There was an association between niacin therapy and coronary heart disease event (OR, 0.75; 95% CI, 0.59 0.96) but not with the incidence of stroke (OR, 0.88; However, there are serious safety concerns about niacin therapy. The Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2- THRIVE) trial involving 25693 patients at high risk for vascu- lar disease showed that extended-release niacin with laropiprant (a prostaglandin D2 signal blocker) caused a significant 4-fold increase in the risk of myopathy in patients taking simvastatin.174 Fibric acid derivatives such as gemfibrozil, fenofibrate, and bezafibrate lower triglyceride levels and increase HDL cho- lesterol. The Bezafibrate Infarction Prevention study, which included patients with prior MI or stable angina and HDL cho- lesterol 45 mg/dL, found that bezafibrate did not significantly decreaseeithertheriskofMIorsuddendeath(primaryendpoint) or stroke (secondary end point).175 The Veterans Administration HDL Intervention Trial of men with coronary artery disease and low HDL cholesterol found that gemfibrozil reduced the risk of all strokes, primarily ischemic strokes.176 In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, fenofibrate neither decreased the composite primary end point of coronary heart disease death or nonfatal MI nor decreased the risk of stroke. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study of patients with type 2 diabetes mellitus, adding fenofibrate to simvastatin did not reduce fatal cardiovascular events, nonfatal MI, or nonfatal stroke compared with simvastatin alone.177 A meta-analysis of 18 trials found that fibrate therapy produced a 10% (95% CI, 0 18) relative reduc- tion in the risk for major cardiovascular but no benefit on the risk of stroke (RR reduction, 3%; 95% CI, 16 to 9).178 Ezetimibe lowers blood cholesterol by reducing intestinal absorption of cholesterol.


In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study of patients with type 2 diabetes mellitus, adding fenofibrate to simvastatin did not reduce fatal cardiovascular events, nonfatal MI, or nonfatal stroke compared with simvastatin alone.177 A meta-analysis of 18 trials found that fibrate therapy produced a 10% (95% CI, 0 18) relative reduc- tion in the risk for major cardiovascular but no benefit on the risk of stroke (RR reduction, 3%; 95% CI, 16 to 9).178 Ezetimibe lowers blood cholesterol by reducing intestinal absorption of cholesterol. In a study of familial hypercholesterol- emia, adding ezetimibe to simvastatin did not affect the progres- sion of carotid IMT more than simvastatin alone.179 In another trial of subjects receiving a statin, niacin led to greater reductions in mean carotid IMT than ezetimibe over 14 months (P=0.003).180 Counterintuitively, patients receiving ezetimibe who had greater reductions in the LDL cholesterol had an increase in the carotid The rate of major cardiovascular events was lower in those randomized to niacin (1% versus 5%; P=0.04). Stroke events were not reported. A clinical outcome trial comparing ezetimibe and simvastatin with simvastatin alone on cardiovascular outcomes is in progress.181 Ezetimibe has not been shown to decrease cardiovascular events or stroke. Dyslipidemia: Recommendations 1. In addition to therapeutic lifestyle changes, treat- ment with an HMG coenzyme-A reductase inhibitor (statin) medication is recommended for the primary prevention of ischemic stroke in patients estimated to have a high 10-year risk for cardiovascular events as recommended in the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults 169 (Class I; Level of Evidence A). 2.


In addition to therapeutic lifestyle changes, treat- ment with an HMG coenzyme-A reductase inhibitor (statin) medication is recommended for the primary prevention of ischemic stroke in patients estimated to have a high 10-year risk for cardiovascular events as recommended in the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults 169 (Class I; Level of Evidence A). 2. Niacin may be considered for patients with low HDL cholesterol or elevated Lp(a), but its efficacy in pre- venting ischemic stroke in patients with these con- ditions is not established. Caution should be used with niacin because it increases the risk of myopathy (Class IIb; Level of Evidence B). 3. Fibric acid derivatives may be considered for patients with hypertriglyceridemia, but their efficacy in pre- venting ischemic stroke is not established (Class IIb; Level of Evidence C). 4. Treatment with nonstatin lipid-lowering therapies such as fibric acid derivatives, bile acid sequestrants, niacin, and ezetimibe may be considered in patients who cannot tolerate statins, but their efficacy in preventing stroke is not established (Class IIb; Level of Evidence C). Diet and Nutrition A large and diverse body of evidence has implicated several aspects of diet in the pathogenesis of high BP, the major modifi- able risk factor for ischemic stroke. A scientific statement from the AHA concluded that several aspects of diet lead to elevated Specifically, dietary risk factors that are causally related to elevated BP include excessive salt intake, low potassium intake, excessive weight, high alcohol consumption, and suboptimal dietary pattern.


A scientific statement from the AHA concluded that several aspects of diet lead to elevated Specifically, dietary risk factors that are causally related to elevated BP include excessive salt intake, low potassium intake, excessive weight, high alcohol consumption, and suboptimal dietary pattern. Blacks are especially sensitive to the BP-raising effects of high salt intake, low potassium intake, and suboptimal In this setting, dietary changes have the potential to sub- stantially reduce racial disparities in BP and stroke.182,183 Nutrition science is generally limited because random- ized trials involving long-term follow-up are challenging to conduct. Nutritional epidemiology faces challenges of mea- surement error, confounders, variable effects of food items, variable reference groups, interactions, and multiple testing.184 Keeping these limitations in mind, it is worth noting that sev- eral aspects of diet have been associated with stroke risk. A meta-analysis found a strong inverse relationship between servings of fruits and vegetables and subsequent stroke.185 Compared with individuals who consumed <3 servings per day, the RR of ischemic stroke was less in those who con- and in those who consumed >5 servings per day (RR, 0.72; 95% CI, 0.66 0.79). The dose-response relationship extends into the higher ranges of intake.186 Specifically, in analyses of the Nurses Health Study and the Health Professionals the RR of incident stroke was 0.69 (95% CI, 0.52 0.92) for people in the highest versus lowest quin- tile of fruit and vegetable intake. Median intake in the high- est quintile was 10.2 servings of fruits and vegetables in men and 9.2 in women. For each serving-per-day increase in fruit and vegetable intake, the risk of stroke was reduced by 6% (95% CI, 1 10).


For each serving-per-day increase in fruit and vegetable intake, the risk of stroke was reduced by 6% (95% CI, 1 10). A subsequent analysis of the Nurses Health showed that increased intake of flavonoids, primarily from citrus fruits, was associated with a reduced risk of isch- emic stroke (RR, 0.81; 95% CI, 0.66 0.99; P=0.04). As high- lighted in the 2010 US Dietary Guidelines, most Americans obtain only 64% and 50% of the recommended daily con- sumption of vegetables and fruits, respectively.188 A randomized, controlled trial of the Mediterranean diet performed in 7447 individuals at high cardiovascular risk showed that those on an energy-unrestricted Mediterranean diet supplemented by nuts (walnuts, hazelnuts, and almonds) had a lower risk of stroke than people on a control diet (3.1 versus 5.9 strokes per 1000 person-years; P=0.003) and that those on an energy-unrestricted Mediterranean diet supple- mented by extra virgin olive oil had a lower risk of stroke than people on a control diet (4.1 strokes per 1000 person- In ecological studies,190 and meta- a higher level of sodium intake was associ- ated with an increased risk of stroke. In prospective studies, a higher level of potassium intake was also associated with a reduced risk of stroke.195 198 It should be emphasized that a plethora of methodological limitations, particularly dif- ficulties in estimating dietary electrolyte intake, hinder risk assessment and may lead to false-negative or even paradoxical results in observational studies. One trial tested the effects of replacing regular salt (sodium chloride) with a potassium-enriched salt in elderly Taiwanese In addition to increased overall survivorship and reduced costs, the potassium-enriched salt reduced the risk of mortality from cerebrovascular disease (RR, 0.50). This trial did not present follow-up BP measurements; hence, it is unclear whether BP reduction accounted for the beneficial effects of the intervention.


This trial did not present follow-up BP measurements; hence, it is unclear whether BP reduction accounted for the beneficial effects of the intervention. In contrast, in the Women s Health Initiative, a low-fat diet that emphasized consumption of whole grains, fruits, and vegetables did not reduce stroke inci- dence; however, the intervention did not achieve a substantial increase in fruit and vegetable consumption (mean difference, only 1.1 servings per day) or decrease in BP (mean difference, <0.5 mmHg for both SBP and DBP).200 The effects of sodium and potassium on stroke risk are likely mediated through direct effects on BP and effects inde- pendent of BP.201 In clinical trials, particularly dose-response studies, the relationship between sodium intake and BP is direct and progressive, without an apparent threshold.202 204 Blacks, hypertensives, and middle-aged and older adults are especially sensitive to the BP-lowering effects of a reduced In other trials, an increased intake of potas- sium was shown to lower BP206 and to blunt the pressor effects Diets rich in fruits and vegetables, including those based on the Dietary Approaches to Stop Hypertension (DASH) diet (rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fat), lower BP.208 As documented in a study by the Institute of Medicine,211 sodium intake remains high and potassium intake quite low in the United States.


In contrast, in the Women s Health Initiative, a low-fat diet that emphasized consumption of whole grains, fruits, and vegetables did not reduce stroke inci- dence; however, the intervention did not achieve a substantial increase in fruit and vegetable consumption (mean difference, only 1.1 servings per day) or decrease in BP (mean difference, <0.5 mmHg for both SBP and DBP).200 The effects of sodium and potassium on stroke risk are likely mediated through direct effects on BP and effects inde- pendent of BP.201 In clinical trials, particularly dose-response studies, the relationship between sodium intake and BP is direct and progressive, without an apparent threshold.202 204 Blacks, hypertensives, and middle-aged and older adults are especially sensitive to the BP-lowering effects of a reduced In other trials, an increased intake of potas- sium was shown to lower BP206 and to blunt the pressor effects Diets rich in fruits and vegetables, including those based on the Dietary Approaches to Stop Hypertension (DASH) diet (rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fat), lower BP.208 As documented in a study by the Institute of Medicine,211 sodium intake remains high and potassium intake quite low in the United States. Other dietary factors may affect the risk of stroke, but the evidence is insufficient to make specific recommendations.182 In Asian countries, a low intake of animal protein, saturated fat, and cholesterol has been associated with a decreased risk but such relationships have been less apparent in A recent prospective study214 showed that higher intake of red meat was associated with a higher risk of stroke, but a higher intake of poultry was associated with a lower risk of stroke.


