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Efficacy and Safety of Very Low Achieved LDL Cholesterol in Patients With Previous Ischemic Stroke
Victorien Monguillon1, Peter Kelly2,3,4, Michelle L O'Donoghue1
1Thrombolysis in Myocardial Infarction Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (V.M., M.L.O., J.-G.P., E.A.B., M.S.S., R.P.G.).
Insights
Lowering low-density lipoprotein cholesterol (LDL-C) to below 40 mg/dL in patients with prior ischemic stroke significantly reduces the risk of major adverse cardiovascular events and recurrent stroke. Intensive LDL-C reduction appears safe and effective for secondary stroke prevention.
Area of Science:
- Cardiovascular Medicine
- Neurology
- Clinical Trials
Background:
- Patients with a history of ischemic stroke face a high risk of recurrent stroke and major adverse cardiovascular events (MACE).
- The optimal target for low-density lipoprotein cholesterol (LDL-C) levels in this high-risk population remains uncertain.
Purpose of the Study:
- To investigate the long-term relationship between achieved LDL-C levels and the incidence of MACE and stroke-related events in patients with prior ischemic stroke.
- To evaluate the safety and efficacy of intensive LDL-C lowering in secondary stroke prevention.
Main Methods:
- Analysis of 5,291 patients with prior ischemic stroke from the randomized FOURIER trial and its open-label extension (FOURIER-OLE).
- Assessment of achieved LDL-C levels (<20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL) and their correlation with primary composite endpoint and stroke outcomes.
- Long-term follow-up (median 7.2 years) to determine incidence rates and risk ratios.
Main Results:
- Lower achieved LDL-C levels demonstrated a monotonic decrease in the incidence of the primary endpoint, all strokes, and ischemic strokes (Ptrend <0.001 to 0.002).
- Patients achieving LDL-C <40 mg/dL showed reduced incidence rate ratios for the primary endpoint (0.69), all stroke (0.73), and ischemic stroke (0.75) compared to those with LDL-C ≥70 mg/dL.
- Hemorrhagic strokes were infrequent and showed no association with achieved LDL-C levels (Ptrend=0.85).
Conclusions:
- Achieving LDL-C levels below 40 mg/dL in patients with prior ischemic stroke is associated with a lower risk of MACE, including recurrent stroke.
- Intensive LDL-C lowering appears to be a safe strategy, as evidenced by the lack of increased risk for hemorrhagic stroke.
- These findings support the consideration of more aggressive LDL-C reduction targets for secondary stroke prevention.
Background:
Patients with previous ischemic stroke are at high risk for recurrent stroke and other major adverse cardiovascular events. The benefits of achieving very low levels of low-density lipoprotein cholesterol (LDL-C) in such patients is unclear.
Methods:
We analyzed patients with previous ischemic stroke enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), a randomized placebo-controlled trial studying evolocumab in patients with stable atherosclerotic cardiovascular disease (median follow-up, 2.2 years), and through the open-label extension (FOURIER-OLE) period (additional median follow-up, 5 years), to examine the relationship between achieved LDL-C and the long-term incidence of the primary end point (cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization) and stroke-related end points.
Results:
The analysis included 5291 patients with previous ischemic stroke (>4 weeks). Of these, 666 (12.6%), 1410 (26.6%), 586 (11.1%), 508 (9.6%), and 2121 (40.1%) patients achieved LDL-C values of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. The incidence of the primary end point, all stroke, and ischemic stroke each decreased in a monotonic fashion with lower achieved LDL-C levels on a continuous scale (Ptrend<0.001, 0.002, and 0.002, respectively). Compared with patients with LDL-C ≥70 mg/dL, those who achieved levels <40 mg/dL had incidence rate ratios of 0.69 (95% CI, 0.57-0.84), 0.73 (95% CI, 0.53-0.99), and 0.75 (95% CI, 0.54-1.05) for the outcomes of the primary end point, all stroke, and ischemic stroke, respectively. Hemorrhagic strokes were infrequent and unrelated to achieved LDL-C (Ptrend=0.85).
Conclusions:
In patients with previous ischemic stroke, it appeared that the lower the LDL-C, down to levels <40 mg/dL, the lower the risk of major adverse cardiovascular events, including recurrent stroke, without a clear increase in risk of hemorrhagic stroke. These findings support the concept that more intensive LDL-C lowering in patients with previous ischemic stroke may be warranted.
Registration:
URL: https://www.clinicaltrials.gov; Unique identifier: NCT01764633/NCT01764633.
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