An Ounce Of Prevention: Considerations For Stroke, Atrial - - PowerPoint PPT Presentation

An Ounce Of Prevention:

Considerations For Stroke, Atrial Fibrillation And Hypertension

Content Development Faculty

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Jason Andrade, MD, FRCPC, FHRS

Clinical Associate Professor of Medicine University of British Columbia Adjunct Professor, Université de Montréal Cardiac Electrophysiologist Vancouver, British Columbia and Montreal, Quebec

Alan Bell, MD, CCFP, FCFP

Assistant Professor Department of Family and Community Medicine University of Toronto Toronto, Ontario

Carl Fournier, MD, CCMF

Clinical Assistant Professor University of Montreal Montreal, Quebec

Jeff Habert, MD, CCFP, FCFP

Assistant Professor Department of Family and Community Medicine University of Toronto Toronto, Ontario

Theodore Wein, MD, FRCPC

Assistant Professor of Neurology and Neurosurgery McGill University Neurologist, Division of Neurology Montreal General and St. Mary’s Hospital Montreal, Quebec

Jordan Weinstein, MD, FRCPC

Assistant Professor of Medicine University of Toronto Nephrologist, St-Michael’s Hospital Toronto, Ontario

Program Learning Objectives

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Identify the benefit and risks associated with oral anticoagulants used for stroke prevention in AF patients Discuss optimal dosage

• f oral anticoagulants

used for stroke prevention in AF patients Describe the best practices in the prevention and management of AF Explain the current Canadian guideline recommendations for the use of oral anticoagulants in AF Recognize the best approaches for treating hypertension to prevent strokes

At the conclusion of this program, participants should be able to:

Principles Of Management for Atrial Fibrillation

Including Prevention, Monitoring And Treatment

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Strokes Associated with Atrial Fibrillation are Associated with Worse Morbidity and Mortality Outcomes than Non-AF Strokes

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• 1. Dulli D, et al. Neurepidemiology 1998;17(2):80-9.
• 2. Kimura K, et al. J Neurol Neurosurg Psychiatry 2005;76:679-683
• 3. Dulli D, et al. Neuroepidemiology 2003; 22(2):118-23.

Death within 28 days of admission and age for patients with atrial fibrillation (AF) and non-AF patients2

Patients with AF have worse outcomes when they have a stroke compared to patients having a stroke without AF1

8.2 7.8 3.5 10.4 13.8 14.2 3.8 1.8 1.8 3.6 4.1 7 2 4 6 8 10 12 14 16 <44 45-54 55-64 65-74 75-84 >85 Percentage Age AF patients Non-AF patients Bedridden patients (%)

40 30 20 10 50

With atrial fibrillation

41.2%

Without atrial fibrillation

23.7%

Morbidity (bedridden patients)3

Overall Interventions For Risk Factor Modification

6 Lau DH, et al. Circulation 2017; 136(6):583-96.

Components of risk factor modification in the ARREST-AF and LEGACY studies Aggressive Risk Factor Management

• Educate for permanent

lifestyle change

• Diet plan
• Initial target: >10%

weight loss. Final target BMI <27 kg/m²

• Avoid weight

fluctuation

• Exercise: 30 minutes

for 3-4x per week

• Increase type and

duration of activity to 250 minutes per week

• Initial lifestyle

measures

• At 3 months, start

statins if LDL > 2.6 mmol/L

• Add fibrates if TG

>2.25 mmol/L

• Start fibrates if TG

>5.65 mmol/L

• Overnight sleep study
• CPAP if AHI ≥30; or

≥20/h with resistant HT

• r daytime somnolence
• Check adherence

regular CPAP machine data download

• Home BP diary: 2-3x

daily

• Reduce salt
• Start ACEI or ARB
• Target: <130/80

mmHg (at rest) & <200/100 mmHg (at peak exercise)

• Glucose tolerance test
• Lifestyle measures
• At 3 months: metformin

if A1C >6.5%

• Diabetes clinic

Diabetes Hypertension Obstructive Sleep Apnea Hyperlipidemia Weight Management and Exercise Smoking Cessation & Alcohol Abstinence (or reduction to 30g per week)

Efficacy And Safety Benefits Of NOACs Vs. Warfarin From RCTs

Ruff CT, et al. Lancet 2014;383:955-62.

Data are n/N, unless otherwise indicated. Heterogeneity: I2=83%; p=0.001. NOAC= non–vitamin K antagonist oral anticoagulants. RR=risk ratio.

