1. Risk Factor Modification Post Stroke Ron Pellegrino, MD November 20, 2015

2. Objectives Become comfortable with risk factor modification and chronic management of the post stroke patient. Review the major modifiable risk factors HTN guidelines for long term management of ischemic stroke Antiplatelet therapy vs. anticoagulants Review lipid guidelines for ischemic stroke

3. Risk Assessment Tools Incorporate Atrial fibrillation Age HTN, and use of anti-hypertensive meds Smoking Presence of LVH Diabetes Presence of CVD

4. Risk Assessment Tools Women age 55-84 (Framingham Data) Men Age 55-84 (Framingham Data) RiskFactorDiff = (Age * 0.0657) + (SysBP * 0.0197) - (SysBP * (HTNMed > 0) * 0.0134) + HTNMed + DM + Cig + CVD + AFib + LVH - 7.5766 RiskDuringPeriod = 100 * (1 - RiskPeriodFactor e(RiskFactorDiff) ) RiskFactorDiff = (Age * 0.0505) + (SysBP * 0.014) + HTNMed + DM + Cig + CVD + AFib + LVH - 5.677 RiskDuringPeriod = 100 * (1 - RiskPeriodFactor e(RiskFactorDiff) )

5. Unmodifiable risk factors Older age, particularly > 80 years Race and ethnicity Gender Male > Female Except age 35-44 and >85 years Family History Genetic disorders Sickle cell Cerebral autosomal dominant arteriopathy

6. What should we worry about? Major treatable atherosclerotic risk factors Hypertension (50 th ) Diabetes mellitus (49 th ) Smoking (50 th ) Dyslipidemia (48 th ) Obesity (49 th )

7. Our patient: JB No medical history at time of event Initial event, then recurrent symptoms Enrolled in Medical Arm of SAMMPRIS trial (December 2010) 3 years after initial event BP 156/84 HbA1c 8.3% BMI 42 Lipids: Chol 198, HDL 32, LDL 135, Trig 157

8. HYPERTENSION

9. Hypertension Most common reason for office visits in US Also most common reason for Rx 70% of patients with recent ischemic stroke ~30% adults in US 76.4 million adults over age 20 National Health Statistics Report 2001-08 BP adequately controlled in only 50% of patients Poor access to care Condition asymptomatic Lack of adherence to therapy Therapeutic inertia Up to 8% remain undiagnosed

10. Hypertension Promotes formation of atherosclerotic lesions Single most important treatable risk factor for stroke Increased likelihood of subclinical event ↑ risk of recurrence and vascular dementia Gradual increase in mortality when BP > 110/75 Risk associated with multiple BP variables BP variability/ instability Nocturnal dipping of pressures

12. Antihypertensive Therapy and Prevention of Recurrent Stroke Which patients should be treated? When should therapy be initiated? Which antihypertensive drugs should be used? What is the goal blood pressure?

13. Which patients? Treat Resume therapy in any patient previously treated for known HTN Initiate therapy in untreated patients with established BP after the first several days >140 systolic or >90 diastolic Untreated patients with SBP >120 or DBP >70 with ischemic stroke or CVA of atherothrombotic, lacunar or cryptogenic type

14. PROGRESS trial RCT: 6100 patients, mean age 64 years Stroke (mostly ischemic) or TIA within 5 years Mean BP 147/86 ACE inhibitor (perindopril) vs. placebo Indapamide added prn to treatment group ↓BP 9/4 mmHg in treatment group 28% RR reduction of fatal or nonfatal stroke Stroke benefit related to degree of blood pressure reduction Most apparent with combination therapy (12/5 mmHg) RR reduction 43% Benefit noted in hypertensive and non-hypertensive patients

15. Which patients? Don’t treat Nonhypertensive patients ( <140/90) if event due to cardioembolic or paradoxical embolus Untreated patients with BP < 120/70 Increased risk of further event if BP drops compared to patients with higher starting BP

16. When should therapy be initiated? Initiation or resumption in hospital U-shaped relationship of blood pressure to outcomes in acute ischemic stroke Management remains controversial Most guidelines suggest BP not be treated acutely unless extreme or significant comorbids If necessary, cautious drop by 15% in first 24 hours Resume meds approximately 24 hours after event in patients with known HTN Patients with large artery stenoses may require slower reduction in BP over 7-10 days Separate goals for patients receiving thrombolytic therapy As outpatient, begin therapy immediately if any of the prior conditions are met BP > 140/90 Untreated patients with SBP >120 or DBP >70 with ischemic stroke or CVA of atherothrombotic, lacunar or cryptogenic type

