Advances in primordial, primary, and secondary prevention of stroke in diverse Populations

Introduction

Prevention is one of the four cardinal pillars of the stroke quadrangle¹ (comprising surveillance, prevention, acute care, and rehabilitation) in diverse populations. ‘Diverse populations’ is used in this paper to capture the spectrum of geographic, racial and socio-economic categories within countries and regions which influence differences in stroke risk, stroke care and stroke outcomes (Figure 1). In this centennial edition of the Stroke journal, we systematically reviewed the literature on advances in stroke prevention over the last decade and provide a synopsis highlighting the new interventions targeting risk factors for primordial, primary, and secondary prevention. Where relevant, we briefly highlight how these new insights and interventions may be applied in Low-and –Middle Income countries (LMICs).

Figure 1. General outline of primordial, primary and secondary stroke prevention³.

Primordial prevention focuses on populations without established modifiable stroke risk factors. Primary prevention focuses on populations with stroke risk factors including the Political, Legal, Anthropological, Socio-educational, Economic, and Environmental (PLEASE) factors that influence stroke risk over the life course. Secondary prevention focuses on behavioral risk factors for stroke. Intermediate risk factors are the modifiable risk factors which predispose to inflammation, atherosclerosis and adverse cardiovascular end-points.

Methods (See supplementary section Table S1–S3, Figure S1)

Primordial prevention

Primordial prevention describes interventions aimed at averting the emergence of stroke risk factors.^2,3 Health disparities and inequities in the social and commercial determinants of health have emerged as challenges to optimal primordial stroke prevention across diverse populations.^1,4,5 The political, legal, ethical, anthropological, social, and economic (PLEASE) conditions of societies are fundamental modifiable primordial factors for stroke and cardiovascular diseases¹. Population-based approaches with the goal of modifying cardiovascular disease (CVD) risk over the life course have been tried with some success in different settings (Supplementary Table S2).

Primary prevention

Landmark prospective studies such as the INTERSTROKE study⁶ have highlighted the major modifiable risk factors for stroke namely hypertension, dyslipidemia, current smoking, waist-to-hip ratio, poor diets, physical inactivity, diabetes mellitus, alcohol intake, psychosocial stress depression, and cardiac disease. A mix of high- risk and population-based approaches to reduce population stroke risk is now recommended⁷.

Risk Stratification

Risk scores⁸ assessing lifetime or 10-year stroke risk are now available. Many e-health risk assessment tools for primary prevention using motivational strategy have also been developed⁹, though data about their impact on population stroke risk is lacking. The Afrocentric stroke risk score ¹⁰ developed from the SIREN study¹¹ into an educational intervention¹² has shown positive efficacy signals as a strategy for primary stroke prevention. Genomic risk scores¹³ have also been developed. Risk scores ¹⁴ for stroke secondary prevention have recently been developed in specific population clusters.

Dietary Risks and Folic Acid

The Mediterranean diet has been shown to reduce cardiovascular outcomes (CVOs)¹⁵. From the SIREN study¹¹, daily consumption of green leafy vegetables was found to be protective against stroke occurrence¹⁶, severity ¹⁷and fatality¹⁸; and hypertension occurrence¹⁶ among Africans. A meta-analysis of individual studies¹⁸ on green leafy vegetable consumption and cardiovascular diseases found that higher green leafy vegetable consumption is associated with a modestly lower incidence of stroke and CVD, highlighting its potential as a primary prevention strategy for CVD and stroke. It is possible that the positive effects of green leafy vegetable consumption on stroke prevention may be due to their high folic acid content and its effects on hyper-homocysteinemia¹⁹. A randomized controlled trial (RCT) on folic acid supplementation in a predominantly Chinese population showed the efficacy of folic acid in addition to enalapril in reducing stroke risk when used as a primary prevention strategy²⁰ which provides some corroborative evidence to the SIREN study. Dietary approaches such as green leafy vegetable consumption may potentially be a low-cost strategy for population stroke risk reduction.

Obesity

The association between obesity and adverse vascular outcomes is well known²¹. Glucagon-Like Peptide 1 (GLP1) receptor agonists, liraglutide and semaglutide, are now used for weight management in obesity with or without diabetes due to the findings of RCTs such as the SCALE trial²². Tirzepatide and dulaglutide have also shown positive efficacy signals^23,24. Meta-analysis of nonrandomized studies²⁵ has demonstrated the efficacy of Bariatric surgery for reducing weight and preventing type 2 diabetes mellitus (T2DM) although randomized CVO trials are lacking.

Lifestyle Interventions

A review of the impact of lifestyle interventions suggests that weight-loss interventions for overweight and obese adults with T2DM can improve HbA1c profiles, improve weight status, and reduce the incidence of T2DM²⁶. Evidence on intensive lifestyle interventions and support for reducing stroke risk in large populations however appears mixed. The LOOK AHEAD trial²⁷- the longest and largest RCT evaluating the impact of lifestyle intervention in weight management in T2DM on CVO trials yielded neutral findings.