Other dietary factors may affect the risk of stroke, but the evidence is insufficient to make specific recommendations.182 In Asian countries, a low intake of animal protein, saturated fat, and cholesterol has been associated with a decreased risk but such relationships have been less apparent in A recent prospective study214 showed that higher intake of red meat was associated with a higher risk of stroke, but a higher intake of poultry was associated with a lower risk of stroke. Additionally, a meta-analysis of prospective studies concluded that intake of fresh, processed, and total red meat is associated with an increased risk of isch- Potentially, the source of dietary protein may affect stroke risk. In the absence of a clinical syndrome of a specific vitamin or nutrient deficiency, there is no conclusive evidence that vitamins or other supplements prevent incident stroke. Diet and Nutrition: Summary and Gaps From epidemiological studies and randomized trials, it is likely that diets low in sodium and rich in fruits and vegeta- bles, such as the Mediterranean and DASH-style diets, reduce stroke risk. Few randomized trials with clinical outcomes have been conducted. US Dietary Guidelines for Americans recom- mend a sodium intake of <2300 mg/d (100 mmol/d) for the general population. In blacks, individuals with hypertension, those with diabetes mellitus, those with chronic kidney dis- ease, and individuals 51 years of age, a sodium intake of The AHA recommends <1500 mg sodium per day.216 The ideal lower limit of dietary salt intake remains ill defined and may depend on comorbidi- ties such as diabetes mellitus and heart failure managed with US Dietary Guidelines for Americans recommend that potassium intake be at least 4700 mg/d (120 Diet and Nutrition: Recommendations 1.


In blacks, individuals with hypertension, those with diabetes mellitus, those with chronic kidney dis- ease, and individuals 51 years of age, a sodium intake of The AHA recommends <1500 mg sodium per day.216 The ideal lower limit of dietary salt intake remains ill defined and may depend on comorbidi- ties such as diabetes mellitus and heart failure managed with US Dietary Guidelines for Americans recommend that potassium intake be at least 4700 mg/d (120 Diet and Nutrition: Recommendations 1. Reduced intake of sodium and increased intake of potassium as indicated in the US Dietary Guidelines for Americans are recommended to lower BP (Class I; Level of Evidence A). 2. A DASH-style diet, which emphasizes fruits, vegeta- bles, and low-fat dairy products and reduced satu- rated fat, is recommended to lower BP127,218 (Class I; Level of Evidence A). 3. A diet that is rich in fruits and vegetables and thereby high in potassium is beneficial and may lower the risk of stroke (Class I; Level of Evidence B). 4. A Mediterranean diet supplemented with nuts may be considered in lowering the risk of stroke (Class IIa; Level of Evidence B). Hypertension The Seventh Joint National Committee defined hypertension as SBP >140 mmHg and DBP >90 mmHg.219 The most recent panel appointed by the National Heart, Lung, and Blood Institute to review hypertension management guidelines was silent on the issue of defining hypertension but chose instead to focus on defining BP thresholds for initiating or modify- Hypertension is a major risk factor for both cerebral infarction and ICH.


Hypertension The Seventh Joint National Committee defined hypertension as SBP >140 mmHg and DBP >90 mmHg.219 The most recent panel appointed by the National Heart, Lung, and Blood Institute to review hypertension management guidelines was silent on the issue of defining hypertension but chose instead to focus on defining BP thresholds for initiating or modify- Hypertension is a major risk factor for both cerebral infarction and ICH. The relationship between BP and stroke risk is strong, continuous, graded, consistent, indepen- dent, predictive, and etiologically significant.221 Throughout the usual range of BPs, including the nonhypertensive range, the higher the BP is, the greater the risk of stroke.222 The prevalence of hypertension has plateaued over the past decade. On the basis of national survey data from 1999 Meschia et al Guidelines for the Primary Prevention of Stroke 3765 to 2000 and 2007 to 2008, the prevalence of hypertension in the United States remained stable at 29%.223,224 Hypertension control has also improved over the past 25 years, with control rates of 27.3% measured in 1988 to 1994 and 50.1% measured in 2007 to 2008. The improved control is likely attributable to heightened awareness and treatment. Awareness of hyperten- sion among US residents significantly increased from 69% in from 54% to 73% over the same period. Despite the improve- ments, however, rates of control were lower among Hispanics compared with whites and among those 18 to 39 years of age compared with older individuals.


Despite the improve- ments, however, rates of control were lower among Hispanics compared with whites and among those 18 to 39 years of age compared with older individuals. BP, particularly SBP, rises with increasing age in both chil- Individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hyperten- More than two thirds of people 65 years of age are Because the risk of stroke increases progressively with increasing BP and because many individuals have a BP level below current drug treatment thresholds,220 nondrug or life- style approaches are recommended as a means of reducing BP in nonhypertensive individuals with an elevated BP (ie, pre-hypertension: 120 to 139 mmHg SBP or 80 to 89 mmHg Pharmacological treatment of prehypertension appears to reduce the risk of stroke.


BP, particularly SBP, rises with increasing age in both chil- Individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hyperten- More than two thirds of people 65 years of age are Because the risk of stroke increases progressively with increasing BP and because many individuals have a BP level below current drug treatment thresholds,220 nondrug or life- style approaches are recommended as a means of reducing BP in nonhypertensive individuals with an elevated BP (ie, pre-hypertension: 120 to 139 mmHg SBP or 80 to 89 mmHg Pharmacological treatment of prehypertension appears to reduce the risk of stroke. In a meta-analysis of 16 trials involving 70664 prehypertensive patients, prehyperten- sive patients randomized to active antihypertensive treatment had a consistent and statistically significant 22% reduction in the risk of stroke compared with those taking placebo Behavioral lifestyle changes are recommended by the Seventh Joint National Committee as part of a comprehen- sive treatment strategy for hypertension.221 Compelling evi- dence from >40 years of clinical trials has documented that drug treatment of hypertension prevents stroke and other BP-related target-organ damage, including heart failure, coro- nary heart disease, and renal failure.221 A meta-analysis of 23 randomized trials showed that antihypertensive drug treatment reduced the risk of stroke by 32% (95% CI, 24 39; P=0.004) compared with no drug treatment.230 The use of antihyper- tensive therapies among those with mild hypertension (SBP, 140 to 159 mmHg; DBP, 90 to 99 mmHg; or both), however, was not clearly shown to reduce the risk of first stroke in a Cochrane Database Systematic Review, although a trend of clinically important magnitude was present (RR, 0.51; 95% CI, 0.24 1.08).


In a meta-analysis of 16 trials involving 70664 prehypertensive patients, prehyperten- sive patients randomized to active antihypertensive treatment had a consistent and statistically significant 22% reduction in the risk of stroke compared with those taking placebo Behavioral lifestyle changes are recommended by the Seventh Joint National Committee as part of a comprehen- sive treatment strategy for hypertension.221 Compelling evi- dence from >40 years of clinical trials has documented that drug treatment of hypertension prevents stroke and other BP-related target-organ damage, including heart failure, coro- nary heart disease, and renal failure.221 A meta-analysis of 23 randomized trials showed that antihypertensive drug treatment reduced the risk of stroke by 32% (95% CI, 24 39; P=0.004) compared with no drug treatment.230 The use of antihyper- tensive therapies among those with mild hypertension (SBP, 140 to 159 mmHg; DBP, 90 to 99 mmHg; or both), however, was not clearly shown to reduce the risk of first stroke in a Cochrane Database Systematic Review, although a trend of clinically important magnitude was present (RR, 0.51; 95% CI, 0.24 1.08). Because 9% of patients stopped therapy as a result of side effects, the authors recommended further trials Several trials have addressed the potential role of antihy- pertensive treatment among patients with prevalent CVD but without hypertension. In a meta-analysis of 25 trials of antihy- pertensive therapy for patients with prevalent CVD (including stroke) but without hypertension, patients receiving antihyper- tensive medications had a pooled RR for stroke of 0.77 (95% CI, 0.61 0.98) compared with control subjects.232 The magni- tude of the RR reduction was greater for stroke than for most other cardiovascular outcomes, although the absolute risk reductions were greater for other outcomes because of their greater relative frequency.


In a meta-analysis of 25 trials of antihy- pertensive therapy for patients with prevalent CVD (including stroke) but without hypertension, patients receiving antihyper- tensive medications had a pooled RR for stroke of 0.77 (95% CI, 0.61 0.98) compared with control subjects.232 The magni- tude of the RR reduction was greater for stroke than for most other cardiovascular outcomes, although the absolute risk reductions were greater for other outcomes because of their greater relative frequency. In a separate meta-analysis of 13 trials involving 80594 individuals, among those either with prevalent atherosclerotic disease or at high risk for developing it, angiotensin-convert- ing enzyme (ACE) inhibitors (ACEIs) or angiotensin receptor blocker (ARB) therapy reduced the risk of a composite primary outcome including stroke by 11%, without variability by base- There was also a significant reduction in fatal and nonfatal strokes (OR, 0.91; 95% CI, 0.86 0.97). Non ACEI/ ARB therapies were allowed, but meta-regression analyses provided evidence that the benefits were not due solely to BP reductions during the trial.


Non ACEI/ ARB therapies were allowed, but meta-regression analyses provided evidence that the benefits were not due solely to BP reductions during the trial. Several other meta-analyses have evaluated whether specific classes of antihypertensive agents offer protection against stroke beyond their BP-lowering In one of these meta-analyses evaluating differ- ent classes of agents used as first-line therapy in subjects with a baseline BP >140/90 mmHg, thiazide diuretics (RR, 0.63; channel blockers (RR, 0.58; 95% CI, 0.41 0.84) each reduced the risk of stroke compared with placebo or no treatment.236 Compared with thiazides, -blockers, ACEIs, and ARBs, cal- cium channel blockers appear to have a slightly greater effect on reducing the risk of stroke, although the effect is not seen for other cardiovascular outcomes and was of small magnitude (8% relative reduction in risk).235 One meta-analysis found that diuretic therapy was superior to ACEI therapy,230 and another found that calcium channel blockers were superior toACEIs.237 Another found that -blockers were less effective in reducing stroke risk than calcium channel blockers (RR, 1.24; 95% CI, 1.11 1.40) or inhibitors of the renin-angiotensin system Subgroup analyses from 1 major trial suggest that the benefit of diuretic therapy over ACEI therapy is especially prominent in blacks,239 and sub- group analysis from another large trial found that -blockers were significantly less effective than thiazide diuretics and ARBs at preventing stroke in those 65 years of age than in The results of a recent trial of the direct renin inhibitor aliskiren in patients with type 2 diabetes mel- litus plus chronic kidney disease or prevalent CVD did not find evidence that aliskiren reduced cardiovascular end points, In general, therefore, although the benefits of lowering BP as a means to prevent stroke are undisputed, there is no definitive evidence that any particular class of anti- hypertensive agents offers special protection against stroke in all patients.