17. Which meds should be used? Monotherapy ACE/ARB, CCB, and diuretics all reasonable No compelling evidence for one class over another Meta-analysis: 7 trials, 30K patients Angiotensin inhibitors modestly reduced risk of recurrent stroke and major CV events 3 trials compare CCB vs. ACE/ARB No significant difference in secondary prevention CCB may be superior for primary prevention PATS trial suggests diuretics moderately effective Beta Blockers may not reduce stroke risk compared to the above classes Reserve use unless other compelling indication

18. PATS Trial 5665 Chinese patients with h/o CVA/TIA Avg. BP 154/93, 2.5 years following event Randomized to indapamide vs. placebo Followed for 2 years, Mean BP reduction 6.8/3.3 mmHg 143 strokes in treatment group vs. 219 in placebo

19. Which meds should be used? Combination Therapy 2014 AHA/ASA guidelines ACE inhibitor + Thiazide diuretic ACCOMPLISH Trial (11,500 high risk patients) Benazepril + HCTZ or amlodipine Better outcomes using long acting dihydropyridine CCB N Engl J Med.N Engl J Med. 2008 Dec 4;359(23):2417-28 Stroke.Stroke. 2014 Jul;45(7):2160-236

20. What are our goals? Presence of hemodynamically significant large artery stenosis Cautious lowering of BP, Minimum ↓10/5 mmHg Do not treat if initial BP less than 120/70 Absence of hemodynamically significant large artery stenosis Minimum ↓10/5 mmHg Do not start meds if initial BP less than 120/70 Treat to below 140/90 SBP preferably below 130 mmHg if tolerated Lacunar stroke Treat to SBP below 130 mmHg In general, Gradual reduction of SBP by 5 mmHg at a time is best tolerated for long-standing uncontrolled HTN Ischemic symptoms are unlikely unless BP acutely drops more than 25% from baseline level

21. BP Targets: SPS3 Randomized trial: 3020 patients Mean age 63 years, recent small vessel infarct SBP target: 130-149 mmHg vs. <130 mmHg Open label, all classes of meds 11 mmHg difference between groups upon treatment Annualized rate of all strokes reduced in lower BP group, but not significantly Rate of ICH decreased in in <130 group (small n=22) Lancet.Lancet. 2013 Aug 10;382(9891):507-15

22. AHA/ASA Rec: Hypertension 1.Initiation of BP therapy is indicated for previously untreated patients with BP >140/90 after the first several days. 2.Resume BP therapy in previously treated patients after the first several days. 3.Goals for target BP level are uncertain and should be individualized. Typically less than 140/90. SBP <130 in lacunar stroke

23. AHA/ASA Rec: Hypertension 4.Lifestyle modifications are a reasonable part of comprehensive BP therapy. Salt restriction, weight loss, aerobic activity, limited alcohol consumption, diet rich in fruits/vegetables/low- fat dairy 5.Optimal drug regimen is uncertain because direct comparisons are limited. Available data suggests diuretics or ACE+ diuretic. 6.Choice of specific drugs and targets should be individualized based on consideration of specific patient characteristics.

24. DYSLIPIDEMIA

25. Dyslipidemia Modification of LDL-C High LDL associated with increased risk of ischemic stroke Low LDL has been suggested with ICH Statins have proved efficacious in reducing primary stroke risk without significant risk of ICH Post hoc analysis of SPARCL trial, LDL <70 resulted in 28% reduction in risk of stroke without a significant rise in risk of hemorrhagic stroke 1. Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol. 2009;8:453–463 2. Amarenco P, Benavente O, Goldstein LB, Callahan A 3rd, Sillesen H, Hennerici MG, Gilbert S, Rudolph AE, Simunovic L, Zivin JA, Welch KMon behalf of the SPARCL Investigators.. Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial by stroke subtypes. Stroke. 2009;40:1405–1409

26. ACC/AHA Lipid Guidelines 4 “statin benefit” groups. Individuals with: Clinical ASCVD Ischemic stroke or TIA presumed of atherosclerotic origin ACS, MI, stable or unstable angina Primary elevations of LDL > 190 Diabetes aged 40-75 years with LDL 70-189 and without clinical ASCVD Without clinical ASCVD or diabetes and LDL 70-189 and estimated 10 year risk >7.5% using pooled cohort equations

27. AHA/ASA Rec: Dyslipidemia 1.Statin therapy with intensive lipid lowering if event of atherosclerotic origin and LDL>100 regardless of other clinical ASCVD. 2.Statin therapy with intensive lipid lowering if event of atherosclerotic origin, LDL<100 without evidence of other clinical ASCVD. 3.Patients with other comorbid ASCVD should otherwise be managed according to 2013 ACC/AHA lipid guidelines Including lifestyle, medication, and diet recommendations

