primary care education progam

Primary Care Education Progam

FAMILY PRACTITIONERS: Dr. Carl Fournier, Montreal, QCDr. Peter Lin, Toronto, ONDr. Vinod Patel, St. John’s, NFLDDr. Kevin Saunders, Winnipeg, MBDr. Richard Ward, Calgary, AB

SPECIALISTS:Dr. Paul Dorian, Toronto, ONDr. Victor Huckell, Vancouver, BCDr. Mukul Sharma, Ottawa, ONDr. Jeffrey Weitz, Hamilton, ON

Steering Committee

Incidence of AF: Expected to Increase as Population Ages

Age- and Sex-Adjusted Incidence of AF in 1995-2000

Projected Number of Persons With AF in the US: 2000- 2050

Mill

ions

Year

Circulation 2006;114:119

• About 80% of all strokes are ischemic1

• Effect of first ischemic stroke in patients with AF: 60% are disabling, 20% are fatal2

• ICH has a 30-day mortality rate of 35% to 52%3

• Severe strokes are viewed by many patients as equal to or worse than death4,5

Perspectives on Stroke

1Heart and Stroke Foundation; 2 Gladstone Stroke 2009;40:235; 3AHA Stroke 1999;30:905-15; 4Gage Arch Intern Med 1996;156:1829; 5Solomon Stroke 1994;25:1721

Embolic Stroke

• Noncontrast CT brain scan showing two discrete areas of infarction (arrows) within the right middle cerebral artery

Kelley RE & Minagar A. Southern Medical Journal 2003;96(4):343-349

Gladstone DJ et al. Stroke 2009; 40:235-240

Effect of first ischemic stroke in patients with AF (n=597)

Stroke Severity in Patients with AF%

of p

atie

nts

Disabling Fatal

60%

40%

0%

50%

30%

20%

10%

AF=atrial fibrillation

• Warfarin reduces stroke in non-valvular AF by 64%- Significant increase in intracranial and other hemorrhage

• Registries show 50-60% of eligible patients receive warfarin

• In clinical trials, time in therapeutic range (TTR) is 60-68%

• In general practice, TTR is typically <50%

Warfarin in Atrial Fibrillation:

1Hart Ann Int Med 2007;146:857; 2Hylek Stroke 2006;37:1075; 3Singer Chest 2008;13;3:546S 4Gladstone Stroke 2009;40:235; 5Matchar Am J Med 2002;113:42; 6Bungard Pharmacotherapy 2000;20:1060

CCS 2012 Update to AF Guidelines

CHADS2 = 0

*Aspirin is a reasonable alternative in some as indicated by risk/benefit

CHADS2 = 1 CHADS2 ≥ 2

No anti-thrombotic

Assess Thromboembolic Risk (CHADS2)

No additional

risk factors for stroke

Increasing stroke risk

ASA OAC* OAC* OAC

Either female sex or vascular

disease

Age ≥ 65 yrs or combination

of female sex and vascular

disease

OAC = Oral anticoagulantASA = Aspirin

Consider stroke risk vs. bleeding risk

Only when the stroke risk is low and bleeding risk is high does the risk/benefit ratio favour no antithrombotic therapy

1. Skanes AC, et al. Can J Cardiol 2012;28:125-136.

CCS 2012 Update to AF Guidelines

When oral anticoagulant therapy is indicated, most patients should receive dabigatran, rivaroxaban, or apixaban*, in

preference to warfarin

• Dabigatran and apixaban have greater efficacy and rivaroxaban has similar efficacy for stroke prevention

• Dabigatran and rivaroxaban have no more major bleeding and apixaban has less

• All three new oral anticoagulants have less intracranial hemorrhage and are much simpler to use

*Not yet approved in Canada

1. Skanes AC, et al. Can J Cardiol 2012;28:125-136.

Prevention of Stroke

Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med 2011;365:883; Granger N Engl J Med 2011;365:981

0.50 0.75 1.00 1.25 1.50

Dabigatran 110 mg BID Dabigatran 150 mg BID

HR (95% CI)Warfarin betterComparator better

Rivaroxaban 20 mg QD Apixaban 5 mg BID

Stroke or Systemic Embolism

Ischemic StrokeDabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD

Apixaban 5 mg BID

Superiorityp-value

Boehringer Ingelheim (Canada) Ltd. cannot recommend the use of products outside the Canadian approved Product Monograph.

