more intensive vs. less intensive treatment. After a median duration of follow-up of 4.9 years, overall, statins reduced the risk of a major vascular event by 21% per each 1.0 mmol/L reduction in LDL-chol (RR=0.79, 95% CI 0.77-0.81), with no significant interaction reported for sex. The risks of any stroke and any vascular death were also decreased significantly with statin therapy (RR=0.85, 95% CI 0.80-0.89, and RR=0·88, 95% CI 0·84−0·91, respectively), again with no significant interaction based on sex. Statins significantly reduced the risk of a major vascular event and vascular death across all age groups from ages ≤55 to >75 years, per each 1.0 mmol reduction in LDL-chol (Armitage et al. 2019). Lipid-lowering treatment was associated with a significant decrease in stroke risk among persons with a >5% to 30%, 5-year risk of stroke (Mihaylova et al. 2012).

The results of many primary prevention trials including participants with cerebrovascular risk factors have demonstrated the effectiveness of statin therapy. Although too many to describe in detail, we present the results of just a few that compared varying doses of statins with placebo, which included persons with differing levels of cardiovascular risk. The Heart Protection Study (2002) randomized 20,536 patients with coronary artery disease, cerebrovascular disease, peripheral vascular disease, diabetes or patients over 65 years with hypertension and a total serum cholesterol of > 3.4 mmol/L to receive 40 mg simvastatin or placebo for a mean duration of five years. There was a significant reduction in ischemic stroke associated with statin therapy (RRR=25%, 95% CI 15%– 44).  In addition, patients in the simvastatin arm required fewer carotid endarterectomies and angioplasties. These benefits were evident across all subgroup, even those whose baseline LDL cholesterol was under 2.6 mmol/L, suggesting the decision to initiate statin therapy should include an assessment of a patient’s absolute risk of cardiovascular disease, rather than just their LDL cholesterol concentration. A statin dose of 20 mg/day was used in the Justification for the Use of Statins in Prevention Trial Evaluating Rosuvastatin (JUPITER) trial (Ridker et al. 2008). This trial, which was terminated early (median of 1.9 years), included 17,802 men (≥50 years) and women (≥60 years) without a history of cardiovascular disease, with a normal LDL-chol level, but with elevated C-reactive protein levels of ≥2.0mg/L. Study participants were randomized to receive 20 mg/day rosuvastatin or placebo. There were significantly more strokes (any and nonfatal) (64 vs. 33 and 58 vs. 30, respectively). The associated hazard ratios were 0.52, 95% CI 0.34-0.79, p=0.002 and 0.52, 95% CI 0.33-0.80, p=0.003. Most recently, in the satin arm blood-pressure lowering arm of the Heart Outcomes Prevention Evaluation (HOPE)-3 trial, (Yusuf et al. 2016), patients at intermediate risk of cardiovascular disease (i.e., those without a history of CVD but with at least one or two risk factors, depending on age) were randomized to treatment with 10 mg/day rosuvastatin or placebo. At the end of follow-up (median of 5.6 years), the mean LDL-chol and apoprotein B-100 were significantly lower in the statin group by 26.5% and 22.0%, respectively.  The risk of the first primary outcome, which included nonfatal stroke was significantly lower in the statin group (3.7% vs. 4.8%, HR=0.76, 95% CI 0.64-0.91, p=0.02). The risk of any stroke was also significantly lower in the statin group (1.1% vs. 1.6%, HR=0.70, 95% CI 0.52-0.95). 

There has only been one large RCT evaluating statin monotherapy for secondary prevention of stroke (Amarenco et al. 2006). The Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial (SPARCL) included 4,731 patients with previous stroke or transient ischemic attack within one to six months before study entry, who had LDL levels of 2.6 to 4.9 mmol/L and had no known coronary artery disease. Participants were randomized to receive treatment with atorvastatin 80 mg once daily or placebo. The mean LDL level during the trial was 1.9 mmol/L among patients receiving atorvastatin versus 3.3 mmol/L in the placebo group. The 5-year absolute reduction in risk of any stroke was 2.2 percent; with a relative risk reduction of 16%, and adjusted hazard ratio (HR) 0.84 (95% CI 0.71–0.99; p = 0.03). Based on this data, 46 patients would need to be treated for 5 years to prevent one stroke. The authors cautioned that the reduction in ischemic stroke (HR=0.78, 95% CI 0.66–0.94) should be weighed against the increased risk of 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).  More recently, the link between statin use and increased risk of intracerebral hemorrhage has been questioned. Using results from the VISTA archive, Scheitz et al. (2016), reported no increased risk of intracerebral hemorrhage following ischemic stroke in patients who were established previously on statin therapy or in those who were newly initiated on it.

When added to background statin therapy, the use of additional agents including, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, a monoclonal antibody; ezetimbe, a cholesterol absorption inhibitor; and icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, have been shown to be effective in further reducing vascular events in persons whose cholesterol and/or triglycerides, remain high on statin monotherapy, or in those who have had a further event.  New recommendations have been made regarding the use of these agents in this update of the Canadian Stroke Best Practice Recommendations. 