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RR (95% Cl) P

RE-LY (dabigatran 150mg Twice daily) 0.66 (0.53-0.82) 0.0001 ROCKET AF (rivaroxaban 20mg once daily) 0.88 (0.75-1.03) 0.12 ARISTOTLE (apixaban 5mg twice daily) 0.80 (0.67-0.95) 0.012 ENGAGE AF-TIMI 48 (edoxaban 60mg once daily) 0.88 (0.75-1.02) 0.10 Combined (random) 0.81 (0.73-0.91) <0.0001

1.0 2.0 0.5

Favours NOAC Favours Warfarin

STROKE OR SYSTEMIC EMBOLIC EVENT

RR (95% Cl) P

RE-LY (dabigatran 150mg Twice daily) 0.94 (0.82-1.07) 0.34 ROCKET AF (rivaroxaban 20mg once daily) 1.03 (0.90-1.18) 0.72 ARISTOTLE (apixaban 5mg twice daily) 0.71 (0.61-0.81) <0.0001 ENGAGE AF-TIMI 48 (edoxaban 60mg once daily) 0.80 (0.71-0.90) 0.0002 Combined (random) 0.86 (0.73-1.00) 0.06

1.0 2.0 0.5

Favours NOAC Favours Warfarin

MAJOR BLEEDING

Who Should Receive Oral Anticoagulant Therapy?

§ In general, OAC is recommended for all patients with AF except those <65 years & no additional risk factors for stroke (prior Stroke/transient ischemic attack, hypertension, heart failure or diabetes) § A NOAC is recommended in preference to a VKA for non- valvular AF (NVAF)

CCS: Canadian Cardiovascular Society; CAD, coronary artery disease Macle L, et al. Can J Cardiol 2016; 32(10):1170-85. 8

“CCS Algorithm” (“CHADS65”) for OAC Therapy in AF

Age ≥ 65

Stroke / TIA / PE or Hypertension or Heart Failure or Diabetes Mellitus (CHADS2 risk factors)

CAD or Arterial vascular disease

(coronary, aortic, peripheral)

No antithrombotic therapy

OAC

YES YES YES NO NO NO

OAC ASA

CCS AF guidelines recommend that AF patients be stratified using the “CCS algorithm” (“CHADS-65”)

Recognizing The Importance Of Oral Anticoagulation For AF

Reducing Stroke Risk while Minimizing Bleeding Risk

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AFASAK-1 (n=671) SPAF (n=421) BAATAF (n=420) CAFA (n=378) SPINAF (n=571) EAFT (n=439) All Trials (n=2900)

Warfarin Has Been Shown To Reduce Stroke Risk In AF

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AFASAK: Atrial Fibrillation, Aspirin, AntiKoagulation; SPAF: Stroke Prevention in Atrial Fibrillation; BAATAF: Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA: Canadian Atrial Fibrillation Anticoagulation; SPINAF: Stroke Prevention in Nonrheumatic Atrial Fibrillation; EAFT: European Atrial Fibrillation Trial Hart RG, et al. Ann Intern Med 2007;146:857-67.

Stroke Prevention in AF 6 Trials of Warfarin vs. Placebo

Warfarin Better Warfarin Worse 0%

• 50%
• 100%

50% 100%

64%

1950s…WARFARIN 2000s…NOACs

High risk of bleeding & hospitalization Less life-threatening bleeding and fewer hospitalizations with some NOACs Well-documented drug/food/ lifestyle interactions Fewer interactions Unpredictable pharmacokinetics Predictable pharmacokinetics Delayed onset and offset of action Rapid onset and offset of action Narrow therapeutic window (frequent INR monitoring) Wide therapeutic window (no monitoring required) Complexity for patient and doctor Simplicity for patient and doctor Poor adherence Better adherence

Although Warfarin Is Effective For Stroke Prevention In AF, NOACs Are The Guideline-recommended Choice1

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• 1. Macle L, et al. Can J Cardiol 2016;32(10):1170-1185.

Anticoagulant Therapy Is Underused In Eligible Patients

From a national chart audit of 7019 patients with AF:

12 Bell AD, et al. Am J Cardiol 2016 Apr 1;117(7):1107-11.

Over 50%

• f patients
• n OAC are

taking warfarin 30.9% of patients

• n warfarin

had not achieved TTR > 65% Of the patients

• n NOACs,

11.7% were on the wrong dose

2.5 mg BID 5 mg BID Age ≥ 80 years Weight ≤ 60 kg Creatinine ≥ 133µmol/L If ≥ 2 criteria If ≤ 1 criteria Age > 80 yrs Age 75-80 yrs 110 mg BID 110 mg BID 150 mg BID CrCL 15-49 ml/min 15 mg OD CrCL 30-50 ml/min Weight ≤ 60kg Strong P-gp inhibitor* 30 mg OD