0.29<0.001

0.12 0.01

0.350.03

0.59 0.42

0.900.65

1.110.76

0.88

0.79

0.94

0.92

Cross-trial comparisons must be interpreted with caution due to differing methodologies and patient populations.

Reducing the Bleeding Risk

HR (95% CI)Warfarin betterComparator better

0.50 0.75 1.00 1.250.25

Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD

Apixaban 5 mg BID

Intracranial Hemorrhage

ISTH Major BleedingDabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD

Apixaban 5 mg BID

Superiorityp-value

<0.001

<0.001

0.02 <0.00

1

0.0030.31

0.58 <0.00

1

Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med 2011;365:883; Granger N Engl J Med 2011;365:981Boehringer Ingelheim (Canada) Ltd. cannot recommend the use of products outside the Canadian approved Product Monograph.

0.80

0.93

0.30

0.410.67

0.42

1.04

0.69


New OAC vs. warfarin in moderate CKD (eGFR <50 ml/min)

RR (95% CI)

Dabigatran 110 mg BID 0.77 (0.51-1.18) Dabigatran 150 mg BID 0.55 (0.40-0.81) Rivaroxaban 15 mg QD 0.86 (0.63-1.17) Apixaban 2.5/5 mg BID 0.79 (0.57-1.20)

0.50 0.75 1.00 1.25 1.50

HR (95% CI)

New Agent Better Warfarin Better

Hart RG, et al. Nat Rev Nephrol 2012 (on line)Connolly SJ, et al. N Engl J Med. 2009; 361:1139

Fox KAA et al. Euro Heart J 2011; 32: 2387Granger C, et al. N Engl J Med. 2011; 365: 981

Stroke or Systemic Embolism

New OAC vs. warfarin in moderate CKD (eGFR <50 ml/min)

RR (95% CI)

Dabigatran 110 mg BID 0.99 (0.76-1.28) Dabigatran 150 mg BID 1.03 (0.80-1.34) Rivaroxaban 15 mg QD 0.95 (0.72-1.26) Apixaban 2.5/5 mg BID 0.50 (0.38-0.66)

0.50 0.75 1.00 1.25 1.50

HR (95% CI)

New Agent Better Warfarin Better

Major bleeding

Hart RG, et al. Nat Rev Nephrol 2012 (on line)Connolly SJ, et al. N Engl J Med. 2009; 361:1139

Fox KAA et al. Euro Heart J 2011; 32: 2387Granger C, et al. N Engl J Med. 2011; 365: 981

Safety Outcomes: RELYD 110mg

Annual rateD 150mg

Annual rateW

Annual rate

D 110 mg vs. WRR

95% CI P

D 150 mg vs. W RR 95% CI P

Major or Minor Bleeding 14.62% 16.42% 18.15%

0.780.73-0.83

<0.0010.91

0.85-0.960.002

Intracranial Bleeding 0.23 % 0.32 % 0.76 %

0.300.19-0.45

<0.0010.41

0.28-0.60<0.001

Major Bleeding 2.87 % 3.32 % 3.57%0.80

0.70-0.930.003

0.930.81-1.07

0.32

Life-Threatening Major Bleed 1.24 % 1.49 % 1.85 %

0.670.54-0.82

<0.0010.80

0.66-0.980.03

Fatal Bleed* 0.19 % 0.23 % 0.33 %0.58

0.35-0.970.039

0.700.43-1.14

0.15

GI Major Bleed 1.15 % 1.56 % 1.07 %1.08

0.85-1.380.52

1.481.18-1.85

0.001

Connolly NEJM 2010;363:1876; *Eikelboom Circulation 2011;123:2363

RivaroxabanEvent Rate (per

100 patient/years)