Smoking and Alcohol Use

Stopping smoking is the most cost-effective intervention in vascular risk prevention²⁸. Behavioral interventions and pharmacotherapy for smoking are effective at improving quit rates²⁹. Behavioral interventions are also effective in alcohol cessation treatments either alone or in addition to drug treatments³⁰.

Hypertension

The SPRINT trial³¹ showed the efficacy of intensive hypertension treatment in reducing the risk of first-ever stroke and other CVOs. This finding was further supported by results of the STEP trial in a predominantly elderly Chinese population³². The mineralocorticoid receptor antagonist, spironolactone, also improves blood pressure control in treatment-resistant hypertension³³ although with unclear CVO effects.

Diabetes mellitus

Results from RCTs such as the SUSTAIN-6 trials³⁴ suggest that GLP-1 agonists in particular may be beneficial for reducing CVOs in patients with established cardiovascular disease(CVD) or those with high CVD risk). The SUSTAIN-6 trial³⁴ showed that among T2DM patients at high risk for cardiovascular events, subcutaneous semaglutide once weekly, compared with placebo, reduced the rate of nonfatal stroke (HR, 0.61; 95% CI, 0.38 to 0.99). In tandem with this finding, the REWIND trial³⁵ also showed that among T2DM patients with either previous cardiovascular disease or cardiovascular risk factors, subcutaneous dulaglutide once weekly, compared with placebo, reduced the rate of ischemic stroke (HR, 0.75; 95% CI, 0.59 to 0.94) and similar effects for dulaglutide on stroke were observed in people with or without a history of stroke or transient ischemic attack. A recent network meta-analysis also confirmed these beneficial effects on stroke risk with injectable semaglutide and dulaglutide³⁶. Many guidelines now recommend GLP 1 receptor agonists such as semaglutide or dulaglutide in T2DM patients at high cardiovascular disease (CVD) risk as add on to metformin-based therapy^37,38.

Dyslipidemia

RCTs³⁹ have demonstrated the efficacy of treatment intensification of low density lipoprotein cholesterol (LDL-C) levels using high intensity statins alone or in combination with ezetimibe, bempedoic acid, proprotein convertase subtilysin/kexin type 9 (PCSK9) inhibitors in reducing stroke risk, predominantly as secondary prevention strategy, in patients with high CVD risk or with established CVD.

Obstructive Sleep Apnea (OSA)

Continuous positive airway pressure (CPAP) has been a major therapy of OSA for many years although benefits on CVOs appear to be neutral⁴⁰. Liraglutide a GLP1 agonist was shown in the SCALE Sleep Apnea trial⁴¹ to be effective in weight management and improving OSA symptoms and may be a complementary strategy to treat OSA.

Sickle Cell Disease

Transcranial Doppler ultrasound is now recommended as a screening strategy for primary stroke prevention in children with sickle cell disease⁴² with regular blood transfusion as a primary and secondary stroke prevention strategy. Hydroxyurea at maximum tolerated dose is recommended as the primary stroke prevention strategy in LMICs where transfusions may be too costly⁴². A recent phase III RCT from Nigeria found that low-dose hydroxyurea may be an effective secondary stroke prevention strategy ⁴³.

Polypill Approach

The POLYIRAN⁴⁴ trial showed the safety and efficacy of a polypill combination, usually consisting of a lipid-lowering agent (statin), antihypertensive drugs and antiplatelet medications such as aspirin, in reducing the risk of stroke and other vascular events, further confirming the benefit of the polypill approach observed in other trials such as the HOPE3⁴⁵ trial. A meta-analysis found that the polypill was associated with better CVOs and improved adherence when used either as primary or secondary prevention⁴⁶. Positive results of the International Polycap Study 3(TIPS3)⁴⁷ trial further validate the polypill primary prevention approach. The recent SECURE study results showed that a polypill combination improves CVOs including strokes in people with previous myocardial infarction,⁴⁸ supporting the polypill as a valid secondary prevention strategy. The polypill strategy is particularly attractive for LMICs as a primary or secondary stroke prevention strategy, where the costs of polypharmacy are substantial and adherence is a challenge. According to the European Society for Hypertension⁴⁹, the polypill strategy may be suitable for patients not adherent to one or more components of best medical therapy or who have predictors of poor adherence, patients who are well controlled on different drug combinations, and patients with multiple co-morbidities with a high pill burden.