Several other meta-analyses have evaluated whether specific classes of antihypertensive agents offer protection against stroke beyond their BP-lowering In one of these meta-analyses evaluating differ- ent classes of agents used as first-line therapy in subjects with a baseline BP >140/90 mmHg, thiazide diuretics (RR, 0.63; channel blockers (RR, 0.58; 95% CI, 0.41 0.84) each reduced the risk of stroke compared with placebo or no treatment.236 Compared with thiazides, -blockers, ACEIs, and ARBs, cal- cium channel blockers appear to have a slightly greater effect on reducing the risk of stroke, although the effect is not seen for other cardiovascular outcomes and was of small magnitude (8% relative reduction in risk).235 One meta-analysis found that diuretic therapy was superior to ACEI therapy,230 and another found that calcium channel blockers were superior toACEIs.237 Another found that -blockers were less effective in reducing stroke risk than calcium channel blockers (RR, 1.24; 95% CI, 1.11 1.40) or inhibitors of the renin-angiotensin system Subgroup analyses from 1 major trial suggest that the benefit of diuretic therapy over ACEI therapy is especially prominent in blacks,239 and sub- group analysis from another large trial found that -blockers were significantly less effective than thiazide diuretics and ARBs at preventing stroke in those 65 years of age than in The results of a recent trial of the direct renin inhibitor aliskiren in patients with type 2 diabetes mel- litus plus chronic kidney disease or prevalent CVD did not find evidence that aliskiren reduced cardiovascular end points, In general, therefore, although the benefits of lowering BP as a means to prevent stroke are undisputed, there is no definitive evidence that any particular class of anti- hypertensive agents offers special protection against stroke in all patients. Further hypothesis-driven trials are warranted, however, to test differences in efficacy of individual agents in specific subgroups of patients.


Further hypothesis-driven trials are warranted, however, to test differences in efficacy of individual agents in specific subgroups of patients. BP control can be achieved in most patients, but most patients require therapy with 2 drugs.242,243 In 1 open-label trial conducted in Japan, among patients taking a calcium channel blocker who had not yet achieved a target BP, the addition of a thiazide diuretic significantly reduced the risk of stroke compared with the addition of either a -blocker (P=0.0109) or an ARB (P=0.0770).244 The advantage of the combination of a calcium channel blocker and thiazide was not seen, however, for other cardiovascular end points. Meta-analyses support that more intensive control of BP (SBP <130 mmHg) reduces risk of stroke more than less intensive control (SBP, 130 139 mmHg), although the effects on other outcomes and in all subgroups of patients remain unclear. Among 11 trials with 42572 participants, the RR of stroke for those whose SBP was <130 mmHg was 0.80 (95% CI, 0.70 0.92). The effect was greater among those with car- diovascular risk factors but without established CVD.245 This benefit of intensive BP lowering may be more specific to stroke than to other cardiovascular outcomes, at least among certain subgroups of patients. Among patients with diabetes mellitus at high cardiovascular risk enrolled in the ACCORD Blood Pressure Trial, more intensive BP control (SBP <120 mmHg) compared with standard control (<140 mmHg) led to a significant reduction in risk of stroke, a prespecified sec- However, there was no effect on either the primary composite outcome or overall mortality. This absence of benefit on nonstroke out- comes was not attributable to obesity because effects were simi- lar across levels of obesity.


This absence of benefit on nonstroke out- comes was not attributable to obesity because effects were simi- lar across levels of obesity. A meta-analysis of 31 trials with 73913 individuals with diabetes mellitus demonstrated that more intensive BP reduction significantly reduced the risk of stroke but not MI.248 For every 5-mmHg reduction in SBP, the risk of stroke decreased by 13% (95% CI, 5 20). In a secondary analysis of the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial, however, among 9193 hyperten- sive patients with left ventricular hypertrophy by ECG criteria, achieving intensive BP control to <130 mmHg was not associ- ated with a reduction in stroke after multivariable adjustment, and there was a significant increase in all-cause mortality (HR, The target for BP reduction, there- fore, may differ by patient characteristics and comorbidities. Pharmacogenomics may contribute to improving individu- alized selection of antihypertensive medications for stroke prevention. For example, in genetic studies ancillary to the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial (ALLHAT), individuals with the stromelysin (matrix metalloproteinase-3) genotype 6A/6A had higher stroke rates on lisinopril than on chlorthalidone, and those with the 5A/6A genotype had lower stroke rates on lisinopril.250 homozygotes had the lowest stroke rates compared with those taking chlorthalidone (HR for interaction=0.51; 95% CI, 0.31 0.85). The effect was not seen for other medications. Carriers of mutations of the fibrinogen- gene also had a lower risk of stroke on lisinopril compared with amlodipine than those who were homozygous for the usual allele, potentially because ACEIs lower fibrinogen levels and this effect is more clinically important among those with mutations associated with higher The role of genetic testing in hypertension management remains undefined at present, however.


Carriers of mutations of the fibrinogen- gene also had a lower risk of stroke on lisinopril compared with amlodipine than those who were homozygous for the usual allele, potentially because ACEIs lower fibrinogen levels and this effect is more clinically important among those with mutations associated with higher The role of genetic testing in hypertension management remains undefined at present, however. Recent evidence suggests that intraindividual variability in BP may confer risk beyond that caused by mean elevations in BP alone.252 There is further observational evidence that calcium channel blockers may have benefits in reducing BP variability that are not present with -blockers and that these benefits may provide additional benefits in stroke risk reduc- Twenty-four hour ambulatory BP monitoring pro- vides additional insight into risk of stroke and cardiovascular events. Measurements of nocturnal BP changes ( reverse dip- ping or extreme dipping ) and the ratio of nocturnal to day- time BPs may provide data about risk beyond that provided Further study of the benefits on stroke risk reduction of treatments focused on reducing intra- individual variability in BP and nocturnal BP changes seem warranted. Controlling isolated systolic hypertension (SBP 160 mmHg and DBP <90 mmHg) in the elderly is also impor- tant.


Controlling isolated systolic hypertension (SBP 160 mmHg and DBP <90 mmHg) in the elderly is also impor- tant. The Systolic Hypertension in Europe (Syst-Eur) Trial randomized 4695 patients with isolated systolic hypertension to active treatment with a calcium channel blocker or placebo and found a 42% (95% CI, 18 60; P=0.02) risk reduction in the actively treated group.257 The Systolic Hypertension in the Elderly Program (SHEP) Trial found a 36% reduction (95% CI, 18 50; P=0.003) in the incidence of stroke from a diuretic- In the Hypertension in the Very Elderly (HYVET) trial, investigators randomized 3845 patients 80 years of age with SBP 160 mmHg to placebo or indap- amide, with perindopril or placebo added as needed to target a BP <150/80 mmHg. After 2 years, there was a reduction in SBP of 15 mmHg, associated with a 30% reduction in risk of stroke (P=0.06), a 39% reduction in fatal stroke (P=0.046), and a 21% reduction in overall mortality (P=0.02).257 No trial has focused on individuals with lesser degrees of isolated sys- tolic hypertension (SBP=140 159 mmHg; DBP <90 mmHg). The most recent National Heart, Lung, and Blood Institute appointed panel provides an evidence-based approach to pharma- cological treatment of hypertension.220 The report focuses on age as a guide for therapeutic targets, with recommendations to lower BP pharmacologically to a target of <150/90 mmHg for patients >60 years of age and target a BP of <140/90mmHg for younger patients.


The most recent National Heart, Lung, and Blood Institute appointed panel provides an evidence-based approach to pharma- cological treatment of hypertension.220 The report focuses on age as a guide for therapeutic targets, with recommendations to lower BP pharmacologically to a target of <150/90 mmHg for patients >60 years of age and target a BP of <140/90mmHg for younger patients. However, these recommendations differ from the 2014 science advisory on high BP control endorsed by the AHA, ACC, and Centers for Disease Control and Prevention in which more aggressive BP targets are recommended (<140/90 mmHg) regardless of age.218 There is concern that raising the SBP thresh- old from 140 to 150 mmHg might reverse some of the gains that have been achieved in reducing stroke by tighter BP control. For patients with diabetes mellitus who are at least 18 years of age, the panel originally appointed by the National Heart, Lung, and Blood Institute to review the evidence on treatment of hyperten- sion recommends initiating pharmacologic treatment to lower BP at SBP of 140 mmHg or DBP of 90 mmHg and to treat to a goal SBP of <140 mmHg and a goal DBP <90 mmHg.220 The International Society on Hypertension in Blacks revised its recommendations for managing BP in this at-risk population in 2010.259 In the absence of target-organ damage, the target should be <135/85 mmHg; in the presence of tar- get-organ damage, the target should be <130/80 mmHg. For patients who are within 10 mmHg above target, monotherapy with diuretic or calcium channel blocker is preferred, and for patients >15/10 mmHg above target, 2-drug therapy is pre- ferred either with a calcium channel blocker plus renin-angio- tensin system blocker or, in edematous or volume-overloaded states, with a thiazide diuretic plus a renin-angiotensin system blocker.


For patients who are within 10 mmHg above target, monotherapy with diuretic or calcium channel blocker is preferred, and for patients >15/10 mmHg above target, 2-drug therapy is pre- ferred either with a calcium channel blocker plus renin-angio- tensin system blocker or, in edematous or volume-overloaded states, with a thiazide diuretic plus a renin-angiotensin system blocker. Largely on the basis of a prespecified subgroup analy- sis of the ALLHAT trial, the National Heart, Lung, and Blood Institute panel originally appointed to address hypertension management recommend that in the general black population, including those with diabetes mellitus, initial antihypertensive therapy should include a thiazide-type diuretic or a calcium Meschia et al Guidelines for the Primary Prevention of Stroke 3767 Population-wide approaches to reducing BP have also been advocated as more effective than approaches focused on screening individual patients for the presence of hypertension and treating them.235,260 Because the benefits of BP reduction can be seen across the range of measurements in the popula- tion, with and without pre-existing CVD, it may be reason- able to provide BP-lowering medications to all patients above a certain age (eg, 60 years of age).235 Similarly, on the basis of observational data from 19 cohorts with 177025 participants showing lower salt intake to be associated with a lower risk of stroke and other cardiovascular outcomes, population-wide reductions in salt intake may be advocated as a way to reduce Self-measured BP monitoring is recommended because with or without additional support such monitoring lowers BP compared with usual care.261 Hypertension: Summary and Gaps Hypertension remains the most important, well-documented modifiable stroke risk factor, and treatment of hypertension is among the most effective strategies for preventing both isch- emic and hemorrhagic stroke.


Largely on the basis of a prespecified subgroup analy- sis of the ALLHAT trial, the National Heart, Lung, and Blood Institute panel originally appointed to address hypertension management recommend that in the general black population, including those with diabetes mellitus, initial antihypertensive therapy should include a thiazide-type diuretic or a calcium Meschia et al Guidelines for the Primary Prevention of Stroke 3767 Population-wide approaches to reducing BP have also been advocated as more effective than approaches focused on screening individual patients for the presence of hypertension and treating them.235,260 Because the benefits of BP reduction can be seen across the range of measurements in the popula- tion, with and without pre-existing CVD, it may be reason- able to provide BP-lowering medications to all patients above a certain age (eg, 60 years of age).235 Similarly, on the basis of observational data from 19 cohorts with 177025 participants showing lower salt intake to be associated with a lower risk of stroke and other cardiovascular outcomes, population-wide reductions in salt intake may be advocated as a way to reduce Self-measured BP monitoring is recommended because with or without additional support such monitoring lowers BP compared with usual care.261 Hypertension: Summary and Gaps Hypertension remains the most important, well-documented modifiable stroke risk factor, and treatment of hypertension is among the most effective strategies for preventing both isch- emic and hemorrhagic stroke. Across age groups, including adults 80 years of age, the benefit of hypertension treatment in preventing stroke is clear. Reduction in BP is generally more important than the specific agents used to achieve this goal. Optimal BP targets for reducing stroke risk are uncer- tain.


