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Lipid Management

5th Edition
2014 UPDATE
December 2014

The Canadian Stroke Best Practice Recommendations for the Secondary Prevention of Stroke, 5th Edition 2014 module is published in the International Journal of Stroke (IJS) (Online Open‑Access available December 2014; Printed Journal scheduled for April 2015).

To access the specific recommendations for Lipid Management and all other sections of the Secondary Prevention of Stroke module, please click on this URL which will take you to the recommendations online in the IJS:  http://onlinelibrary.wiley.com/doi/10.1111/ijs.12439/full. For the French version of these recommendations, open the appendix at this link : http://onlinelibrary.wiley.com/store/10.1111/ijs.12439/asset/supinfo/ijs12439-sup-0001-si.pdf?v=1&s=b0ed4fff1d7fc435cf4e2a83ccbcbffbdad767de.

All other supporting information, including performance measures, implementation resources, evidence summaries and references, remain available through www.strokebestpractices.ca, and not through the IJS.  Please click on the appropriate sections below for this additional content.

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.

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 on dyslipidemia diagnosis and management for healthcare providers across the continuum of care.
  • Continued alignment with recommendations and guidelines developed by the Canadian Cardiovascular Society Dyslipidemia group.
  • Improved access to pharmaceuticals through private and public drug coverage plans.
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 physician.

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.
Implementation Resources and Knowledge Transfer Tools

Health Care Provider Information

Patient Information

Summary of the Evidence, Evidence Tables and References

Lipid Management Evidence Tables and Reference List

The causal relationship between dyslipidemia and the development of atherosclerosis is well documented; therefore, appropriate management is important for both primary and secondary prevention of stroke. The most recent update (2012) of the Canadian dyslipidemia guidelines provide a detailed description of the current recommended treatment levels and management modalities for dyslipidemia, which emphasize the 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 confirmed that the risk of ischemic stroke is reduced, with little effect on hemorrhagic stroke and the reduction in risk is constant irrespective of the baseline risk of stroke, suggesting that patients with a history of stroke or transient ischemic attack, who have a markedly higher baseline risk of recurrent cerebrovascular events, may experience greater benefit. A recent review by Manktelow & Potter (2013) included 8 RCTs (n=10,000) of adults with a history of stroke or TIA. Statin therapy, evaluated in 5 of the trials was associated with a 12% reduction in the risk of recurrent stroke (OR= 0.88, 95% CI 0.77-1.00, p=0.05). Based on the results from 2 trials (SPARCL & HPS) statin therapy was associated with a reduction in the risk of ischemic stroke, but an increase in the risk of hemorrhagic stroke (OR= 0.78, 95% CI 0.67- 0.92, p=0.002 and OR= 1.72, 95% CI 1.20- 2.46, p=0.0033, respectively). The Cholesterol Treatment Trialists (Baigent et al. 2010) included 26 RCTS in which the treatment aim was solely the reduction of LDL cholesterol. Overall, a 1 mmol/L reduction in LDL-chol was associated with a significantly decreased risk of any major vascular event (RR=0.78, 95% CI 0.76-0.80, p<0.0001), but was not associated with reductions in stroke mortality (RR=0.96, 95% CI 0.84-1.09). O’Regan et al. (2008) evaluated statin therapy for all stroke prevention, using the results from 42 trials (n = 121 285). The risk of all-cause mortality associated with statin treatment was significantly reduced (RR=0.88, 95% CI 0.83-0.93) as was the risk of all strokes (RR=0.84, 95% CI 0.79-0.91). In meta-regression, LDL-chol was the only predictor of effect size, whereby each unit increase in serum cholesterol was associated with a 0.3% increase in mortality risk (RR=1.003, 95% CI 1.005-1.006, p=0.02). Statin treatment was associated with a reduction in cardiovascular death and ischemic stroke, but not hemorrhagic or fatal stroke.

The results of primary preventions trial including participants with cerebrovascular risk factors have demonstrated the effectiveness of statin therapy. The Heart Protection Study (2004) 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. Higher doses of statins have been associated with greater protection. In the Treating to New Targets (TNT) Trial, 10,001 participants, with clinically evident CHD and LDL-chol of <3.4 mmol/L were randomized to receive 80 vs. 10 mg/day of atorvastatin for approximately 5 years. LDL chol levels were reduced from 2.6 to 2.0 mmol/L (80 mg group), but were unchanged in the 10 mg group. Fewer persons in the 80 mg group experienced a fatal/non-fatal stroke or TIA (HR=0.77, 95% CI 0.64-0.93, p=0.007). In the Study of the Effectiveness of additional Reductions in Cholesterol & Homocysteine (SEARCH) Collaborative Group Study (Armitage et al. 2010), participants were randomized to receive 20 vs. 80 mg simvastatin for almost 7 years. The reduction in the risk of stroke associated with 80 mg simvastatin was significantly lower for the outcome of any stroke (RR=0.91, 95% CI 0.77-1.08, p=0.03), although cases of definite myopathy were higher.

There has only been a single large RCT evaluating statin therapy for secondary prevention of stroke. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial (SPARCL 2006) randomly assigned 4731 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 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 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%, and adjusted hazard ratio (HR) 0.84 (95% CI 0.71–0.99; p = 0.03). On the basis of 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). In posthoc analysis of the SPARCL trial, examining the issue of increased risk of hemorrhagic stroke, atorvastatin treatment, history of hemorrhage stroke, male gender, increased age, and Stage II hypertension (SBP > 160 mmHg or DBP > 100 mmHg.) were all found to be significant independent predictors (Goldstein et al. 2008). A small retrospective study including 215 persons aged 15 to 49 years with first-ever ischemic stroke of unknown etiology explored the relationship between subsequent stroke and statin use (Putaala et al. 2011). Compared with patients who had been continuous users of statins, after a mean of 9 years follow-up, statin therapy (continuous and non-continuous) was associated with a significant reduction in the occurrence of stroke, myocardial infarction and other vascular events(HR=0.23, 95% CI 0.08-0.66, p=0.006).