In persons with established atherosclerotic cardiovascular disease, the combination of 10 mg ezetimibe and 40 mg of simvastatin was found to be superior to monotherapy with simvastatin for reduction of the risk of vascular outcomes, including stroke (Cannon et al. 2015). The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) included 18,144 patients recently hospitalized with acute coronary syndrome with elevated LDL cholesterol. The risk of the primary outcome (a composite of fatal and nonfatal cardiovascular events) over 7 years was significantly lower in the dual-therapy group (32.7% vs. 34.7%; HR=0.936, 95% CI 0.89-0.99, p=0.016). The risks of any stroke and ischemic stroke were significantly lower in the dual therapy group (HR=0.86, 95% CI 0.73-1.00, p=0.05 and HR=0.79, 95% CI 0.67-0.94, p=0.008, respectively), while the risk of hemorrhagic stroke was not reduced significantly.  The use of ezetimibe to achieve further reductions in LDL cholesterol may help to protect against recurrent cardiovascular/cerebrovascular events. The Treat Stroke to Target trial (Amarenco et al. 2020) randomized 2,860 participants who had sustained an ischemic stroke in the previous 3 months or a transient ischemic attack within the previous 15 days, who had confirmed atherosclerotic disease, to receive treatment with either a statin or a statin + ezetimibe, if required, to achieve a target LDL cholesterol level of < 1.8 mmol/L, (lower-target group) or a target range of 2.3 to 2.8 mmol/L, (higher-target group), for the duration of the trial. At the end of follow-up (mean 3.5 years), the mean LDL cholesterol was 1.7 mmol/L in the lower-target group and 2.5 mmo/L in the higher-target group. The risk of major cardiovascular events, the primary outcome, was significantly lower in the lower-target group (8.5% vs. 10.9%, HR=0.78, 95% CI 0.61 to 0.98; p=0.04).

PCSK9 inhibitors have also been shown to reduce the risk of cardiovascular events, in addition to statin therapy. 19,924 persons with elevated LDL cholesterol and a hospitalization for an acute coronary syndrome who received 75 mg alirocumab subcutaneously every 2 weeks, in addition to maximum statin therapy, for an average of 2.8 years, had a 15% reduced risk of the primary outcome (a composite of death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) compared with persons taking a statin only in the ODYSSEY OUTCOMES Trial (Schwartz et al. 2018). In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) Trial (Sabatine et al. 2017), 27,564 patients from 49 countries, with established atherosclerotic cardiovascular disease and a fasting LDL cholesterol level of ≥1.8 mmol/L, or HDL chol level of ≥2.6 mmol/L, who were already receiving ≥20 mg/day of a statin were randomized receive evolocumab (140 mg every 2 weeks or 420 mg every month, by subcutaneous injection) or placebo. At 48 weeks, the mean absolute reduction in serum LDL-cholesterol associated with evolocumab was 1.45 mmol/L. The risk of the primary outcome (a composite of cardiovascular events including stroke) was significantly lower for patients in the evolocumab group (9.8% vs. 11.3%, HR=0.85, 95% CI 0.79–0.92, p<0.001). The risk of any stroke was also significantly lower for patients receiving evolocumab (1.5% vs. 1.9%, HR=0.79, 95% CI 0.66–0.95, p<0.01). Among the subgroup of patients with previous ischemic stroke (Giugliano et al. 2020), there were significantly fewer patients in the evolocumab group who experienced a primary end point event (259 vs. 300; HR= 0.85, 95% CI 0.72–1.00, p=0.047). A recent Cochrane review (Schmidt et al. 2017) included the results of 20 RCTs examining the use of additional PCSK9 inhibitors, such as alirocumab, in persons with and without established cardiovascular disease. Compared with placebo, at maximum follow-up of 6-36 months, treatment with a PCSK-9 inhibitor was associated with a significantly reduced risk of any cardiovascular events (OR=0.86, 95% CI 0.80 to 0.92) and any stroke (OR=0.77, 95% CI 0.69 to 0.85).

Icosapent ethyl is another example of an agent that can be added to a background statin regimen to reduce cardiovascular events. In the REDUCE-IT trial (Bhatt et al. 2019), 8,179 patients with established cardiovascular disease or with diabetes and other risk factors, who had a fasting triglyceride level of 1.52 to 5.63 mmol per liter and an LDL level of 1.06 to 2.59 mmol per liter were randomized to receive two grams of icosapent ethyl twice daily or placebo. After a median of 4.9 years, the risk of the primary outcome (a composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina), was significantly lower in the icosapent ethyl group (17.2% vs. 22%; HR=0.75, 95% CI 0.68-0.83, p<0.001, NNT=21). The risk of ischemic stroke was also significantly lower in the icosapent ethyl group (2.0% vs. 3.0%, HR=0.64, 95% CI 0.49, 0.85).

Sex and Gender Considerations:
There does not appear to be a sex difference associated with increasing cholesterol levels and risk of stroke. Data from 34 studies included in a meta-analysis found that for each 1-mmol/L increase in total cholesterol the risks of any stroke were increased by 1% in women, and 3% in men (Peters et al. 2016). The pooled ratio of relative risks was 0.99 (95% CI 0.93- 1.04). The corresponding risks for ischemic stroke were increased by 16% in women, and 9% in men, with a pooled ratio of relative risks of 1.09 (95% CI 0.94-1.27). In the Cholesterol Treatment Trialists’ Collaboration study examining sex differences (Fulcher et al. 2015), which included 27 RCTs, statin therapy reduced the risk of major vascular events similarly in men and women. For each 1 mmol/L decrease in LDL cholesterol, the risk of stroke was reduced by 17% in men and 10% for women (p>0.05).


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