*Except verapamil and amiodarone

Clear Criteria For Dose Reduction With The NOACs

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• 1. Pfizer Canada Inc. Apixaban Product monograph. June 16, 2016. 2. Boehringer Ingelheim Canada Ltd. Dabigatran Product monograph. August 11, 2016. 3. SERVIER

CANADA INC. Edoxaban Product monograph. July 26, 2017. 4. Bayer Inc. Rivaroxaban Product monograph. July 20, 2015. CrCl: creatinine clearance; P-gp: P-glycoprotein *e.g. Renal impairment, extensive cerebral infarction (haemorrhagic or ischemic) within the last 6 months, active peptic ulcer disease with recent bleeding

Apixaban Dabigatran

Low thromboembolic risk and high risk of bleeding*?

Edoxaban Rivaroxaban

NB: In patients with CrCl 15-30 mL/min, rivaroxaban plasma levels may be significantly elevated, which may lead to an increased bleeding risk. Rivaroxaban must be used with caution in these patients.

No Yes

Fear Of Bleeding Should Not Preclude Use Of Anticoagulant Therapy

§ Weigh the benefits (prevention of ischemic stroke) against the risks (e.g., major bleeding) for each individual patient1,2 § Potential benefit usually outweighs risk,3 particularly with the NOACs which, compared to warfarin, have:

§ Lower risk of intracranial hemorrhage4 § Similar rates of other major bleeding4

§ Consider and modify (if possible) all factors influencing risk of bleeding during OAC treatment2

14 NSAID, nonsteroidal anti-inflammatory drug; INR: international normalized ratio

• 1. Cairns JA, et al. Can J Cardiol 2011; 27(1):74-90.
• 2. Macle L, et al. Can J Cardiol 2016; 32(10):1170-85.
• 3. Shoeb M, et al. J Thromb Thrombolysis 2013; 35(3): 312–9.
• 4. Ruff CT, et al. Lancet 2014; 383(9921):955-62.

Address Reversible Risk Factors For Bleeding

15 Olesen JB, et al. Thromb Haemost 2011; 106(4):739–49.

Anticoagulation should not be withheld based on bleeding risk, unless bleeding is active

• r risk is extreme

Measure and monitor renal function Ensure blood pressure controlled to target Correct anemia and determine cause Co-prescribe PPI (If recurrent GI bleeding) Encourage alcohol abstinence Provide mobility aids Discontinue ASA and NSAIDs if possible

Anticoagulant Therapy For AF: Use The Right Drug, At The Right Dose

Optimizing The Use Of Anticoagulants In AF

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Characteristics Of NOACs Available In Canada

17 From Current Canadian Product Monographs

Apixaban Dabigatran Edoxaban Rivaroxaban Mechanism of action Direct Factor Xa inhibitor Direct thrombin inhibitor Direct Factor Xa inhibitor Direct Factor Xa inhibitor Oral bioavailability ~50% ~6.5% 62% 80-100%

(when taken with food)

Food effect No No No Yes

(needs to be taken with food*)

Pro-drug No Yes No No Renal clearance ~27% 85% 50% 36% Mean half-life (t½) ~12 h 11-17 h 10-14 h 5-13 h Tmax 3-4 h 0.5-2 h 1-2 h 2-4 h Standard dosage 5 mg 150 mg 60 mg 20 mg Dosing frequency Twice daily Twice daily Once daily Once daily

*Due to reduced oral bioavailability under fasting conditions, rivaroxaban should be taken with a full meal.

1.35 0.6 2.6 2.7 2.84 2.38 2.11 0.78 6.77 4.78 4.28 3.6

2 4 6 8 10 Stroke, non- CNS embolism

• r TIA

MI Death MACNE Major bleeding Bleeding hospitalization Event rate / 100 patient-years

Appropriate standard dose (n=5,895) Inappropriately reduced dose (n=689)

Inappropriate NOAC Dose Reduction Is Associated with Trend Towards Increased Risk of Events with No Benefit on Bleeding Risk

18 Steinberg BA et al. J Am Heart Assoc. 2018 Feb 16;7(4).

Event rates (per 100 patient-years) and Propensity-weighted hazard ratios by NOAC dose received (Rivaroxaban or Apixaban) among patients recommended for standard NOAC dosing (n=6584)

CI indicates donfidence interval; CNS, central nervous system; HR, hazard ratio; MACNE, major adverse cardiovascular and neurological events, including a composite of TIA, stroke, non-CNS embolism, MI, or cardiovascular death; MI myocardial infarction; NOAC, non-vitamin K antagonist oral anticoagulant; TIA, transient ischemic attack. *HR for inappropriately reduced-dose subjects relative to appropriately standard-dose subjects.

