Residual Recurrence Risk of Ischemic Cerebrovascular Events: Elements and Implications

There has been a substantial reduction in the rate of recurrent stroke through the identification and management of risk factors including lifestyle management and achieving targets for antithrombotic medication, low-density lipoprotein cholesterol (LDL-C), blood pressure, blood sugar level, atrial fibrillation prevention, and carotid revascularization in accordance with current guideline-recommended standards of care. However, there is still an appreciable risk of stroke recurrence after ischemic cerebrovascular events. This risk is defined as residual recurrence risk of ischemic cerebrovascular events (R³ICE). R³ICE is a dynamic and evolving concept that keeps pace with updates in guideline recommendations and the up-to-date consensus in defining standards of care, and is mediated via pathways not directly addressed by current management algorithms. For atherosclerotic cardiovascular diseases (ASCVDs), a number of new pharmacological agents that conceptually target distinct pathophysiological targets have been demonstrated to reduce the residual cardiovascular risk in patients with guideline-recommended medical care. It is fundamental to explore non-traditional risk factors and new directions that may be helpful in preventing subsequent events for patients with ischemic cerebrovascular events.

Residual Risk of Traditional Risk Factors

Residual Lipoprotein Risk

As the most-studied lipid, LDL-C is the primary target for stroke. Additional benefits of lowering LDL-C levels beyond the recommended goals, such as 1.4 mmol/L or even 0.78 mmol/L, have been demonstrated, suggesting that it is an important determinant of residual risk [1, 2]. However, this also brings the target level of LDL-C into question. Furthermore, despite reduction of the LDL-C level, recurrent vascular events still occur. Other lipid components, such as the cholesterol content within triglyceride-rich lipoproteins and triglycerides might be important contributors of residual recurrence risk [3], in addition to lipoprotein a [Lp(a)].

Lp(a) may promote thrombosis, atheroma progression, and pro-inflammatory responses through its oxidized phospholipid content [4, 5]. Elevated Lp(a) levels are associated with recurrent vascular events in treated patients at high risk of cardiovascular disease, suggesting its role in residual risk [5]. Antisense oligonucleotides have been shown to induce substantial reductions (70%–90%) in circulating Lp(a) levels [6]. Whether targeting these lipid components provides additional benefit in reducing the residual risk needs further research (Table 1).

Table 1.

The component and potential approach for recurrence risk of ischemic cerebrovascular events (R³ICE).

Component of R3ICE	Potential approach
Residual lipoprotein risk	Further lowering low-density lipoprotein cholesterol or other targets, such as Lp(a)
Residual thrombotic risk	Dual antiplatelet therapy; anticoagulation
Residual inflammatory risk	Anti-inflammatory therapy targeting the IL-1β–IL-6–hsCRP axis
Residual intracranial stenosis (ICAS) risk	Endovascular treatment in selected patients with symptomatic ICAS
Residual genetic risk	–
Residual risk of undetermined mechanisms	Multi-omics analyses for finding new potential therapy targets

Residual Thrombotic Risk

Dual Antiplatelet Therapy

In the CHANCE trial, combining clopidogrel with aspirin has been shown to be effective for minor ischemic stroke or transient ischemic attack [7]. The THELAS trial showed that the addition of ticagrelor to aspirin was also superior to aspirin alone in reducing the residual risk of recurrent stroke [8].

The pharmacomics of anti-platelets, particularly clopidogrel, may account for variations in residual thrombotic risks. CYP2C19 plays an essential role in the metabolism of clopidogrel; the risk of recurrent stroke is increased in the carriers of loss-of-function alleles of CYP2C19 [9]. In addition, some protein biomarkers associated with diabetes (glycated albumin) [10], hyperhomocysteinemia (homocysteine) [11], and inflammation (highly-sensitive C-reactive protein, hsCRP) [12] have been found to influence patients’ response to clopidogrel.

Anticoagulation

The COMPASS study has demonstrated that adding rivaroxaban to aspirin is effective in reducing the rate of stroke [13]. In the ATLAS ACS 2-TIMI 51 study, the benefit of adding low-dose rivaroxaban to antiplatelet therapy has been shown to reduce the risk of subsequent cardiovascular disease [14]. In addition, pharmacomics and genomics are important considerations when prescribing anticoagulation agents. Pharmacogenetic testing of VKORC1 and CYP2C9 for warfarin has been approved by the FDA. And a genome-wide association analysis revealed that carriers of the CES1 rs2244613 show lower active metabolite levels of dabigatran [15].

Residual Risk of Non-traditional Risk Factors

Residual Inflammatory Risk

Inflammation has been considered as a likely mediator of ASCVDs. An early clinical trial demonstrated the efficacy of targeting residual inflammatory risk in the primary prevention of cardiovascular disease [16]. The CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) trial confirmed the inflammation hypothesis in 2017. It showed that treatment with selective inhibitor of interleukin (IL)-1β results in a reduction in major adverse cardiovascular events in patients with established ASCVDs and elevated hsCRP [17]. A recent study of LoDoCo2 showed that targeting upstream of IL-1β, colchicine reduces vascular events in coronary disease patients receiving secondary prevention therapies [18].

