New Guidelines for the Primary Stroke Prevention: A Closer Step Toward Personalized Medicine

The American Heart Association and the American Stroke Association (AHA/ASA) released new Guidelines for the Primary Prevention of Stroke in 2014. This statement follows several other AHA statements released in 2013 on general cardiovascular risk assessment, reducing the risks of cardiovascular disease and stroke, including lifestyle management, treatment of blood cholesterol, and the management of overweight and obesity.^1-5 These new statements are important for practicing physicians, clinical researchers and other professionals, as well as patients, families, caregivers, policy makers and other stakeholders invested in reducing the burden of stroke and health promotion.

Stroke continues to be a common and debilitating disease posing a major public health problem. There have been encouraging positive trends in risk factor control, stroke prevention and treatments in the last decade. Stroke mortality declined from the 3rd leading cause of death to the 4th cause of death in the US.⁶ Despite these advances, there is substantial ongoing regional and race-ethnic disparities in stroke risk, incident stroke, received care, and outcomes.⁷ With aging population, the global burden of stroke is likely to substantially increase and therefore, implementation of effective primary stroke prevention strategies is more important than ever. The real challenge, however, remains to successfully implement evidence-based lifestyle and medical practices to the stroke prevention programs and translate them to individuals.

New guidelines for the Primary Prevention of Stroke offer up-to-date comprehensive evidence-based recommendations for the primary stroke prevention, including the control of well-recognized risk factors such as hypertension, atrial, diabetes, obesity, diet and lifestyle behaviors and less well-recognized stoke risk factors including migraine, metabolic syndrome, hyperhomocysteinemia, alcohol consumption, obstructive sleep apnea, inflammation and infection, interventional approaches (e.g., asymptomatic carotid stenosis) and antithrombotic treatments. Although these new guidelines follow the format of the previous primary stroke prevention guidelines, recent accumulated evidence for the importance of lifestyle and healthy behaviors as well as genetics and pharmacogenomics in the stroke prevention has been included, marking a trajectory for future individualized stroke prevention.

New guidelines for the Primary Prevention of Stroke take a shy, but nonetheless important step towards personalized medicine. Personalized medicine with patient-centered approach has emerged as a new strategy to prevention and treatment of disease and will likely revolutionize the prevention and practice of medicine. Individual patients become important partners in medical decision-making and take responsibility for their health. A “one size fits all” treatment model has been recognized as potentially ineffective, while personalized medicine offers the use of “tailored” approach to the prevention of disease. This commentary highlights some of the important recommendations from new guidelines for the Primary Prevention of Stroke with the potential for faster transition to the personalized and more integrative prevention approaches.

Hypertension continues to be a major well-documented and modifiable risk factor for stroke. Treatment of hypertension is the most effective strategy for stroke prevention across all populations. However, optimal blood pressure (BP) targets are still intensely debated. Lowering BP is strongly associated with reduction of stroke risk, but reduction of BP to lower targets may not be beneficial in all groups of individuals, such as in patients with diabetes or in the very elderly. The 2014 Primary Prevention of Stroke guidelines rely on the Joint National Committee 7 (JNC-7) report, which was less controversial than the recently published JNC-8 recommendations⁸ that were not endorsed by other professional organizations.⁹ In the JNC-8, a lack of definitive benefit from BP clinical trials among older populations was used as a base to raise the systolic BP treatment goal recommendation from 140 mmHg to 150 mmHg. Whether this was a good reason for the JNC-8 panel to change the existing treatment goal of systolic BP at 140 mmHg continues to be debated. Nevertheless, hypertension remains undertreated and personalized approach to lifestyle changes and medical therapy of hypertension is critical for successful stroke prevention. Personal approach to treatment of hypertension based on pharmacogenomics is also on horizon.

New stroke prevention guidelines offer individualized approach to lifestyle modification including physical activity, diet and nutrition, smoking cessation, obesity and dyslipidemia. Although evidence from clinical trials for reduction of many of these factors is lacking in primary stroke prevention, evidence from observational studies is convincingly strong to make recommendations for routine physical activity, diet, smoking cessation (in combination with drug therapy using nicotine replacement, bupropion or varenicline for active smokers) and weight loss to prevent stroke with a high level of recommendations. Some of these risk factors have alarmingly increasing trends. In the US, obesity has tripled for children and doubled for adults since 1980.¹⁰ The prevalence of obesity in the US is 36% among adults and 17% among children, with the highest rates in non-Hispanic Blacks (50%), followed by Mexican-Americans (41%), then all Hispanics (39%).¹¹ While there is strong evidence that increased weight is associated with an increased stroke incidence, there is no clear evidence that weight loss in isolation reduces the risk of stroke. A reduction of sodium intake and increased intake of potassium to lower BP as well as DASH and Mediterranean style diet is considered beneficial for stroke prevention. In addition to lifestyle changes, treatment with statin to LDL cholesterol goals from National Cholesterol Education Program Guidelines (NCEP)¹² is recommended for primary prevention of ischemic stroke in patients with coronary heart disease or diabetes mellitus. However, the effectiveness of medical treatment of low HDL cholesterol with niacin or fibric acid derivatives for hypertriglyceridemia has not been firmly established. Individualized approach to cholesterol targets and effectiveness of lifestyle changes as well as tolerance to medical treatments is now recommended.