Optimal BP targets for reducing stroke risk are uncer- tain. Although the benefits of BP reduction on stroke risk continue to be seen at progressively lower pressures, adverse effects on mortality and other outcomes may limit the lower level to which BP targets can be pushed, particularly among certain subgroups of patients such as patients with diabetes mellitus. Future studies are needed to determine the effects of treating BP variability beyond the effects of treatment of mean BP levels. Hypertension remains undertreated in the commu- nity, and additional programs to improve treatment adherence need to be developed, tested, and implemented. Both person- alized approaches to pharmacotherapy based on pharmacoge- netics and population-level approaches to reducing BP require further study. Hypertension: Recommendations 1. Regular BP screening and appropriate treatment of patients with hypertension, including lifestyle modi- fication and pharmacological therapy, are recom- mended (Class I; Level of Evidence A). 2. Annual screening for high BP and health-promoting lifestyle modification are recommended for patients with prehypertension (SBP of 120 to 139 mmHg or DBP of 80 to 89 mmHg) (Class I; Level of Evidence A). 3. Patients who have hypertension should be treated with antihypertensive drugs to a target BP of <140/90 mmHg (Class I; Level of Evidence A). 4. Successful reduction of BP is more important in reducing stroke risk than the choice of a specific agent, and treatment should be individualized on the basis of other patient characteristics and medication tolerance (Class I; Level of Evidence A). 5. Self-measured BP monitoring is recommended to improve BP control. (Class I; Level of Evidence A). Obesity and Body Fat Distribution Stroke, along with hypertension, heart disease, and diabetes mellitus, is associated with being overweight or obese.


Obesity and Body Fat Distribution Stroke, along with hypertension, heart disease, and diabetes mellitus, is associated with being overweight or obese. The prevalence of obesity in the United States has tripled for chil- dren and doubled for adults since 1980.262 Only in the last 3 years has a leveling off been seen.263 265 Increasing public awareness and government initiatives have placed this public health issue in the forefront. According to the National Center for Health Statistics data from the Department of Health and Human Services, in 2009 and 2010, the prevalence of obesity was 35.7% among adults and 16.9% among children, with a higher prevalence in adults >60 years of age and adolescents.263 265 Among the race/eth- nic groups surveyed in the United States, age-adjusted rates of obesity indicate the highest rates in non-Hispanic blacks (49.5%), followed by Mexican Americans (40.45%) and then all Hispanics (39.1%), with the lowest rate being among non- Hispanic whites (34.3%).263 265 A patient s body mass index (BMI), defined as weight in kilograms divided by the square of the height in meters, is used to distinguish overweight (BMI, 25 to 29 kg/m2 ) from obesity ) and morbid obesity (BMI >40 kg/m2 Men presenting with a waist circumference of >102 cm (40 in) and women with a waist circumference >88 cm (35 in) are catego- rized as having abdominal obesity.267 Abdominal obesity can also be measured as the waist-to-hip ratio.


According to the National Center for Health Statistics data from the Department of Health and Human Services, in 2009 and 2010, the prevalence of obesity was 35.7% among adults and 16.9% among children, with a higher prevalence in adults >60 years of age and adolescents.263 265 Among the race/eth- nic groups surveyed in the United States, age-adjusted rates of obesity indicate the highest rates in non-Hispanic blacks (49.5%), followed by Mexican Americans (40.45%) and then all Hispanics (39.1%), with the lowest rate being among non- Hispanic whites (34.3%).263 265 A patient s body mass index (BMI), defined as weight in kilograms divided by the square of the height in meters, is used to distinguish overweight (BMI, 25 to 29 kg/m2 ) from obesity ) and morbid obesity (BMI >40 kg/m2 Men presenting with a waist circumference of >102 cm (40 in) and women with a waist circumference >88 cm (35 in) are catego- rized as having abdominal obesity.267 Abdominal obesity can also be measured as the waist-to-hip ratio. For every 0.01 increase in waist-to-hip ratio, there is a 5% increase in risk of CVD.268 Abdominal body fat has proved to be a stronger predictor of stroke risk than BMI.269,270 In contrast, another study reported that in men only BMI was significantly associated with stroke, whereas for women it was waist-to-hip ratio.271 Adiposity, how- ever, correlated with risk of ischemic heart disease for both sexes. When fat distribution measured by dual-energy x-ray absorpti- ometry in relation to incidence of stroke was studied, there was a significant association in both men and women between stroke and abdominal fat mass. This association, however, was not independent of diabetes mellitus, smoking, and hypertension.272 Mounting evidence shows a graded positive relationship between stroke and obesity independent of age, lifestyle, or other cardiovascular risk factors.


This association, however, was not independent of diabetes mellitus, smoking, and hypertension.272 Mounting evidence shows a graded positive relationship between stroke and obesity independent of age, lifestyle, or other cardiovascular risk factors. Prospective studies of the relationship between weight (or measures of adiposity) and incident stroke indicate that in the BMI range of 25 to 50 kg/ there was a 40% increased stroke mortality with each 5-kg/ increase in BMI. However, in the BMI range of 15 to 24 kg/ , there was no relationship between BMI and mortality.273 A meta-analysis of data from 25 studies involving >2.2 million people and >30000 events found an RR for ischemic stroke of 1.22 (95% CI, 1.05 1.41) for overweight people and For hemor- rhagic stroke, the RR was 1.01 (95% CI, 0.88 1.17) for over- weight people and 1.24 (95% CI, 0.99 1.54) for obese people. This meta-analysis showed an increased risk of ischemic stroke compared with normal-weight individuals of 22% in overweight individuals and 64% in obese individuals. When diabetes mellitus, hypertension, dyslipidemia, and other con- founders were taken into account, there was no significant increase in the incidence of hemorrhagic stroke. These find- ings have been subsequently borne out in a Chinese study of In Japan, a meta-analysis of 44000 patients found a positive correlation in both sexes of elevated BMI with both ischemic and hemorrhagic events.276 ARIC exam- ined a population of 13000 black and white participants and found that obesity was a risk factor for ischemic stroke inde- pendently of race.277 Adjustments for covariates in all these studies significantly reduced these associations. The effects of stroke risk and weight reduction have not been studied extensively.


The effects of stroke risk and weight reduction have not been studied extensively. A Swedish study that followed 4000 patients over 10 to 20 years, comparing individuals with weight loss through bariatric surgery and obese subjects receiving usual care, showed significant reductions in diabetes mellitus, MI, and Thirty-six thousand Swedish subjects followed for >13 years again showed a significant decrease in stroke incidence when more than 3 healthy lifestyle goals, including normal weight, were met.279 The Sibutramine Cardiovascular Outcomes (SCOUT) trial followed up 10000 patients with CVD or type 2 diabetes mellitus and found that even modest weight loss reduced cardiovascular mortality in the following 4 to 5 years.280 Reduction in body weight improves control of hypertension.A meta-analysis of 25 trials showed mean SBP and DBP reductions of 4.4 and 3.6 mmHg, respectively, with a 5.1-kg weight loss.281 The US Preventive Services Task Force currently recom- mends that all adults be screened for obesity and that patients with a BMI of 30 kg/m2 be referred for intensive multicom- ponent behavioral interventions for weight loss.282 Obesity and Body Fat Distribution: Summary and Gaps Although there is ample evidence that increased weight is associ- ated with an increased incidence of stroke, with stronger associa- tions for ischemic events, many questions remain unanswered. There is no clear and compelling evidence that weight loss in isolation reduces the risk of stroke because of the difficulty in isolating the effects of weight loss as a single contributing fac- tor rather than as a component contributing to better control of hypertension, diabetes mellitus, metabolic syndrome, and other stroke risk factors. It remains to be determined whether the dis- parities among studies stem from choosing BMI, waist-to-hip ratio, or waist circumference as the measure of obesity.


It remains to be determined whether the dis- parities among studies stem from choosing BMI, waist-to-hip ratio, or waist circumference as the measure of obesity. Obesity and Body Fat Distribution: Recommendations ) and obese ) individuals, weight reduction is recommended for lowering BP (Class I; Level of Evidence A). )and obese ) individuals, weight reduction is rec- ommended for reducing the risk of stroke (Class I; Level of Evidence B). Diabetes Mellitus People with diabetes mellitus have both an increased suscepti- bility to atherosclerosis and an increased prevalence of athero- genic risk factors, notably hypertension and abnormal blood lipids. In 2010, an estimated 20.7 million adults or 8.2% of adultAmericans had diabetes mellitus.283 Moreover, the preva- lence of prediabetes among Americans >65 years of age tested in 2005 through 2008 was estimated to be 50%.283 Diabetes mellitus is an independent risk factor for stroke.284 Diabetes mellitus more than doubles the risk for stroke, and 20% of patients with diabetes mellitus will die of stroke. Duration of diabetes mellitus also increases the risk of non- hemorrhagic stroke (by 3%/y of diabetes duration).284 For those with prediabetes, fasting hyperglycemia is associated In a study of 43933 men (mean age, 44.3 9.9 years) free of known CVD and diabetes mellitus at baseline between 1971 and 2002, a total of 595 stroke events (156 fatal and 456 nonfatal strokes) occurred.


Duration of diabetes mellitus also increases the risk of non- hemorrhagic stroke (by 3%/y of diabetes duration).284 For those with prediabetes, fasting hyperglycemia is associated In a study of 43933 men (mean age, 44.3 9.9 years) free of known CVD and diabetes mellitus at baseline between 1971 and 2002, a total of 595 stroke events (156 fatal and 456 nonfatal strokes) occurred. Age-adjusted fatal, nonfatal, and total stroke event rates per 10000 person-years for normal fasting plasma glucose (80 109 mg/dL), impaired fasting glucose (110 125 mg/dL), and undiagnosed diabetes (Ptrend In the Greater Cincinnati/Northern Kentucky Stroke Study, ischemic stroke patients with diabetes mellitus were younger, more likely to be black, and more likely to have hypertension, MI, and high cholesterol than patients without diabetes mel- Age-specific incidence rates and rate ratios showed that diabetes mellitus increased ischemic stroke incidence for all ages but that the risk was most prominent before 55 years of age in blacks and before 65 years of age in whites. Although Mexican Americans had a substantially greater incidence rate for the com- bination of ischemic stroke and ICH than non-Hispanic whites,40 there is insufficient evidence that the presence of diabetes mel- litus or other forms of glucose intolerance influenced this rate.