Taken together, IL-1β–IL-6–hsCRP axis might be a critical pathway in atheroprotection. Inflammation might be considered as a driver of residual risk in patients with events despite optimal LDL-C levels and other traditional risk factors. However, it is still unknown whether blocking IL-1β or targeting residual inflammatory risk would be effective in patients with ischemic stroke. The randomized controlled trial CONVINCE is currently enrolling patients with stroke to evaluate the effect of a daily low dose of colchicine in diminishing recurrent stroke, which may shed light on this mechanism.

Residual Intracranial Stenosis (ICAS) Risk

The reduction of residual ICAS risk depends on the implementation of individualized treatment. The WEAVE registry (Wingspan Stent System Post Market Surveillance) [19] reported relatively low rates of complications (2.6%) with endovascular treatment in selected patients with symptomatic ICAS, which may be partially related to the rigorous selection criteria of symptomatic ICAS lesions of 70%–99% and to have experienced two strokes. The results of another registry that enrolled symptomatic ICAS patients with poor collaterals and hypoperfusion showed that the 30-day recurrence of stroke, transient ischemic attack, and death was 4.3% [20].

Residual Genetic Risk

Advances in sequencing technology facilitate the identification and diagnosis of Mendelian stroke, which requires care beyond standard stroke care, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and hypertension with brachydactyly caused by PDE3A mutation. Genetics can also successfully establish the causality of risk factors for stroke recurrence by Mendelian randomization.

Residual Risk of Undetermined Mechanisms

Omics Analyses

Blood biomarkers have been shown to be useful in predicting the prognosis of stroke [21]. Advances in technology have enabled the application of high-throughput techniques, including genomics, transcriptomics, epigenomics, proteomics, and metabolomics, to generate extensive candidate molecules at the same time for evaluation as novel drug targets.

Various genome-wide association studies (GWASs) have identified loci associated with ischemic stroke and its subtype. A meta-analysis of GWAS datasets verified previous associations for cardioembolic stroke near PITX2 and ZFHX3, and for large-vessel stroke at a 9p21 locus and HDAC9 [22]. The EuroCLOT study further showed that the ABO gene variants of rs505922 were associated with large-vessel and cardioembolic stroke but not small-vessel disease [23]. Furthermore, several risk loci identified in MEGASTROKE [24] were integrated into previously suspected biological pathways for stroke; however, 11 loci (ANK2, CDK6, KCNK3, LINC01492, LRCH1, NKX2-5, PDE3A, PRPF8, RGS7, TM4SF4-TM4SF1, and WNT2B) showed no relationship with known pathways, pointing to mechanisms not previously implicated in stroke pathophysiology [24, 25]. However, most of the existing studies were conducted on case-control studies and focused on the risk of stroke, while genetic factors underlying the residual recurrence risk of stroke were less studied. The whole-genome sequencing data together with stroke outcomes and imaging data of CNSR-III could provide an opportunity to elucidate the genetic mechanisms of the residual recurrence risk of stroke [26]. Recent studies have shown that differential methylation patterns in PPM1A are associated with recurrence of vascular events in patients with stroke and treated with aspirin [27]. Innovative proteomic approaches have also enabled us to improve our understanding of cerebrovascular pathologies and increase its applicability to clinical stroke care. A recent small-sample study using mass spectroscopy-based proteomics identified platelet basic protein as a candidate biomarker of ischemic stroke [28]. Metabolite entities are small enough to cross the blood-brain barrier and are more stable than RNA or DNA. Metabolomics science may thus serve as a reservoir of biomarker discovery. Recent studies have found improvement of the predictive power of the ABCD2 score after integrated plasma metabolic profiles. Furthermore, another study showed that linoleic acid levels are correlated with the risk of ischemic stroke, and this might be useful for dietary recommendations [29, 30].

Implications and Perspectives

Lowering the residual risk of stroke recurrence calls for comprehensive measures including improving the quality of care and patient compliance, which can be done clinically but is not done well, determining the best targets of metabolic risk, facilitating the translation of research to clinical practice for eliminating the residual inflammatory, thrombotic, and intravascular stenosis risk, which might be potential approaches, and persistent exploration of new targets for prevention. For the latter, multiple omics analysis might be a useful tool, integrating data to better understand the relationship between different omics levels as well as their combined influence on pathophysiological processes, unlike the single layer of ‘omics’ only providing limited value into the biological mechanisms of stroke.

Factors contributing to the risk of recurrence beyond the scope of this review such as socioeconomic status and mental health are also important drivers of ischemic stroke, calling for interventions with rigor similar to those targeting biological pathways. Further research on these risk factors is needed to improve outcomes for patients as we reach the limits of current treatment paradigms.

Conflict of interest

The authors declare that they have no conflict of interest.