HR: 1.11 p=0.7 HR: 1.27 p=0.6 HR: 1.48 p=0.07 HR: 1.40 p=0.1 HR: 1.15 p=0.5 HR: 1.04 p=0.9

Inappropriate Use Of Antithrombotic Medication: Canadian Chart Audit Of AF Patients (CONNECT-AF)

19 Bell AD, et al. Am J Cardiol 2016;117(7):1107-11.

Connect-AF: 7019 AF patients from 735 primary-care physicians in Canada

NOAC contraindicated (therapy given below recommended CrCl) Underdosed Overdosed Patients not on recommended treatment* Apixaban (n=352)

12 (3.4%) 59 (16.8%) 5 (1.4%) 76 (21.6%)

Dabigatran (n=1164)

35 (3.0%) 23 (2.0%) 58 (5.0%)

Rivaroxaban (n=1340)

44 (3.3%) 151 (11.3%) 65 (7.1%) 290 (21.6%)

Warfarin (n=3371)

1043 (30.9%) 1043 (30.9%)

ASA only (n=371)

134 (36.1%) 134 (36.1%)

No antithrombotic (n=310)

203 (65.5%) 203 (65.5%)

Underdosing criteria: apixaban –CrCI > 25, only one or none of the following: age > 80: weight <60kg: serum creatinine >133, 2.5 mg Twice-daily; rivaroxaban-CrCI>50, 15 mg od: warfarin-TTR <65%: ASA only: CHADS2>1; no antithrombotics-met criteria for treatment: age >65 or ag <65, CHADS2>10, or <65 but CVD (myocardial infarction, coronary artery disease, peripheral artery disease) + female gender: overdosing criteria: on higher dose despite meeting criteria for dose reduction per product monograph. * Includes all criteria (under and overdosing)

Less Than 50% Of Patients On Anticoagulant Therapy Are Adherent

20 Yao X, et al. J Am Heart Assoc 2016; 5(2)

Adjusted* adherence (PDC ≥80%) p value (all DOACs vs. warfarin) Apixaban (n=3,900) Dabigatran (n=10,235) Rivaroxaban (n=12,336) All NOACs (n=26,471) Warfarin (n=38,190) All patients

52.1% 45.9% 47.6% 47.5% 38.7% <0.001

CHA2DS2 VASc score 0-1

40.6% 28.6% 30.8% 30.8% 25.2% <0.001

CHA2DS2 VASc score 2-3

51.9% 46.9% 48.8% 48.3% 37.3% <0.001

CHA2DS2 VASc score ≥4

54.1% 48.7% 50.1% 50.1% 42.0% <0.001

Nonadherence to NOACs is Associated with Increased Stroke Risk, Regardless of Once- or Twice-daily Dosing

21 Alberts MJ, et al. Int J Cardiol 2016;215:11-3.

CI = confidence interval; HR = hazard ratio; N = sample size; DOAC = direct oral anti-coagulant; PDC = proportion of days covered; PY = person years.

kidney disease, liver disease, predisposition to bleeding, depression, alcohol and drug abuse and prior warfarin use.

Adjusted HRs (95% CI) for ischemic stroke with suboptimal adherence (<80% vs. ≥80% PDC) ≥80% PDC better <80% PDC better 0.5 1.0 2.0 1.5

All NOACs

HR: 1.50 (1,30-1.73)

Once-daily users

HR: 1.47 (1.20-1.80)

Twice-daily users

HR: 1.50 (1.23-1.83)

Improved Patient Persistence With Once-daily Vs. Twice-daily Anticoagulation

22 Andrade JG, et al. Can J Cardiol 2016;32(6):747-53.

Patients with once-daily dosing were less likely to consider stopping treatment compared with those taking Twice-daily agents

(8% for Rivaroxaban vs. 18% for warfarin, P = 0.022; 18% for Dabigatran, P = 0.080; and 27% for apixaban, P = 0.022) 17 27 18 8 18 5 10 15 20 25 30 Overall Apixaban Dabigatran Rivaroxaban Warfarin % of patients who considered stopping OAC

Considered stopping

What’s New In Hypertension?