28. DIABETES MELLITUS DISORDERS OF GLUCOSE METABOLISM

29. Disorders of Glucose Metabolism Pre-DM Impaired fasting glucose (Glucose 100-125) Impaired Glucose Tolerance (2 hour plasma glucose 140-199) A1c 5.7-6.4% DM Fasting glucose >126 OGTT 2 hour glucose >200 A1c >6.5%

30. Diabetes Mellitus 11.3% of adults in US Incidence rises to 26.9% adults over 65 DM responsible for more than 8% of first ischemic strokes Associated with 60% increased risk for recurrence No major trials for specific DM interventions for prevention of secondary stroke Some evidence for metformin, pioglitazone, and DPP-4 inhibitors PROactive trial Pioglitazone associated with 47%RR reduction in recurrent stroke

31. AHA/ASA Rec: Diabetes 1.After TIA or ischemic stroke, all patients should be screened for DM with testing of fasting plasma glucose, HbA1c, or an oral glucose tolerance test. 2.Use of existing guidelines from the ADA for glycemic control and CV risk factor management is recommended for patients with an ischemic stroke or TIA who also have DM or pre-DM.

32. OBESITY

33. Obesity Defined as BMI above 30 kg/m2 Associated with increased risk for incident stroke Risk increases in near linear fashion starting at BMI = 20 Increased prevalence of vascular risk factors Obesity Paradox- unexpected relationship of obesity with improved prognosis after stroke Insufficient trials for bariatric surgery

34. Look AHEAD Trial Assumption that weight loss among patients with DM and obesity would reduce risk for vascular events 5145 overweight or obese patients with DM2 Randomized to behavioral intervention (6% weight loss) vs. usual care (3.5% weight loss) No significant difference in CV outcomes between groups

35. AHA/ASA Rec: Obesity 1.All patients with TIA or stroke should be screened for obesity with measurement of BMI 2.Despite beneficial effects of weight loss on CV risk factors, usefulness of weight loss among patients with recent TIA or ischemic stroke is uncertain

36. SLEEP APNEA

37. OSA Present in more than 50% of patients with stroke or TIA 70-80% with OSA are not diagnosed or treated Fatigue and BMI not reliable indicators in stroke population Epworth sleepiness scale is often normal Largest cohort study (n=189) Patients >2 months after stroke with sleep apnea Higher recurrent stroke risk in those not using CPAP (32% vs. 14%) NNT to prevent 1 new vascular event was 4.9 patients

38. AHA/ASA Rec: OSA 1.Sleep study might be considered for patients with an ischemic stroke or TIA on the basis of very high prevalence of sleep apnea and beneficial outcomes in the general population 2.Treatment with CPAP might be considered given emerging evidence in support of improved outcomes

39. AHA/ASA Rec: Activity and Nutrition 3-4 sessions per week of moderate to vigorous intensity aerobic exercise which last an average of 40 minutes Consider nutrition evaluation Reduce sodium intake to less than 2.4g/d Follow Mediterranean-type diet

40. ANTI-THROMBOTIC THERAPY

41. Anti-thrombotic therapy In patients without atrial fibrillation No statistically significant difference between ASA and anticoagulants for reducing risk of recurrent ischemic stroke Risk of major hemorrhage higher with warfarin WASID trial 569 patients with stroke or TIA 50-99% stenosis of MCA, ICA, basilar, or vertebral 1300 mg ASA vs. warfarin Trial stopped early due to high rate of death and major hemorrhage in warfarin arm

42. SAMMPRIS Trial 451 patients, aggressive medical management +/- wingspan stent Medical management ASA 325 mg/d Clopidogrel 75 mg/d for 90 days Target SBP <140 Target LDL <70 Lifestyle modification program Enrollment ended due to high mortality in stent arm Medical arm better results than WASID 30 day rate of stroke or death: 5.8% vs. 10.7% 1 year rate of stroke or death: 12.2% vs. 25%

43. AHA/ASA Rec: Intracranial Atherosclerosis [Meds] 1.Stroke or TIA due to 50-99% stenosis of a major IC artery, ASA 325 mg recommended over warfarin. 2.Recent stroke or TIA (30days) due to 70-99% stenosis, addition of clopidogrel 75 mg/d to ASA for 90 days may be beneficial. 3.If 50-99% stenosis, data are insufficient to recommend clopidogrel alone, ASA + dipyridamole, or cilostazol alone.

44. Antiplatelet Agents Charisma trial ASA vs. ASA/clopidogrel MATCH trial Clopidogrel vs. ASA/clopidogrel PRoFESS trial Clopidogrel vs. ASA/dipyridamole ESPRIT ASA vs. ASA/dipyridamole

45. AHA/ASA Rec: Antiplatelet Agents 1.Noncardioembolic ischemic stroke, antiplatelet agents rather than anticoagulation is recommended. 2.ASA (50-325 mg/d) monotherapy or combination or ASA 25 mg and extended-release dipyridamole 200 mg bid is indicated as initial therapy after TIA or ischemic stroke for prevention of future stroke. 3.Clopidogrel 75 mg/d is a reasonable option for secondary prevention in place of ASA or ASA/dipyridamole. 4.Selection of antiplatelet agent should be individualized based on cost, tolerance, etc.