Secondary prevention

Novel and repurposed molecules

Studies such as the LoDoCo2 trial⁵⁰ demonstrated the efficacy of low- dose colchicine (0.5mg daily) in reducing stroke risk in populations with established CVD. However, a recent trial of colchicine in Chinese patients with ischemic stroke or transient ischemic attack (TIA) was neutral⁵¹ The results of the REDUCE-IT⁵² trials showed that high dose (4g/day) purified Icosa-Pent-Ethyl reduces the risk of stroke and other CVOs. Icosa-Pent-Ethyl, a highly purified, stable ester of eicosapentaenoic acid is also attractive for primary prevention of stroke because of its effect on lowering elevated triglyceride levels in addition to other pleiotropic effects⁵³.

The IL-1β monoclonal antibody Canakinumab, was shown in the CANTOS trial⁵⁴ to reduce the rate of stroke and other CVOs in high-risk post-myocardial infarction patients although risk of serious infections was also high in the intervention arm of the study.

Antiplatelet and Anticoagulation Therapy

Dual antiplatelet treatment (combinations of aspirin with clopidogrel, cilostazol, or ticagrelor) as secondary prevention in mild acute ischemic strokes or high-risk TIA is effective from the results of studies such as the CHANCE trial ⁵⁵. It is recommended to use a dual antiplatelet strategy for up to 21–30 days of such mild acute ischemic stroke as longer treatment durations may increase bleeding risks⁵⁶. The COMPASS trial⁵⁷ results showed that rivaroxaban plus aspirin was associated with fewer adverse cardiovascular events, but had a higher bleeding risk than aspirin alone.

Patent Foramen Ovale (PFO)

PFOs are present in about 25% of the general adult population but their prevalence in people with cryptogenic stroke is about 40%⁵⁸ suggesting a possible role of PFOs in cryptogenic strokes, likely through paradoxical embolism. Results from studies such as the DEFENSE-PFO trial⁵⁹ have demonstrated the efficacy of PFO closure in preventing recurrent strokes. PFO closure may be more beneficial in PFOs with atrial septal aneurysm or large shunts⁶⁰. PFO closure is usually now offered to selected patients 18–60 years of age who have had a cryptogenic stroke and where a PFO is suspected to be causally linked. Atrial fibrillation (AF) has been reported as the major peri-procedural complication⁶¹. However, recent data from a large Danish nationwide cohort study⁶² comparing the long term risk of AF in a PFO closure group, a PFO non-closure group and a general population comparison cohort suggest that the risk of AF after PFO closure may not be substantial in the long-term.

Carotid stenosis

Trans-carotid artery revascularization is a novel method that may be an alternative procedure, especially in patients considered high risk for traditional carotid endarterectomy ⁶³. Guidelines⁶⁴ now recommend Carotid Endarterectomy over Carotid artery stenting for high-risk patients with symptomatic carotid stenosis >50–99% and for patients with asymptomatic stenosis >70–99% in addition to medical therapy. The ongoing CREST-2 trial⁶⁵ will provide definitive information about the benefits of endarterectomy and stenting compared to intensive medical therapy for patients with high-grade, asymptomatic carotid stenosis.

Atrial Fibrillation (AF)

Anticoagulation remains the mainstay of primary and secondary prevention of cardioembolic stroke in patients with AF⁶⁶. The ELAN study showed that early anticoagulation after stroke with AF was safe and associated with lower rates of ischemic stroke⁶⁷ In patients unable to take anticoagulation due to high bleeding risks, left atrial appendage occlusion has become an effective alternative. Data from RCTs such as the PINNACLE FLX trial⁶⁸ have shown the efficacy and safety of left atrial appendage occlusion devices for reducing the risk of cardio-embolic strokes.

Structured Interventions

The data on structured interventions using motivational strategies in secondary stroke prevention has been mixed. RCTs such as the The SPRINT-INDIA⁶⁹ trials failed to show the effectiveness of multidisciplinary intervention packages in reducing recurrent stroke.

Blood pressure

RCTs such as the Past-BP trial⁷⁰ investigating the efficacy of intensive blood pressure control (<120/80mmHg) after stroke have not shown clear benefits even compared to usual blood pressure targets (<140/90mmHg) though an updated meta-analysis from the Blood Pressure Lowering Treatment Triallist Collaboration suggested there may be a benefit in stroke prevention⁷¹.

Future directions and Conclusion

Pragmatic solutions⁷ for reducing population and individual stroke risks already exist (Figure 1,). Population approaches to primordial prevention including dietary approaches such as folic acid supplementation in folate-deficient populations, green leafy vegetable consumption and other interventions such as use of Icosa-Pent-Ethyl and the polypill strategy seem attractive and offer many practical advantages especially in low- resource settings.

Non-Standard Abbreviations and Acronyms

AF

Atrial Fibrillation

CVO

Cardiovascular Outcomes

CVD

Cardiovascular Disease

T2DM

Type 2 Diabetes Mellitus

LMIC

Low-and-Middle-Income Countries

TIA

Transient Ischemic Attacks

RCT

Randomized Controlled Trial

LDL

C-Low Density Lipoprotein Cholesterol

NCDs

Non-Communicable Diseases

PFO

Patent Foramen Ovale