WarfarinEvent Rate (per

100 patient/years)

HR (95% CI) P-value

Primary: Major and Non-Major Clinically Relevant Bleeding 14.9 14.5 1.03 (0.96, 1.11) 0.44

Major: >2 g/dL Hgb dropTransfusion (> 2 units)Critical BleedingFatal Bleeding

3.6 2.81.60.80.2

3.42.31.31.20.5

1.04 (0.90, 1.20)1.22 (1.03, 1.44)1.25 (1.01, 1.55)0.69 (0.53, 0.91)0.50 (0.31, 0.79)

0.58 0.020.04

0.0070.003

Intracranial Hemorrhage 0.5 0.7 0.67 (0.47, 0.93) 0.02

Major GI Bleeding 3.2 % of pts 2.2% of pts Not reported <0.001

Non-Major Clinically Relevant Bleeding 11.8 11.4 1.04 (0.96, 1.13) 0.35

Epistaxis 10.1% of pts 8.6 % of pts Not reported <0.05

Safety Outcomes*: ROCKET AF

*Based on Safety On-Treatment Population Patel N Engl J Med 2011;365:883

ApixabanEvent Rate (per

100 patient/years)

WarfarinEvent Rate

(per 100 patient/years)

HR (95% CI) P-value

Primary: Major Bleeding 2.13 3.09 0.69 (0.60, 0.80) <0.001

Intracranial Hemorrhage 0.33 0.80 0.42 (0.30, 0.58) <0.001

Other Location 1.79 2.27 0.79 (0.68, 0.93) 0.004

Major GI Bleeding 0.76 0.86 0.89 (0.70, 1.15) 0.37

Major or Clinically Relevant Non-Major 4.07 6.01 0.68 (0.61, 0.75) <0.001

Net Clinical Outcome* 6.13 7.20 0.85 (0.78, 0.92) <0.001

Bleeding and Net Clinical Outcomes: ARISTOTLE

*Net Clinical Outcome: Stroke, systemic embolism, death, or major hemorrhageBoehringer Ingelheim (Canada) Ltd. cannot recommend the use of products outside the Canadian approved Product Monograph.

Similarities Across the 3 Novel Oral Anticoagulants:Comparing Dabigatran 150 mg, Rivaroxaban, and Apixaban Vs. Warfarin


• All 3 agents were non-inferior to warfarin in reducing the risk of stroke / systemic embolism

• All 3 agents reduced ICH

• The 3 agents seem to demonstrate a consistent trend towards mortality reduction



Differences:Comparing Dabigatran 150 mg, Rivaroxaban, and Apixaban Vs. Warfarin


• Dabigatran and apixaban demonstrated superiority over warfarin in reducing stroke/systemic embolism

• Dabigatran reduced ischemic stroke

• Apixaban reduced major bleeding

• Rivaroxaban is dosed once daily



AF patients not recommended for therapy with new anticoagulant agents approved for stroke prevention include:• Patients with valvular heart disease• Patients with mechanical valves• Patients with advanced renal impairment (CrCl<30

mL/min)• Patients with active bleeding

Patients unsuitable for new anticoagulants

1. Pradax™ (Dabigatran Etexilate Capsules) Product Monograph, 2012, Boehringer Ingelheim Canada Ltd.2. Xarelto™ (Rivaroxaban tablet) Product Monograph, February 2012, Bayer Inc.

Case: Patient with hypertension, diabetes, prior

TIA

Patient Profile:Jack

• Jack is a 64-year old Caucasian man• Married, lives with wife • Works from home but frequently travels

to the US for work • Goes to the gym twice/week

• He is 5’ 11” tall (180 cm)• Weighs 187 lb (85 kg), • BMI is 26.1

• “I’m here only because of my wife … she thinks I had a stroke”

Jack

• Jack’s medical conditions are as follows:- Diagnosed with atrial fibrillation 3 years ago - on warfarin- His INR has been stable although he admits this is difficult

because of his lifestyle and work-related activities- Hypertension – on ramipril and thiazide- Diabetes – on metformin

