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25 September 2011

After SPARCL: Targeting cardio-cerebrovascular metabolic risk and thrombosis to reduce residual risk of stroke

Prof. Pierre AMARENCO

University Paris -VII Paris, France
Prof. Pierre AMARENCO SPARCL (1) was a trial performed in patients with non-cardioembolic TIA and stroke to assess the efficacy and safety of atorvastatin 80 mg per day versus placebo, with a 5-year follow-up. In the atorvastatin group, the reduction in LDL cholesterol was very substantial, more than 53% from baseline, and, the risk of recurrent stroke was significantly reduced by 16% at 5 years. In addition, the risk of major coronary events was reduced by 35%. This trial represents a landmark study, since it was the first demonstration that targeting LDL cholesterol with a statin resulted in a reduction of cerebrovascular events. The American, European, Asian-Pacific guidelines were updated to take into account the findings of SPARCL. It is now acknowledged that after following stroke or TIA, patients may benefit of being treated with a statin to intensively decrease LDL cholesterol.

However, despite the efficacy of high-dose statin therapy, a residual risk of stroke persists in patients who experienced a first stroke or TIA. In SPARCL, this risk was at least 12% in patients receiving atorvastatin 80 mg per day. It is clear that this residual risk must now be addressed.

One approach to reduce this residual risk might be to define target LDL cholesterol levels lower than those reached in SPARCL, i.e. 71 mg/dL on average. The Treat Stroke to Target trial currently ongoing in France compares the outcome of bringing down LDL cholesterol levels of <70 mg/dL versus 100 mg/dL. All commercially available statins may be used, plus or minus ezetimibe if needed, to reach the LDL cholesterol target. It is possible that in the future, it will be demonstrated that reaching even lower LDL cholesterol levels is beneficial. Noteworthy, PCSK9 inhibitors, which enhance the efficacy of statins through action on the LDL receptor, are currently under investigation.

We have shown in SPARCL that reducing LDL cholesterol to very low levels was not associated with hemorrhagic stroke. The slight increase in hemorrhagic stroke observed in SPARCL was not due to reduction of LDL cholesterol but to small-vessel disease and uncontrolled hypertension. This is important for the selection of patients for future trials. Trials exploring the effects of LDL cholesterol reduction should target patients with atherosclerotic disease, not those with small-vessel disease.

Another possibility is to use HDL-raising or triglyceride-lowering agents. In the VA-HIT trial, lowering triglycerides using gemfibrozil without lowering LDL cholesterol or raising HDL cholesterol resulted in a reduction of the primary endpoint and a reduction of stroke (2). The systematic review of all trials in which triglyceride levels were reduced confirmed an association with stroke reduction (3).

Since low HDL cholesterol is strongly associated with increased risk of neurovascular events, HDL-raising agents could also be used to reduce residual risk in patients with TIA or stroke. This was observed in the SPARCL trial and in a systematic review of all niacin trials in which HDL cholesterol was increased, showing a reduction of progression of carotid atherosclerosis and stroke events (4) .
Therefore, raising HDL cholesterol might reduce residual risk in patients with TIA and stroke.

Finally, atherogenic dyslipidemia (combining low HDL cholesterol and elevated triglycerides levels) is a strong predictor of recurrent stroke. It could prove a relevant target to reduce the residual risk of recurrent stroke using agents that increase HDL cholesterol and decrease triglycerides.

Besides the cardio-cerebrovascular metabolic risk, platelet aggregation and thrombosis in general is another potential target. In the PLATO trial, the P2Y-12 inhibitor ticagrelor was shown to be more effective than clopidogrel in patients with acute coronary syndromes (5). It could be worth to prospectively assess the efficacy of ticagrelor in acute cerebrovascular syndrome or in secondary prevention after the acute phase.

New anticoagulants are also in development. Oral antithrombin or factor Xa inhibitors are more effective than vitamin K antagonists to prevent stroke in patients with atrial fibrillation. It would be interesting to demonstrate whether using these agents in a SPARCL-like population could be more effective than aspirin and clopidogrel, thus providing another means to address the residual risk of residual risk of stroke.

The real unmet needs in the field of stroke prevention are related to cardio-cerebrovascular metabolic risk and thrombosis. Elevated blood pressure is a key risk factor for stroke, and it is well established that the lower the blood pressure, the lower the risk of stroke.

In summary, we can reasonably hope that residual risk of recurrent stroke will be effectively addressed in the future. However, this hope will be fulfilled only if high-quality outcome clinical trials show a reduction of residual risk of recurrent stroke in patients otherwise treated according to current standards of care.

1. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. N Engl J Med 2006;355:549-59.
2. Bloomfield Rubins H, Davenport J, Babikian V, et al; VA-HIT Study Group. Circulation. 2001 Jun 12;103(23):2828-33.
3. Labreuche J, Deplanque D, Touboul PJ, Bruckert E, Amarenco P. Atherosclerosis. 2010 Sep;212(1):9-15.
4. Bruckert E, Labreuche J, Amarenco P. Atherosclerosis. 2010 Jun;210(2):353-61. Epub 2009 Dec 21.
5. James SK, Roe MT, Cannon CP, et al; PLATO Study Group. BMJ. 2011 Jun 17;342:d3527. doi: 10.1136/bmj.d3527.