46. AHA/ASA Rec: Antiplatelet Agents 5.Combination of ASA and clopidogrel might be considered for initiation within 24 hours of a minor ischemic stroke or TIA for continuation for 21 days. 6.Combination of ASA and clopidogrel, when continued for 2-3 years, increases the risk of hemorrhage relative to either agent alone and is not recommended for routine long-term secondary prevention. 7.For ischemic stroke or TIA while on ASA, there is no evidence that increasing the dose provides additional benefit. 8.Patients with history of ischemic stroke or TIA, AF, and CAD, the usefulness of adding antiplatelet therapy to VKA therapy is uncertain.

47. ATRIAL FIBRILLATION

48. Atrial Fib 2.7 million Americans Increased prevalence with age Estimated cause of 10-12% ischemic strokes Most TIA/stroke patients without A. Fib started on antiplatelet therapy Antiplatelet therapy inferior to anticoagulation for A. Fib Cryptogenic Ischemic event Failure to diagnose A. Fib results in suboptimal therapy 2 recent studies (30 day event and ICM) Both found increased detection of A. Fib vs. 24-hour monitoring/ conventional follow up N Engl J Med.N Engl J Med. 2014 Jun 26;370(26):2467-77 N Engl J Med.N Engl J Med. 2014 Jun 26;370(26):2478-86

49. CHADS 2 -> CHA 2 DS 2 VASc CHA2DS2-VASc RiskScore CHF or LVEF < 40%1 Hypertension1 Age > 752 Diabetes1 Stroke/TIA/ Thromboembolism 2 Vascular Disease1 Age 65 - 741 Female1 CHADS2 RiskScore CHF1 Hypertension1 Age > 751 Diabetes1 Stroke or TIA2 From ESC AF Guidelines http://www.escardio.org/guidelines-surveys/esc- guidelines/GuidelinesDocuments/guidelines-afib-FT.pdf

50. CHADS 2 -> CHA 2 DS 2 VASc CHADS2 score Unadjusted stroke rate %/year 00.6% 13.0% 24.2% 37.1% 411.1% 512.5% 613.0% CHA2DS2 -VASc score Unadjusted stroke rate (%/year) 00.2% 10.6% 22.2% 33.2% 44.8% 57.2% 69.7% 711.2% 810.8% 912.2% From ESC AF Guidelines: http://www.escardio.org/guidelines-surveys/esc- guidelines/GuidelinesDocuments/guidelines-afib-FT.pdf

51. Atrial Fib Treatment Meta-analysis of 20 RCT (79,908 participants) Direct thrombin inhibitor/ Factor Xa inhibitors No difference in stroke risk reduction or bleed risk when compared to warfarin or each other Novel anticoagulants and warfarin superior to ASA for stroke reduction Novel anticoagulants Acceptable alternative to warfarin Convenient, no need for monitoring Limiting factors: Cost, Lack of reversibility CKD- dose reduction

52. AHA/ASA Rec: Atrial Fibrillation 1.Acute ischemic stroke or TIA with no other apparent cause, prolonged rhythm monitoring (30 days)for AF is reasonable within 6 months of event. 2.VKA therapy, apixaban, and dabigatran are all indicated for prevention of recurrent stroke in patients with nonvalvular AF. Selection should be individualized based on cost, renal function, etc. 3.Rivaroxaban is reasonable for prevention of recurrent stroke in nonvalvular AF. 4.Target INR of 2.5 for VKA therapy 5.Combination of anticoagulants with antiplatelet therapy is not recommended with stroke, but is reasonable with CAD.

53. AHA/ASA Rec: Atrial Fibrillation 6.If unable to take oral anticoagulants, ASA alone is recommended. Addition of clopidogrel may be reasonable. 7.It is reasonable to initiate therapy within 14 days of neurologic symptoms in setting of AF. 8.If high risk for hemorrhagic conversion, it is reasonable to delay initiation of oral anticoagulants beyond 14 days. 9.Bridging with LMWH (or equivalent) is reasonable if temporary interruption of therapy.

54. Summary Major modifiable risk factors are HTN, DM, smoking, atrial fibrillation, and dyslipidemia. Treat HTN gradually and typically to a goal of <140/90, lower in lacunar strokes. High dose statin therapy recommended when tolerated. Antiplatelet agents preferred for ischemic stroke or TIA if not due to A fib. Investigate for atrial fib to determine need for anticoagulants. Diet, exercise, and smoking cessation are always the appropriate first step.

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