• Jack smokes 5-6 cigarettes/day, especially when he is travelling

• Jack also drinks 1-2 glasses of wine or beer/day- This increases to 2-3 glasses of wine or beer/day when he is

travelling (about once/month)

Medical History

• About 3 weeks ago Jack had a “spell”- While eating dinner he suddenly stopped speaking- The right side of his mouth drooped - The fork fell from his hand- It lasted 20 min

• Jack did not go the emergency department - “I felt fine and was about to go on a trip”

• His INR one week ago was 1.5

Medical History

Discussion Questions

1. What was the “spell”? - Do you need any other clinical information

or investigations?

2. What are the options for management?

Important Points• The episode was focal, abrupt in onset and brief

- It meets the clinical diagnosis of TIA- New criteria require the exclusion of tissue damage with brain

imaging

• The physical examination is directed toward excluding a deficit which would suggest stroke- Speech, motor function, facial strength, visual fields- BP ( correlates with risk of hemorrhage)

• Investigations are directed toward exclusion of other causes of TIA and excluding rare mimics- CT head, carotid Doppler or CTA/MRA

1. Lindsay MP et al. Canadian Best Practice Recommendations for Stroke Care (Update 2010) Canadian Stroke Network. www.hsf.sk.ca/siss/documents/2010

• Jack wants to know when he can travel- “They really need me in Peoria next week”

• What if his Doppler shows:- < 50% carotid artery stenosis?- 50-69% carotid artery stenosis?

• What if Jack’s CT report reads:- Small area of hypodensity in the right centrum semiovale

consistent with infarction

What-if Scenarios

Most recent guidelines for stroke prevention in patients with AF (CCS, 2012)

TIA / minor disabling ischemic stroke is associated with a high early risk of recurrent stroke.

TIA is defined as a transient episode of neurologic dysfunction caused by focal brain, spinal or retinal ischemia without infarction while ischemic stroke is defined as an infarction [tissue injury] of central nervous system tissue.

Key Evidence

1. Skanes AC, et al. Can J Cardiol 2012;28:125-136.2. Lindsay MP et al. Canadian Best Practice Recommendations for Stroke Care (Update 2010)

Canadian Stroke Network. www.hsf.sk.ca/siss/documents/2010

A clinical syndrome characterized by the

sudden onset of a focal neurological deficit

presumed to be on a vascular basis

The Definition of Stroke/TIA

1. Lindsay MP et al. Canadian Best Practice Recommendations for Stroke Care (Update 2010) Canadian Stroke Network. www.hsf.sk.ca/siss/documents/2010

2. Johnston et al. Ann Neurol 2006; 60: 301–313.

Tissue Based TIA Definition

Albers GW et al. N Engl J Med 2002;347:1713-1716.

• Brief episode (typically <1h) caused by focal brain or retinal ischemia without evidence of infarction

• Indicates risk• Encourages neurodiagnostic tests• Facilitates rapid intervention

Early risk of stroke after discharge from the emergency department among patients with a first-ever TIA

1. Gladstone D et al. CMAJ. 2004 Mar 30;170(7):1099-104.

CHA2DS2- Vasc performed better when patients were categorized as low [score = 0] moderate [score=1] or high [score = >2] risk principally because of more precise estimates of thromboembolic risk in patients with CHADS2 score of 0 or 1.

2 points for age >75 yrs and 1 point for age 65-74 yrs.

1 point each for vascular disease [prior MI, peripheral arterial disease or aortic plaque] or female sex

Key Evidence

1. Lip GY et al. Chest 2010;137:263-272.2. Skanes AC, et al. Can J Cardiol 2012;28:125-136.

• 1 point for Congestive Heart Failure

• 1 point for Hypertension

• 1 point for Age ≥ 75 years

• 1 point for Diabetes Mellitus

• 2 points for Prior Stroke or TIA

CHADS2 Score* Stroke Rate, %/yr(95 %CI)

0 1.9 (1.2 – 3.0)

1 2.8 (2.0 – 3.8)