Although Mexican Americans had a substantially greater incidence rate for the com- bination of ischemic stroke and ICH than non-Hispanic whites,40 there is insufficient evidence that the presence of diabetes mel- litus or other forms of glucose intolerance influenced this rate. In the Strong Heart Study (SHS), 6.8% of 4549 Native American participants 45 to 74 years of age at baseline without prior stroke had a first stroke over 12 to 15 years, and diabetes mellitus and impaired glucose tolerance increased the HR to 2.05.43 In NOMAS, which included 3298 stroke-free community residents, 572 reported a history of diabetes mellitus, and 59% (n=338) had elevated fasting blood glucose.287 Those subjects with an elevated fasting glucose had an increased stroke risk (HR, 2.7; 95% CI, 2.0 3.8), but those with a fasting blood glucose level of <126 mg/dL were not at increased risk. Stroke risk can be reduced in patients with diabetes mellitus. In the Steno-2 Study, 160 patients with type 2 diabetes mellitus and persistent microalbuminuria were assigned to receive either intensive therapy, including behavioral risk factor modification and the use of a statin, an ACEI, an ARB, or an antiplatelet drug as appropriate, or conventional therapy with a mean treatment Patients were subsequently followed up for an average of 5.5 years. The primary end point was time to death resulting from any cause. The risk of cardiovascular events was intensive versus conventional therapy, and strokes were reduced from 30 to 6. In addition, intensive therapy was associated with a 57% lower risk of death from cardiovascular causes (HR, 0.43; 95% CI, 0.19 0.94; P=0.04). Eighteen of the 30 strokes were fatal in the conventional group, and all 6 were fatal in the inten- sive group.


Eighteen of the 30 strokes were fatal in the conventional group, and all 6 were fatal in the inten- sive group. Meschia et al Guidelines for the Primary Prevention of Stroke 3769 In the Euro Heart Survey on Diabetes and the Heart, 3488 patients were enrolled, 59% without and 41% with diabetes Evidence-based medicine was defined as the com- bined use of renin-angiotensin-aldosterone system inhibitors, -adrenergic receptor blockers, antiplatelet agents, and statins. In patients with diabetes mellitus, the use of evidence-based independent protective effect on 1-year mortality and on car- compared with those without diabetes mellitus. Although stroke rates were not changed, there was an 50% reduction in cerebrovascular revascularization procedures. Glycemic Control The effect of previous randomization of the UK Prospective Diabetes Study (UKPDS)290 to either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control was assessed in an open-label extension study. In post- trial monitoring, 3277 patients were asked to attend UKPDS clinics annually for 5 years; however, there were no attempts to maintain their previously assigned therapies.291 A reduction in MI and all-cause mortality was found; however, stroke inci- dence was not affected by assignment to either sulfonylurea/ insulin or metformin treatment. Three major recent trials have evaluated the effects of reduced glycemia on CVD events in patients with type 2 dia- betes mellitus. The ACCORD recruited 10251 patients (mean age, 62 years) with a mean glycated hemoglobin of 8.1%.292 Participants were then randomized to receive intensive (gly- cated hemoglobin goal, <6.0%) or standard (goal, 7.0% 7.9%) therapy. The study was stopped earlier than planned because of an increase in all-cause mortality in the intensive therapy group with no difference in the numbers of fatal and nonfatal strokes.


The study was stopped earlier than planned because of an increase in all-cause mortality in the intensive therapy group with no difference in the numbers of fatal and nonfatal strokes. TheAction in Diabetes andVascular Disease: Preterax and Diamacron MR Controlled Evaluation (ADVANCE) Trial included 11140 patients (mean age, 66.6 years) with type 2 diabetes mellitus and used a number of strategies to reduce glycemia in an intensive treatment group.293 Mean glycated hemoglobin levels were 6.5% versus 7.4% at 5 years, with no effect of more intensive therapy on the risk of CVD events or on the risk of nonfatal strokes between groups. In another study, 1791 US veterans (Veterans Affairs Diabetes Trial) with an average duration of diabetes mellitus of >10 years (mean age, 60.4 years) were randomized to a regimen to decrease glycated hemoglobin by 1.5% or standard care.294 years, the mean levels of glycated hemoglobin were 6.9% versus 8.4%, with no difference in the number of macrovas- cular events, including stroke, between the 2 groups.295 From the available clinical trial results, there is no evidence that reduced glycemia decreases the short-term risk of macrovas- cular events, including stroke, in patients with type 2 diabetes mellitus. A glycated hemoglobin goal of <7.0% has been rec- ommended by the American Diabetes Association to prevent long-term microangiopathic complications in patients with Whether control to this level also reduces the long-term risk of stroke requires further study.


A glycated hemoglobin goal of <7.0% has been rec- ommended by the American Diabetes Association to prevent long-term microangiopathic complications in patients with Whether control to this level also reduces the long-term risk of stroke requires further study. In patients with recent-onset type I diabetes mellitus, intensive diabetes therapy aimed at achieving near-normal glycemia can be accomplished with good adherence but with more fre- quent episodes of severe hypoglycemia.297 Although glyce- mia was similar between the groups over a mean 17 years of follow-up in the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, intensive treatment reduced the risk of any CVD event by 42% (95% CI, 9 63; P=0.02) and the com- bined risk nonfatal MI, stroke, or death from CVD events by The decrease in glycated hemoglobin was associated with the positive effects of inten- sive treatment on the overall risk of CVD. There were too few strokes, however, to evaluate the effect of improved glycemia during the trial, and as with type 2 diabetes mellitus, there remains no evidence that tight glycemic control reduces risk of stroke. Despite the lack of convincing support from any individual clinical trial for intensified glycemic control to reduce stroke incidence in patients with diabetes mellitus, a recent meta- analysis provided some supportive evidence in a subgroup of patients with diabetes mellitus. From 649 identified studies, the authors identified 9 relevant trials, which provided data Overall, inten- sive control of glucose compared with usual care had no effect however, in a stratified analyses, a beneficial effect was seen in patients with diabetes mellitus and a BMI >30 kg/m2 (RR, 0.86; 95% CI, 0.75 0.99; P=0.041).


From 649 identified studies, the authors identified 9 relevant trials, which provided data Overall, inten- sive control of glucose compared with usual care had no effect however, in a stratified analyses, a beneficial effect was seen in patients with diabetes mellitus and a BMI >30 kg/m2 (RR, 0.86; 95% CI, 0.75 0.99; P=0.041). Diabetes Mellitus and Hypertension More aggressive lowering of BP in patients with diabetes mel- litus and hypertension reduces stroke incidence.300 In addition to comparing the effects of more intensive glycemic control and standard care on the complications of type 2 diabetes mellitus, the UKPDS found that tight BP control (mean BP, 144/82 mmHg) resulted in a 44% reduction (95% CI, 11 65; P=0.013) in the risk of stroke compared with more liberal control (mean BP, 154/87 mmHg).301 There was also a nonsta- reduction with antihypertensive treatment in subjects with dia- betes mellitus in SHEP.302 In UKPDS, 884 patients with type 2 diabetes mellitus who attended annual UKPDS clinics for 5 years after study completion were evaluated.303 Differences in BP between the 2 groups, standard of care and more aggres- sive BP lowering, disappeared within 2 years. There was a nonsignificant trend toward reduction in stroke with more intensive BP control (RR, 0.77; 95% CI, 0.55 1.07; P=0.12). Continued efforts to maintain BP targets might have led to maintenance of the benefit. The Heart Outcomes Prevention Evaluation (HOPE) study compared the addition of an ACEI to the current medical regi- men in high-risk patients.


The Heart Outcomes Prevention Evaluation (HOPE) study compared the addition of an ACEI to the current medical regi- men in high-risk patients. The substudy of 3577 patients with diabetes mellitus with a previous cardiovascular event or an additional cardiovascular risk factor (total population, 9541 participants) showed a reduction in the ACEI group in the primary combined outcome of MI, stroke, and cardiovascular Whether these benefits repre- sent a specific effect of the ACEI or were simply the result of BP lowering remains unclear. The LIFE study compared the effects of an ARB with a -adrenergic receptor blocker in 9193 people with essential hypertension (160 200/95 115 mmHg) and electrocardiographically determined left ventricular hyper- BP reductions were similar for each group. The 2 regimens were compared among the subgroup of 1195 people who also had diabetes mellitus in a prespeci- There was a 24% reduction (RR, 0.76; 95% CI, 0.58 0.98) in major vascular events and a nonsignificant 21% reduction (RR, 0.79; 95% CI, 0.55 1.14) in stroke among those treated with the ARB. The ADVANCE Trial also determined whether a fixed combination of perindopril and indapamide or matching pla- cebo in 11140 patients with type 2 diabetes mellitus would decrease major macrovascular and microvascular events.307 After 4.3 years of follow-up, subjects assigned to the com- bination had a mean reduction in BP of 5.6/2.2 mmHg. The risk of a composite of major macrovascular and microvascu- lar events was reduced by 9% (HR, 0.91; 95% CI, 0.83 1.00; P=0.04), but there was no reduction in the incidence of major macrovascular events, including stroke.


The risk of a composite of major macrovascular and microvascu- lar events was reduced by 9% (HR, 0.91; 95% CI, 0.83 1.00; P=0.04), but there was no reduction in the incidence of major macrovascular events, including stroke. IntheAnglo-ScandinavianCardiacOutcomesTrial(ASCOT), the effects of 2 antihypertensive treatment strategies (amlodipine with the addition of perindopril as required [amlodipine-based] or atenolol with addition of thiazide as required [atenolol- based]) for the prevention of major cardiovascular events were compared in 5137 patients with diabetes mellitus.308 The target BP was <130/80 mmHg. The trial was terminated early because of reductions in mortality and stroke with the amlodipine-based regimen. In patients with diabetes mellitus, the amlodipine- based therapy reduced the incidence of total cardiovascular events and procedures compared with the atenolol-based regi- reduction (P=0.017) in fatal and nonfatal strokes. The open-label ACCORD trial randomized trial 4733 par- ticipants to 1 of 2 groups with different treatment goals: SBP <120 mmHg as the more intensive goal and SBP <140 mmHg as the less intensive goal. Randomization to the more intensive goal did not reduce the rate of the composite outcome of fatal and nonfatal major CVD events (HR, 0.88; 95% CI, 0.73 1.06; P=0.20). Stroke was a prespecified secondary end point occur- ring at annual rates of 0.32% (more intensive) and 0.53% (less In the Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, 11506 patients (6746 with diabetes mellitus) with hypertension were randomized to treatment with benazepril plus amlodipine or benazepril plus hydro- The primary end point was the composite of death resulting from CVD, nonfatal MI, nonfatal stroke, hospitalization for angina, resuscitated cardiac arrest, and cor- onary revascularization.


