R3i Editorial

Stroke, predominantly ischaemic stroke, is a leading cause of mortality, morbidity and serious long-term disability. Moreover, the fact that one in four strokes occur in individuals who have previously had a stroke, highlights the need for urgent action to reduce the residual risk of recurrent events.¹

Guidelines recommend low-density lipoprotein cholesterol (LDL-C) as the primary lipid target for reducing the risk of recurrent stroke. However, mounting evidence suggests that other lipid parameters might be also predictive of cardiovascular risk and provide additional benefit. Little is so far known about the effects of non-traditional lipid factors or emerging biomarkers on recurrent stroke risk.

Previous studies have indicated that atherogenic dyslipidaemia, the combination of elevated triglycerides and low plasma concentration of high-density lipoprotein cholesterol (HDL-C) may be implicated in recurrent stroke risk. For example, in the Vitamin Intervention for Stroke Prevention study database including 3680 patients with a recent (<120 days) noncardioembolic stroke, the triglycerides/high-density lipoprotein cholesterol (HDL-C) ratio, often termed the atherogenic index, was consistently and independently associated with stroke risk, with the highest triglycerides/HDL-C ratio quintile associated with a 56% increase in recurrent stroke risk versus reference (lowest quintile).² Consistent findings were also reported for the Women's Health Initiative Observational Study in postmenopausal women.³

Recent analyses from the PERFORM (Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack) and SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trials, discussed in this month’s Landmark trial, add to this body of evidence.⁴ Atherogenic dyslipidaemia, defined as low HDL-C (?40 mg/dL or 1.01 mmol/L) and elevated triglycerides (?150 mg/dL or 1.7 mmol/L), was an important contributor to residual cardiovascular risk in patients with a prior stroke or transient ischaemic attack (TIA) who were receiving best medical therapy, including statin. In both trials, patients with this dyslipidaemic profile had a 36-40% increased risk of recurrent stroke, despite other cardiovascular risk factors including LDL-C being well controlled by best evidence-based medicine.

The question remains: how best to address this high residual risk for recurrent stroke. Clinical trials of current therapies, including fibrates and niacin, have been less than definitive. Whether novel therapies offer future potential has yet to be addressed by prospective trials specifically targeting atherogenic dyslipidaemia. Indeed, the Residual Risk Reduction Initiative echoes the call to action made by the authors of this analysis for trials in this patient population.

Finally, while much of the focus has been on lipid-related residual cardiovascular risk, a recent analysis from the Treating to New Targets Study also makes the case for consideration of non-lipid biomarkers. In patients with established coronary heart disease (CHD) at LDL-C goal, plasma levels of lipoprotein(a), neopterin, NT-proBNP, and sRAGE were all shown to be associated with the risk of recurrent major cardiovascular events. ⁵ Lipoprotein(a) has already been linked with risk for ischaemic stroke,⁶ however, with the exception of niacin, current therapies are ineffective in targeting this lipoprotein. Whether novel agents in development may provide benefit has been the subject of much interest, given that monoclonal antibody therapy targeting PCSK9 has been shown to be effective in lowering liporprotein(a) levels by 25-30%, on top of statin therapy.⁷ Clinical trials in patients with a previous stroke are clearly needed to address the paucity of evidence relating to emerging biomarkers that may contribute to residual risk for recurrent stroke in patients receiving best evidence-based medicine.

References
1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015 ;e29-322.
2. Park JH, Lee J, Ovbiagele B. Nontraditional serum lipid variables and recurrent stroke risk. Stroke 2014;45:3269-74.
3. Berger JS, McGinn AP, Howard BV et al. Lipid and lipoprotein biomarkers and the risk of ischemic stroke in postmenopausal women. Stroke 2012;43:958-66.
4. Sirimarco G, Labreuche J, Bruckert E et al; on behalf of the PERFORM and SPARCL Investigators and Committees. Atherogenic dyslipidemia and residual cardiovascular risk in statin-treated patients. Stroke 2014;45:1429-36.
5. Arsenault BJ, Barter P, DeMicco DA et al; Treating to New Targets (TNT) Investigators. Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers. PLoS One 2014;9(12):e114519.
6. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53
7. Raal FJ, Giugliano RP, Sabatine MS et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 2014;63(13):1278-88.