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. Guidelines differ with respect to their global approach to treatment, with some suggesting a treat to target approach (e.g. 2016 Canadian Cardiovascular Society Guidelines), a lifetime risk, or lowest is best approach, while others make no recommendations for or against specific LDL-C or non–HDL-C targets for either primary or secondary prevention of atherosclerotic cardiovascular disease (ASCVD), while recommending that high-intensity statin therapy should be used in persons with ASCVD or significant elevations in LDL-C (e.g. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Risk in Adults).
Evidence from several systematic reviews have demonstrated a significant reduction in overall risk of ischemic stroke associated with lipid-lowering therapies. Patients with a history of stroke or transient ischemic attack, or who have a markedly higher baseline risk of recurrent cerebrovascular events, may experience greater benefit. 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 significant reduction in the 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). In a more recent CTT publication that included the results from 27 RCTs, the benefits of therapy between men and women were compared. Overall, statins reduced the risk of major vascular events by 21% per each 1.0 mmol/L reduction in LDL-chol (RR=0.79, 95% CI 0.77-0.81, p<0.0001), with no significant interaction reported for sex. Similarly, for the outcome of stroke, the risk was significantly reduced with statin therapy (RR=0.85, 95% CI 0.80-0.89, p<0.00001), with no significant differences by sex. In another CTT analysis (Mihaylova et al. 2012) patients were classified into one of 5 groups, based on 5-year risk of major vascular events from <5% to ≥30%. There was a significant reduction in the risk of major vascular events in all risk groups in patients with and without a previous history of vascular disease. For the outcome of stroke, except for the lowest risk group, lipid-lowering treatment was associated with a significantly reduced risk of stroke. Other meta-analyses have also demonstrated a reduction in stroke risk associated with statin therapy. 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 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 apoproteinB-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). 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 cardiovascular 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.
Higher doses of statins have been associated with greater protection. In the Treating to New Targets (TNT) Trial, 10,001 participants, with clinically evident coronary heart disease 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 one large RCT evaluating statin therapy 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 TIA 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). Post hoc analysis in the SPARCL trial found the following characteristics to be independent predictors to 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.) (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).
Evolocumab is an example of a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin Type 9 (PCSK9), and reduces low-density lipoprotein (LDL) C. While no recommendations have been made regarding the addition of specific agents to standard statin treatment in this update of the Canadian Best Practice Recommendations, the results from a recent large RCT suggests its potential clinical application. 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 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). 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).