Stroke was a prespecified secondary end point occur- ring at annual rates of 0.32% (more intensive) and 0.53% (less In the Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, 11506 patients (6746 with diabetes mellitus) with hypertension were randomized to treatment with benazepril plus amlodipine or benazepril plus hydro- The primary end point was the composite of death resulting from CVD, nonfatal MI, nonfatal stroke, hospitalization for angina, resuscitated cardiac arrest, and cor- onary revascularization. The trial was terminated early after a mean follow-up of 36 months when there were 552 primary outcome events in the benazepril/amlodipine group (9.6%) and 679 in the benazepril/hydrochlorothiazide group (11.8%), an absolute risk reduction of 2.2% (HR, 0.80; 95% CI, 0.72 0.90; P<0.001). There was, however, no difference in stroke between the groups. Of the participants in the ACCOMPLISH trial with diabetes mellitus, the primary outcome results were similar. Two recent meta-analyses investigated the effect of BP lowering in patients with type 2 diabetes mellitus. The first included 37760 patients with type 2 diabetes mellitus or impaired fasting glucose/impaired glucose tolerance with achieved SBP of 135 versus 140 mmHg, and the follow-up was at least 1 year.310 Intensive BP control was associated with a 10% reduction in all-cause mortality (OR, 0.90; 95% CI, 0.83 0.98) and a 17% reduction in stroke, but there was a 20% increase in serious adverse effects. Meta-regression analysis showed continued risk reduction for stroke to a SBP of <120 mmHg. However, at levels of <130 mmHg, there was a 40% increase in serious adverse events with no benefit for other outcomes.


However, at levels of <130 mmHg, there was a 40% increase in serious adverse events with no benefit for other outcomes. In the second meta-analysis, 73913 patients with diabetes mellitus (295652 patient-years of exposure) were randomized Overall, more aggressive treatment reduced stroke incidence by 9% (P=0.006), and lower versus less aggressive BP control reduced the risk of stroke by 31% (RR, 0.61; 95% CI, 0.48 0.79). In a meta-regression analy- sis, the risk of stroke decreased by 13% (95% CI, 0.05 0.20; P=0.002) for each 5-mmHg reduction in SBP and by 11.5% in DBP.


In a meta-regression analy- sis, the risk of stroke decreased by 13% (95% CI, 0.05 0.20; P=0.002) for each 5-mmHg reduction in SBP and by 11.5% in DBP. Lipid-Altering Therapy and Diabetes Mellitus Although secondary subgroup analyses of some studies did not find a benefit of statins in patients with diabetes mellitus,311,312 the Medical Research Council/British Heart Foundation Heart Protection Study (HPS) found that the addition of a statin to existing treatments in high-risk patients resulted in a 24% reduction (95% CI, 19 28) in the rate of major CVD events.313 A 22% reduction (95% CI, 13 30) in major vascular events (regardless of the presence of known coronary heart disease or cholesterol levels) and a 24% reduction (95% CI, 6 39; P=0.01) in strokes were found among 5963 diabetic individu- als treated with the statin in addition to best medical care.314 The Collaborative Atorvastatin Diabetes Study (CARDS) reported that in patients with type 2 diabetes mellitus, at least 1 additional risk factor (retinopathy, albuminuria, current smoking, or hypertension), and an LDL cholesterol level <160 mg/dL but without a history of CVD, treatment with a statin resulted in a 48% reduction (95% CI, 11 69) in stroke.315 In a post hoc analysis of the Treating to New Targets (TNT) study, the effects of intensive lowering of LDL cholesterol with high-dose (80 mg daily) versus low-dose (10 mg daily) atorvastatin on CVD events were compared for patients with coronary heart disease and diabetes mellitus.316 After a median follow-up of 4.9 years, higher-dose treatment was associated with a 40% reduction in the time to a CVD event (HR, 0.69; 95% CI, 0.48 0.98; P=0.037).


Lipid-Altering Therapy and Diabetes Mellitus Although secondary subgroup analyses of some studies did not find a benefit of statins in patients with diabetes mellitus,311,312 the Medical Research Council/British Heart Foundation Heart Protection Study (HPS) found that the addition of a statin to existing treatments in high-risk patients resulted in a 24% reduction (95% CI, 19 28) in the rate of major CVD events.313 A 22% reduction (95% CI, 13 30) in major vascular events (regardless of the presence of known coronary heart disease or cholesterol levels) and a 24% reduction (95% CI, 6 39; P=0.01) in strokes were found among 5963 diabetic individu- als treated with the statin in addition to best medical care.314 The Collaborative Atorvastatin Diabetes Study (CARDS) reported that in patients with type 2 diabetes mellitus, at least 1 additional risk factor (retinopathy, albuminuria, current smoking, or hypertension), and an LDL cholesterol level <160 mg/dL but without a history of CVD, treatment with a statin resulted in a 48% reduction (95% CI, 11 69) in stroke.315 In a post hoc analysis of the Treating to New Targets (TNT) study, the effects of intensive lowering of LDL cholesterol with high-dose (80 mg daily) versus low-dose (10 mg daily) atorvastatin on CVD events were compared for patients with coronary heart disease and diabetes mellitus.316 After a median follow-up of 4.9 years, higher-dose treatment was associated with a 40% reduction in the time to a CVD event (HR, 0.69; 95% CI, 0.48 0.98; P=0.037). Clinical trials with a statin or any other single intervention in patients with high CVD risk, including the presence of dia- betes mellitus, are often insufficiently powered to determine an effect on incident stroke.


Clinical trials with a statin or any other single intervention in patients with high CVD risk, including the presence of dia- betes mellitus, are often insufficiently powered to determine an effect on incident stroke. In 2008, data from 18686 indi- viduals with diabetes mellitus (1466 with type 1 and 17220 with type 2 diabetes mellitus) were assessed to determine the impact of a 1.0-mmol/l ( 40-mg/dL) reduction in LDL choles- During a mean follow-up of 4.3 years, there were 3247 major cardiovascular events with a 9% proportional reduction Meschia et al Guidelines for the Primary Prevention of Stroke 3771 in all-cause mortality per 1-mmol/L LDL cholesterol reduction were also reductions in MI or coronary death (RR, 0.78; 95% 0.93; P=0.0002). A subgroup analysis was carried out from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) in which subjects received either gemfibrozil (1200 mg/d) or placebo for 5.1 years.318 Compared with those with normal fasting plasma glucose, the risk for major cardiovascular events was higher in subjects with either mellitus. Gemfibrozil treatment did not affect the risk of stroke among subjects without diabetes mellitus, but treatment was associated with a 40% reduction in stroke in those with diabe- tes mellitus (HR, 0.60; 95% CI, 0.37 0.99; P= 0.046). The FIELD study assessed the effect of fenofibrate on car- diovascular events in 9795 subjects 50 to 75 years of age with type 2 diabetes mellitus who were not taking a statin therapy at study entry.319 The study population included 2131 people with and 7664 people without previous CVD. Over 5 years, 5.9% of patients (n=288) on placebo and 5.2% (n=256) on fenofibrate had a coronary event (P=0.16). There was a 24% MI. There was no effect on stroke with fenofibrate.


There was a 24% MI. There was no effect on stroke with fenofibrate. A higher rate of statin therapy initiation occurred in patients allocated to placebo, which might have masked a treatment effect. The ACCORD trial randomized 5518 patients with type 2 diabetes mellitus who were being treated with open-label simvastatin to double-blind treatment with fenofibrate or placebo.177 There was no effect of added fenofibrate on the primary outcome (first occurrence of nonfatal MI, nonfatal stroke, or death from cardiovascular causes [HR, 0.92; 95% CI, 0.79 1.08; P=0.32]) and no effect on any secondary outcome, including stroke (HR, 1.05; 95% CI, 0.71 1.56; P=0.80). A recent meta-analysis examining the effects of fibrates on stroke in 37791 patients included some patients with diabetes Overall, fibrate therapy was not associated with a significant reduction on the risk of stroke (RR, 1.02; 95% CI, 0.90 1.16; P=0.78). However, a subgroup analysis suggested that fibrate therapy reduced fatal stroke (RR, 0.49; 95% CI, 0.26 0.93; P=0.03) in patients with diabetes mellitus, CVD, or stroke. Diabetes Mellitus, Aspirin, and Stroke The benefit of aspirin in the primary prevention of cardiovascu- lar events, including stroke in patients with diabetes mellitus, remains unclear. A recent study at 163 institutions throughout Japan enrolled 2539 patients with type 2 diabetes mellitus and no history of atherosclerotic vascular disease.321 Patients were assigned to receive low-dose aspirin (81 or 100 mg/d) or no aspirin. Over 4.37 years, a total of 154 atherosclerotic vascu- lar events occurred (68 in the aspirin group [13.6 per 1000 person-years] and 86 in the nonaspirin group [17.0 per 1000 single fatal stroke occurred in the aspirin group, but 5 strokes occurred in the nonaspirin group; thus, the study was insuf- ficiently powered to detect an effect on stroke. Severallargeprimarypreventiontrialshaveincludedsubgroup analyses of patients with diabetes mellitus.


Over 4.37 years, a total of 154 atherosclerotic vascu- lar events occurred (68 in the aspirin group [13.6 per 1000 person-years] and 86 in the nonaspirin group [17.0 per 1000 single fatal stroke occurred in the aspirin group, but 5 strokes occurred in the nonaspirin group; thus, the study was insuf- ficiently powered to detect an effect on stroke. Severallargeprimarypreventiontrialshaveincludedsubgroup analyses of patients with diabetes mellitus. The Antithrombotic Trialists Collaboration meta-analysis of 287 randomized trials reported effects of antiplatelet therapy (mainly aspirin) versus There was a nonsignificant 7% reduction in serious vascular events, including stroke, in the subgroup of 5126 patients with diabetes mellitus. A meta-analysis covering the interval between 1950 and 2011 included 7 studies in patients with diabetes mellitus without previous CVD and helps to shed new light on this controversial A total of 11618 participants were included in the anal- ysis. The overall relative risk for major cardiovascular events was 0.91 (95% CI, 0.82 1.00), but an effect on stroke incidence was not found (RR, 0.84; 95% CI, 0.64 1.11). Because hyper- glycemia reduces platelet sensitivity to aspirin,324 an important consideration in patients with diabetes mellitus is aspirin dose. In another meta-analysis, there was no evidence that aspirin dose explained the lack of an aspirin effect on cardiovascular and stroke mortality in patients with diabetes mellitus.325 However, the systematic review identified an important gap in random- ized, controlled trials for using anywhere between 101 to 325 mg aspirin daily in patients with diabetes mellitus. Diabetes: Summary and Gaps A comprehensive program that includes tight control of hyper- tension with ACEI or ARB treatment reduces the risk of stroke in people with diabetes mellitus. Glycemic control reduces microvascular complications, but there remains no evidence that improved glycemic control reduces the risk of incident stroke.