Preventing Stroke And Other Complications Through Optimal Control Of Blood Pressure

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Recommended Office BP Treatment Targets (Hypertension Canada Guidelines)

§ Clinical or subclinical cardiovascular disease other than stroke; OR § Chronic kidney disease, excluding polycystic kidney disease, with an estimated glomerular filtration rate (eGFR) of 20 to 60 mL/min/ 1.73 m2, calculated with the use of the four-variable Modification of Diet in Renal Disease equation; OR § 10-year risk of CVD of 15% or greater on the basis of the Framingham risk score; OR § Age ≥ 75 years.

24 Nerenberg KA, et al. Can J Cardiol. 2018 ; 34(5):506-25.

Patient Population BP threshold for initiation of antihypertensive therapy BP treatment target

SBP mmHg DBP mmHg SBP mmHg DBP mmHg

Hypertension Canada Hight-Risk Patient* ≥ 130 N/A < 120 N/A Diabetes mellitus** ≥ 130 ≥ 80 < 130 < 80 Low Risk (No TOD

• r CV risk factors)**

≥ 160 ≥ 100 < 140 < 90 All others ≥ 140 ≥ 90 < 140 < 90

* BP treatment threshold and target based on AOBP measurements ** BP treatment threshold and targets refer to non-AOBP measurements performed in office.

Definition of the High-risk Patient

Single-pill Combinations

§ Recommended as a first line treatment choice, regardless of the extent of BP elevation

§ Use of low dosage is recommended at initiation since effect on BP can be very pronounced with certain combinations (e.g. diuretics + ACEi or ARBs) Diuretics

§ Longer acting (thiazide-like) diuretics are preferred vs. shorter acting (thiazides)

§ Longer-acting (thiazide-like): chlorthalidone, indapamide § Shorter-acting (thiazides): hydrochlorothiazide

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New (Post-2017) Hypertension Canada Recommendations For Particular Antihypertensive Medications

Nerenberg KA, et al. Can J Cardiol. 2018 May;34(5):506-525.

Advantages Of Single Pill Combinations (SPCs)

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• 1. Sherrill B, et al. J Clin Hypertens 2011;13:898-909;
• 2. Feldman RD, et al. Hypertension 2009;53:646-53;
• 3. Corrao G, et al. Hypertension 2011;58:566-72;
• 4. Gradman AH, et al. Hypertension 2013;61(2):309-18.

SPC therapy is associated with better adherence

• vs. free combinations1

A regimen featuring initial prescription of SPC leads to better BP control2 Initial combination therapy is associated with ↓ risk of CV events than monotherapy3,4

Pharmacotherapy For Hypertension In Patients With Diabetes

27 Nerenberg KA, et al. Can J Cardiol. 2018 May;34(5):506-525.

Threshold ≥130/80 mmHg and Target <130/80 mmHg

ACE Inhibitor

• r ARB
• 1. ACE Inhibitor
• r ARB or
• 2. DHP-CCB
• r Thiazide/

thiazide-like diuretic

Check serum potassium and creatinine at baseline and within 1 to 2 weeks of initiation of an ACEI or ARB Combinations of agents that block the RAAS (ACEi, ARB, DRI) should not be used More than 3 drugs may be needed to reach target values for people with diabetes

Most people with diabetes should receive standard- dose monotherapy for initial management; however, there is emerging evidence for supporting earlier use

• f single

pill combination therapy ≥ 2-drug combinations With CKD or CVD Without CKD or CVD Diabetes

Hypertension Canada And Diabetes Canada Guidelines For Choice Of Drug For People With Diabetes And Hypertension

§ Persons with diabetes mellitus should be treated to attain SBP of <130 mm Hg (Grade C) and DBP of <80 mm Hg (Grade A)(these target BP levels are the same as the BP treatment thresholds). § For persons with cardiovascular or kidney disease, including microalbuminuria, or with cardiovascular risk factors in addition to diabetes and hypertension, an ACE inhibitor or an ARB is recommended as initial therapy (Grade A). § For persons with diabetes and hypertension (without cardiovascular or kidney disease), appropriate choices include (in alphabetical order): ACE inhibitors (Grade A), ARBs (Grade B), dihydropyridine CCBs (Grade A), and thiazide/thiazide-like diuretics (Grade A). § If target BP levels are not achieved with standard-dose monotherapy, additional antihypertensive therapy should be used. For persons in whom combination therapy with an ACE inhibitor is being considered, a dihydropyridine CCB is preferable to a thiazide/thiazide- like diuretic (Grade A).

28 Nerenberg KA, et al. Can J Cardiol. 2018 May;34(5):506-525. Tobe S, et al. Can J Diabetes 2018; 42(suppl.1):S186–S189