Atrial fibrillation (AFib) is a prevalent, potent, and treatable risk factor for ischemic stroke. AFib is associated with 4 to 5-fold increased risk of ischemic stroke.¹³ The widely used CHADS2¹⁴ and the CHA2DS2-VASc¹⁵ schemes offer an individualized prediction model for primary stroke prevention. However, the optimal treatment, which balances benefits and risks for an individual patient remains challenging. AFib is currently a rapidly changing field with considerable improvements in our ability to predict risk of stroke and treatment-related hemorrhage. In addition, a number of new effective therapies including novel oral anticoagulants such as dabigatran, apixaban, rivaroxaban and edoxaban have became available. The new Primary Prevention of Stroke guidelines emphasize an individualized approach to the selection of AFib antithrombotic agent on the basis of patient risk factors, risk for stroke and risk for intracranial hemorrhage, tolerability, potential for drug interactions, cost and other clinical characteristics, and increasingly important patient preference. Despite large improvements in treatments of AFib and public awareness, anticoagulation for appropriate AFib patients remains underutilized, particularly among the elderly with the highest prevalence of AFib.

New guidelines for the Primary Prevention of Stroke recommend the use of aspirin for prevention of cardiovascular disease as well as stroke for individuals whose risk is sufficiently high (10-year risk grater than 10%) for the benefits to outweigh the risks associated with aspirin therapy. In low risk individuals however, aspirin is not recommended in the primary stroke prevention or in people with diabetes and without other high-risk factors. However, little evidence is available in support of the use of antiplatelet therapy for the primary stroke prevention from relevant clinical trials. In addition, the complexity of risk factors within an individual makes stroke risk estimation a challenging proposition.¹⁶ More research is needed for individualized approaches to the use of antithrombotics for the primary stroke prevention.

Novel recommendations are provided for genetic and pharmacogenomic testing in the primary stroke prevention. A positive family history of stroke as well as sex-specific risk depending on parental history of stroke is recognized as an important risk factor for stroke. Knowledge of genetic of stroke and CVD has markedly expanded in recent years. For instance common variants on chromosome 9p21 adjacent to the tumor suppressor genes CDKN2A and CDKN2B, have been associated with ischemic stroke and myocardial infarction.¹⁷ Pharmacogenomics and personalizing medicine has the potential to improve the safety and efficacy of primary stroke prevention therapies. One example is genetic variability in cytochrome P450 2C9 gene (CYP2C9) and vitamin K oxide reductase complex 1 (VKORC1), which pharmacogenomic guiding management strategy resulted with less serious adverse events.¹⁸ These data have supported the recommendation to consider a pharmacogenomic-guided management strategy for initiating warfarin. With the rapid evolution of the genomic medicine it is anticipated that in the near future we will be able to determine genetically based disease susceptibility within individuals, families, and populations as proposed in the recent AHA scientific statement on genetics for prevention and treatment of CVD.¹⁹ However, studies have yet to prove that altering preventive therapies based on individualized genotype leads to reduced stroke risk.

In any guidelines, evidence-based recommendations usually assign level of evidence based on the results from multiple clinical trials, which in general have specific inclusion criteria. The applicability of these results may be questionable at the level of individual if a person does not fulfill eligibility criteria required in clinical trials. Personalized medicine refers to the tailoring of medical treatment to the characteristics of individual. This requires our ability to prevent disease according to the individual susceptibility to disease. The conflict between guideline-based medicine and personalized medicine mainly occurs when considering withholding a treatment that is recommended or supported by the guidelines which may not be beneficial for an individual.²⁰ Balance between patient centered medicine and evidence-based guideline practices can be achieved as integrated approach to prevention and shared decision-making is the pinnacle of individualized stroke prevention. Primary stroke prevention remains the object of intense medical research. Based on updated information provided in the 2014 guidelines for the Primary Prevention of Stroke, most management strategies for stroke prevention should be individualized. Although we are not there yet, these guidelines have made a closer step towards personalized medicine, which soon will substantially transform our approaches to the primary prevention of stroke.