Glycemic control reduces microvascular complications, but there remains no evidence that improved glycemic control reduces the risk of incident stroke. Adequately powered studies show that treatment of patients with diabetes mellitus with a statin decreases the risk of a first stroke. Although a subgroup analysis of VA-HIT suggests that gemfi- brozil reduces stroke in men with diabetes mellitus and dyslip- idemia, a fibrate effect was not seen in FIELD, and ACCORD found no benefit of adding fenofibrate to statin. However, the subgroup analysis from fibrate trials suggests a benefit of fibrates in patients with diabetes mellitus and a BMI >30 kg/m2 . Diabetes: Recommendations 1. Control of BP in accordance with an AHA/ACC/ to a target of <140/90 mmHg is rec- ommended in patients with type 1 or type 2 diabetes mellitus (Class I; Level of Evidence A). 2. Treatment of adults with diabetes mellitus with a statin, especially those with additional risk factors, is recommended to lower the risk of first stroke (Class I; Level of Evidence A). 3. The usefulness of aspirin for primary stroke prevention for patients with diabetes mellitus but low 10-year risk of CVD is unclear (Class IIb; Level of Evidence B). 4. Adding a fibrate to a statin in people with diabetes mellitus is not useful for decreasing stroke risk (Class III; Level of Evidence B). Cigarette Smoking Virtually every multivariable assessment of stroke risk factors and the Honolulu Heart Study327 ) has identified cigarette smoking as a potent risk factor for ischemic stroke, associated with an approximate doubling of risk.


Cigarette Smoking Virtually every multivariable assessment of stroke risk factors and the Honolulu Heart Study327 ) has identified cigarette smoking as a potent risk factor for ischemic stroke, associated with an approximate doubling of risk. Data from studies largely conducted in older age groups also pro- vide evidence of a dose-response relationship, and this has been extended to young women from an ethnically diverse cohort.328 Smoking is also associated with a 2- to 4-fold increased risk for The data for ICH (apart from SAH), however, are inconsistent. A multicenter case-control study found an adjusted for ICH, and analyses from the Physicians Health Study332 also found such an association, but other studies, including a pooled analysis of the ARIC and CHS cohorts, found no relationship between smoking and ICH risk.135,334 336 A meta-analysis of 32 studies estimated the RR for ischemic stroke to be 1.9 (95% CI, 1.7 2.2) for smokers versus nonsmokers, the RR for SAH to be 2.9 (95% CI, 2.5 3.5), and the RR for ICH to be 0.74 (95% CI, 0.56 0.98).335 The annual number of stroke deaths attributed to smoking in the United States is estimated to be between 21400 (with- out adjustment for potential confounding factors) and 17800 (after adjustment), which suggests that smoking contributes to From data available from the National Health Interview Survey and death certificate data for 2000 through 2004, the Centers for Disease Control and Prevention estimated that smoking resulted in an annual average of 61616 stroke deaths among men and 97681 stroke deaths among women.338 Cigarette smoking may potentiate the effects of other stroke risk factors, including SBP339 For example, a synergistic effect exists between the use of OCs and smoking on the risk of cerebral infarction.


A multicenter case-control study found an adjusted for ICH, and analyses from the Physicians Health Study332 also found such an association, but other studies, including a pooled analysis of the ARIC and CHS cohorts, found no relationship between smoking and ICH risk.135,334 336 A meta-analysis of 32 studies estimated the RR for ischemic stroke to be 1.9 (95% CI, 1.7 2.2) for smokers versus nonsmokers, the RR for SAH to be 2.9 (95% CI, 2.5 3.5), and the RR for ICH to be 0.74 (95% CI, 0.56 0.98).335 The annual number of stroke deaths attributed to smoking in the United States is estimated to be between 21400 (with- out adjustment for potential confounding factors) and 17800 (after adjustment), which suggests that smoking contributes to From data available from the National Health Interview Survey and death certificate data for 2000 through 2004, the Centers for Disease Control and Prevention estimated that smoking resulted in an annual average of 61616 stroke deaths among men and 97681 stroke deaths among women.338 Cigarette smoking may potentiate the effects of other stroke risk factors, including SBP339 For example, a synergistic effect exists between the use of OCs and smoking on the risk of cerebral infarction. With nonsmoking, non-OC users serving as the reference group, the odds of cerebral infarc- tion were 1.3 times greater (95% CI, 0.7 2.1) for women who smoked but did not use OCs, 2.1 times greater (95% CI, 1.0 4.5) for nonsmoking OC users, and 7.2 times greater (95% CI, 3.2 16.1) for OC users who smoked.340 There was also a syn- ergistic effect of smoking and OC use on hemorrhagic stroke risk.


With nonsmoking, non-OC users serving as the reference group, the odds of cerebral infarc- tion were 1.3 times greater (95% CI, 0.7 2.1) for women who smoked but did not use OCs, 2.1 times greater (95% CI, 1.0 4.5) for nonsmoking OC users, and 7.2 times greater (95% CI, 3.2 16.1) for OC users who smoked.340 There was also a syn- ergistic effect of smoking and OC use on hemorrhagic stroke risk. With nonsmoking, non-OC users as the reference group, the odds of hemorrhagic stroke were 1.6 times greater (95% CI, 1.2 2.0) for women who smoked but did not use OCs, 1.5 times greater (95% CI, 1.1 2.1) for nonsmoking OC users, and 3.7 times greater (95% CI, 2.4 5.7) for OC users who smoked.341 Exposure to environmental tobacco smoke (also referred to as passive or second-hand smoke) is an established risk factor for heart disease.342,343 Exposure to environmental tobacco smoke may also be a risk factor for stroke, with a risk approaching the doubling found for active smoking,344 349 although 1 study found no association.350 Because the dose of exposure to environmental tobacco smoke is substantially lower than for active smoking, the magnitude of the risk associated with environmental tobacco smoke is surpris- ing. This apparent lack of a dose-response relationship may be explained in part by physiological studies suggesting a tobacco smoke exposure threshold rather than a linear dose- Recent studies of the effects of smok- ing bans in communities have also shown that these bans are associated with a reduction in the risk of stroke. After Arizona enacted a statewide ban on smoking in most indoor public places.


After Arizona enacted a statewide ban on smoking in most indoor public places. including workspaces, restaurants, and bars, there was a 14% reduction in strokes in counties that had not previously had a ban in place.352 A study of New York State did not find a reduction in strokes despite a decrease in risk of MI when it enacted a comprehensive smoking ban in enclosed work- spaces, restaurants, and construction sites.353 Smoking likely contributes to increased stroke risk through both short-term effects on the risk of thrombus generation in ath- erosclerotic arteries and long-term effects related to increased Smoking as little as a single cigarette increases heart rate, mean BP, and cardiac index and decreases arterial dis- Beyond the immediate effects of smoking, both active and passive exposure to cigarette smoke is associated with the development of atherosclerosis.357 In addition to placing indi- viduals at increased risk for both thrombotic and embolic stroke, cigarette smoking approximately triples the risk of cryptogenic stroke among individuals with a low atherosclerotic burden and no evidence of a cardiac source of emboli.358,359 Although the most effective preventive measures are to never smoke and to minimize exposure to environmental tobacco smoke, risk is reduced with smoking cessation.


including workspaces, restaurants, and bars, there was a 14% reduction in strokes in counties that had not previously had a ban in place.352 A study of New York State did not find a reduction in strokes despite a decrease in risk of MI when it enacted a comprehensive smoking ban in enclosed work- spaces, restaurants, and construction sites.353 Smoking likely contributes to increased stroke risk through both short-term effects on the risk of thrombus generation in ath- erosclerotic arteries and long-term effects related to increased Smoking as little as a single cigarette increases heart rate, mean BP, and cardiac index and decreases arterial dis- Beyond the immediate effects of smoking, both active and passive exposure to cigarette smoke is associated with the development of atherosclerosis.357 In addition to placing indi- viduals at increased risk for both thrombotic and embolic stroke, cigarette smoking approximately triples the risk of cryptogenic stroke among individuals with a low atherosclerotic burden and no evidence of a cardiac source of emboli.358,359 Although the most effective preventive measures are to never smoke and to minimize exposure to environmental tobacco smoke, risk is reduced with smoking cessation. Smoking cessa- tion is associated with a rapid reduction in the risk of stroke and other cardiovascular events to a level that approaches, but does not reach, that of those who never smoked.354,360 362 Although sustained smoking cessation is difficult to achieve, effective behavioral and pharmacological treatments for nicotine dependence are available.363 365 Comprehensive reviews and recommendations for smoking cessation are pro- vided in the 2008 Surgeon General s report,363 the 2008 update from the Public Health Service,366 and the 2009 affirmation of these recommendations from the US Preventive Services Task The combination of counseling and medications is more effective than either therapy alone.367 With regard to specific pharmacotherapy, in a meta-anal- ysis current to January 2012, nicotine replacement therapy, bupropion, and varenicline were all superior to inert control medications, but varenicline was superior to each of the other active interventions in direct comparisons.368 Emerging evi- dence suggests that varenicline may be more cost-effective than nicotine replacement therapy.369 Cigarette Smoking: Summary and Gaps Cigarette smoking increases the risk of ischemic stroke and SAH, but the data on ICH are inconclusive.


Smoking cessa- tion is associated with a rapid reduction in the risk of stroke and other cardiovascular events to a level that approaches, but does not reach, that of those who never smoked.354,360 362 Although sustained smoking cessation is difficult to achieve, effective behavioral and pharmacological treatments for nicotine dependence are available.363 365 Comprehensive reviews and recommendations for smoking cessation are pro- vided in the 2008 Surgeon General s report,363 the 2008 update from the Public Health Service,366 and the 2009 affirmation of these recommendations from the US Preventive Services Task The combination of counseling and medications is more effective than either therapy alone.367 With regard to specific pharmacotherapy, in a meta-anal- ysis current to January 2012, nicotine replacement therapy, bupropion, and varenicline were all superior to inert control medications, but varenicline was superior to each of the other active interventions in direct comparisons.368 Emerging evi- dence suggests that varenicline may be more cost-effective than nicotine replacement therapy.369 Cigarette Smoking: Summary and Gaps Cigarette smoking increases the risk of ischemic stroke and SAH, but the data on ICH are inconclusive. Epidemiological studies show a reduction in stroke risk with smoking cessation and with community-wide smoking bans. Although effective programs to facilitate smoking cessation exist, data show- ing that participation in these programs leads to a long-term reduction in stroke are lacking. Cigarette Smoking: Recommendations 1. Counseling, in combination with drug therapy using nicotine replacement, bupropion, or varenicline, is recommended for active smokers to assist in quitting smoking (Class I; Level of Evidence A). 2. Abstention from cigarette smoking is recommended for patients who have never smoked on the basis of epidemiological studies showing a consistent and overwhelming relationship between smoking and both ischemic stroke and SAH (Class I; Level of Evidence B).


Abstention from cigarette smoking is recommended for patients who have never smoked on the basis of epidemiological studies showing a consistent and overwhelming relationship between smoking and both ischemic stroke and SAH (Class I; Level of Evidence B). Meschia et al Guidelines for the Primary Prevention of Stroke 3773 3. Community-wide or statewide bans on smoking in public spaces are reasonable for reducing the risk of stroke and MI (Class IIa; Level of Evidence B). Atrial Fibrillation AF, even in the absence of cardiac valvular disease, is associ- ated with a 4- to 5-fold increased risk of ischemic stroke result- ing from embolism of stasis-induced thrombi forming in the left atrial appendage (LAA).370 About 2.3 million Americans have either sustained or paroxysmal AF.370 Embolism of appendage thrombi associated with AF accounts for 10% of all ischemic strokes and an even higher fraction in the very elderly in the United States.371 The absolute stroke rate aver- ages 3.5%/y for 70-year-old individuals with AF, but the risk varies 20-fold among patients, depending on age and other clinical features (see below).372,373 AF is also an independent predictor of increased mortality.374 Paroxysmal AF increases stroke risk similar to sustained AF.375 There is an important opportunity for primary stroke pre- vention in patients with AF because the dysrhythmia is diag- nosed before stroke in many patients. However, a substantial minority of AF-related stroke occurs in patients without a prior diagnosis of the condition.


However, a substantial minority of AF-related stroke occurs in patients without a prior diagnosis of the condition. Studies of active screening of patients >65 years of age for AF in primary care settings show that pulse assessment by trained personnel increases the detection of undiagnosed AF.376,377 Systematic pulse assess- ment during routine clinic visits followed by 12-lead ECG in those with an irregular pulse resulted in a 60% increase in the detection of AF.376 Risk Stratification in Patients With AF Once the diagnosis of AF is established, the next step is to estimate an individual s risks for cardioembolic stroke and for hemorrhagic complications of antithrombotic therapy. For estimating risk of AF-related cardioembolic stroke, more than a dozen risk stratification schemes have been proposed on the basis of various combinations of clinical and echocar- The widely used CHADS2 scheme (Table 3) yields a score of 0 to 6, with 1 point each given for congestive heart failure, hypertension, age 75 years, and diabetes mellitus and with 2 points given for prior stroke or transient ischemic attack (TIA).378 This scheme has been tested in multiple independent cohorts of AF patients, with 0 points corresponding to low risk (0.5% and 2 points indicating high risk (1.9%/y 7.6%/y).373 The -VASc scheme (Table 3) modifies CHADS2 by add- ing an age category (1 point for age 65 to 74 years, 2 points for age 75 years) and adding 1 point each for diagnosis of vas- cular disease (such as peripheral artery disease, MI, or aortic plaque) and for female sex. The main advantage of the more -VASc scheme for primary stroke pre- vention is improved stratification of individuals estimated to be at low to moderate risk using CHADS2 (scores of 0 to 1).


The main advantage of the more -VASc scheme for primary stroke pre- vention is improved stratification of individuals estimated to be at low to moderate risk using CHADS2 (scores of 0 to 1). A study of 45576 such patients found combined stroke and thromboembolism rates per 100 person-years ranging from -VASc of 0 to 1.79, respectively, resulting in significantly improved prediction.383 Instruments have also been proposed for stratifying risk of bleeding associated with warfarin treatment for AF. In the HAS-BLED scheme (Table 3), 1 point is assigned each for hypertension, abnormal renal or liver function, past stroke, past bleeding history or predisposition, labile INR (ie, poor time in therapeutic range), older age (age >65 years), and use of certain drugs (concomitant antiplatelet or nonsteroidal anti- inflammatory agent use, alcohol abuse).381 In a validation anal- ysis of data from 2293 subjects randomized to idraparinux or vitamin K antagonist therapy, the HAS-BLED score was mod- erately predictive (HAS-BLED >2: HR, 1.9 for clinically rele- vant bleeding; HR, 2.4 for major bleeding).382 The ATRIA Risk derived its point scheme from the Anticoagulation and Risk Factors in Atrial Fibrillation study, assigning 3 points for anemia or severe renal disease (estimated glomerular filtra- tion rate <30 mL/min or dialysis dependent), 2 for age 75 years, and 1 for any prior hemorrhage diagnosis or hyperten- sion. Subjects in a validation cohort were successfully divided into groups at low (ATRIA score of 0 to 3, <1%/y) and high (ATRIA score of 5 to 10, >5%/y) risk for major hemorrhage. Table 3.


Subjects in a validation cohort were successfully divided into groups at low (ATRIA score of 0 to 3, <1%/y) and high (ATRIA score of 5 to 10, >5%/y) risk for major hemorrhage. Table 3. Stroke Risk Stratification Schemes for Patients With Atrial Fibrillation Scoring system Congestive heart failure 1 point Diabetes mellitus 1 point Risk scores range: 0 6 points Levels of risk for thromboembolic stroke Low risk for stroke=0 points Moderate risk=1 point High risk 2 points Scoring system Congestive heart failure 1 point Diabetes mellitus 1 point Vascular disease (eg, peripheral artery disease, myocardial infarction, aortic plaque) 1 point Female sex 1 point Risk scores range: 0 9 points Levels of risk for thromboembolic stroke Low risk=0 points Moderate risk=1 point High risk 2 points ACCP treatment guidelines based on estimated risk for thromboembolic Low risk: no therapy Moderate risk: OAC High risk: OAC Abnormal renal function 1 point Abnormal liver function 1 point Prior stroke 1 point Prior major bleeding or bleeding INR in therapeutic range <60% of time 1 point Use of antiplatelet or nonsteroidal Excessive alcohol use 1 point Risk scores range: 0 9 points Score >2 associated with clinically relevant and major bleeding.382 ACCP indicates American College of Chest Physicians; INR, international normalized ratio; OAC, oral anticoagulation; and TIA, transient ischemic attack. Most of these analyses stratifying risk of future bleeding have not focused on intracranial hemorrhages, the category of major bleeding with the greatest long-term effect on quality of life. Another limitation of prediction scales for hemorrhage is that several of their components such as age and hypertension are also risks for cardioembolic stroke.


Another limitation of prediction scales for hemorrhage is that several of their components such as age and hypertension are also risks for cardioembolic stroke. Selecting Treatment to Reduce Stroke Risk in Patients With AF Adjusted-dose warfarin has generally been the treatment of choice for patients at high risk for cardioembolic stroke and acceptably low risk of hemorrhagic complications, particu- larly intracranial hemorrhage. Treatment with adjusted-dose warfarin (target INR, 2 to 3) robustly protects against stroke (RR reduction, 64%; 95% CI, 49 74), virtually eliminating the excess risk of ischemic stroke associated with AF if the intensity of anticoagulation is adequate and reducing all-cause In addition, anticoagu- lation reduces stroke severity and poststroke mortality.386 388 Compared with aspirin, adjusted-dose warfarin reduces stroke Three newer oral anticoagulants have been approved in the United States for stroke prevention in patients with nonvalvu- lar AF: the direct thrombin inhibitor dabigatran (dosed at 150 mg twice daily in patients with creatinine clearance 30 mL/ min) and the direct factor Xa inhibitors rivaroxaban (20 mg once daily for patients with creatinine clearance 50 mL/min) and apixaban (5 mg twice daily for patients with no more than 1 of the following characteristics: age 80 years, serum creati- nine 1.5 mg/dL, or body weight 60 kg). Clinical trial data and other information for these agents were recently reviewed in an AHA/American Stroke Association science advisory390 and are briefly summarized here. The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial391 randomized 18113 patients to dabi- gatran 150 mg or 110 mg twice daily or adjusted-dose war- farin (target INR, 2 to 3).


The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial391 randomized 18113 patients to dabi- gatran 150 mg or 110 mg twice daily or adjusted-dose war- farin (target INR, 2 to 3). The study enrolled patients with and without a history of prior stroke but with overall mod- erate to high risk of stroke (mean CHADS2 score, 2.1) and excluded patients who had stroke within 14 days (6 months for severe stroke), increased bleeding risk, creatinine clear- ance <30 mL/min, or active liver disease. The primary out- come of stroke or systemic embolism during the mean 2-year follow-up occurred at a rate of 1.7%/y in the warfarin (INR, 2 to 3) group compared with 1.11%/y in the 150 mg dabi- gatran group (RR=0.66 versus warfarin; 95% CI, 0.53 0.82; P<0.001 for superiority). Intracranial hemorrhage rates were strikingly lower with 150 mg dabigatran relative to adjusted- 0.27 0.60). However, the overall rates of major bleeding were not different between the groups (3.11%/y versus 3.36%/y; P=0.31), and gastrointestinal bleeding was more frequent 95% CI, 1.19 1.89). MI was also increased in the 150 mg although this difference was no longer sig- nificant when silent MIs or unstable angina, cardiac arrest, and cardiac death were included.391 Meta-analysis of 7 trials of dabigatran use for various indications has supported the possibility of a small but consistent increased risk of MI or acute coronary syndrome versus the risk observed in various control arms of these studies (OR, 1.33; 95% CI, 1.03 1.71; Finally, analyses of multiple patient subgroups, categorized by nationality,394 and the pres- ence or absence of prior TIA/stroke, have not found evidence for differences in the risk/benefit profile for dabigatran.


MI was also increased in the 150 mg although this difference was no longer sig- nificant when silent MIs or unstable angina, cardiac arrest, and cardiac death were included.391 Meta-analysis of 7 trials of dabigatran use for various indications has supported the possibility of a small but consistent increased risk of MI or acute coronary syndrome versus the risk observed in various control arms of these studies (OR, 1.33; 95% CI, 1.03 1.71; Finally, analyses of multiple patient subgroups, categorized by nationality,394 and the pres- ence or absence of prior TIA/stroke, have not found evidence for differences in the risk/benefit profile for dabigatran. In the subgroup of patients 75 years of age,396 mg was associated with increased gastrointestinal hemor- rhage relative to warfarin (OR, 1.79; 95% CI, 1.35 2.37) but reduced ICH (OR, 0.42; 95% CI, 0.25 0.70). The Rivaroxaban Versus Warfarin in Nonvalvular Atrial Fibrillation (ROCKETAF) Trial397 randomized 14264 patients with nonvalvular AF to rivaroxaban 20 mg/d or adjusted-dose warfarin (target INR, 2 to 3). A CHADS2 score of 2 was required, yielding a mean score for enrolled subjects of 3.5, which was higher than in the RE-LY and ARISTOTLE trials; more than half of the participants had a stroke, TIA, or sys- temic embolism before enrollment. Over a median follow-up of 707 days, the primary end point of ischemic and hemor- rhagic stroke and systemic embolism in patients as actually treated (the prespecified analysis plan for efficacy in this study) occurred in 1.7%/y in those receiving rivaroxaban and 2.2%/y in those on warfarin (HR, 0.79; 95% CI, 0.66 0.96; P<0.001 for noninferiority; analyzed by intention to treat, HR, for superiority).