2 4.0 (3.1 – 5.1)

3 5.9 (4.6 – 7.3)

4 8.5 (6.3 – 11.1)

5 12.5 (8.2 – 17.5)

6 18.2 (10.5 – 27.4)*Score 0: Patients can be administered aspirin*Score 1: Patients can be administered aspirin or anticoagulant therapy*Score ≥2: Patients should be administered anticoagulant therapy

CHADS2 Score(Simple prediction tool for assessing stroke risk)

1. Gage BF, et al. JAMA. 2001;285:2864-2870.

CHA2DS2-VASc Score• 1 point for Congestive Heart Failure/

LV Dysfunction• 1 point for Hypertension

• 2 points for Age ≥ 75 years

• 1 point for Diabetes Mellitus

• 2 points for Prior Stroke or TIA1 or TE2

• 1 point for Vascular Disease3

• 1 point for Age 65-74 years

• 1 point for Sex category (female gender)

CHA2DS2-VASc Score*

One year event rate (95% CI) of hospital admission and death due to

thromboembolism† per 100 person year

0 0.78 (0.78 – 1.04)

1 2.01 (1.70 – 2.36)

2 3.71 (3.36 – 4.09)

3 5.92 (5.53 – 6.34)

4 9.27 (8.71 – 9.86)

5 15.26 (14.35 – 16.24)

6 19.74 (18.21 – 21.41)

7 21.5 (18.75 – 24.64)

8 22.38 (16.29 – 30.76)

9 23.64 (10.62 – 52.61)*Score 0: Patients can be administered aspirin*Score 1: Patients can be administered aspirin or anticoagulant therapy*Score ≥2: Patients should be administered anticoagulant therapy†Includes peripheral artery embolism, ischemic stroke, and pulmonary embolism

1TIA = Transient ischemic attack; 2TE = Thromboembolism3Prior myocardial infarction, peripheral artery disease, aortic plaque1. Lip GY et al. Chest 2010;137:263-272

2. Olesen JB, et al. BMJ 2011;342:d1243. Task Force or the Management of Atrial Fibrillation of the ESC. Eur Heart J 2010;31:236902429

• What if this patient has experienced a TIA more recently, e.g., this morning? - What investigations should be conducted; what are any

differences between these investigations and those done if the TIA was experienced 3 weeks ago?

- EKG, Blood work (including INR), renal function and lipid profile.

• Brain/neurovascular imaging to exclude a bleed or a large infarct

What-if Scenarios

• Switch to a newer OAC if INR and eGFR are within normal limits

• Antithrombotic therapy in CKD patients depends on eGFR - If eGFR >30 such patients should receive antithrombotic therapy

according to CHADS2 score as outlined in recommendation for patients with normal renal function

Expert Recommendations

Poor Prognosis in Warfarin-Associated Intracranial Hemorrhage Despite Anticoagulant Reversal

Dowlatshahi D, et al. Stroke 2012. DOI: 10.1161/STROKEAHA.112.652065

• Anticoagulant-associated ICH (aaICH) presents with large hematoma volumes, high risk of expansion, worse outcomes than spontaneous hemorrhage

• Prothrombin complex connectrates (PCC) indicated for urgent reversal of anticoagulation

Background

Dowlatshahi D, et al. 2012. DOI: 10.1161/STROKEAHA.112.652065

• Determined outcomes in patients (N=141) with aaICH treated with PCC

• Prospective inpatient registry of inpatients with aaICH treated with Octaplex at stroke centres:- Calgary, Edmonton, Ottawa

• Primary outcomes: - INR correction- Thrombotic events- In-hospital mortality

CanPro Registry


Low Rate of Thrombotic Events

• 30 day thrombotic event rate was 5%• Only 3 events within 7d of therapy (2%)

Thrombotic Event Type Time from PCC infusion Warfarin Indication

Ischemic stroke 21 days Atrial fibrillation

Ischemic stroke 5 days Atrial fibrillation

Ischemic stroke 1 day Atrial fibrillation

Deep vein thrombosis 30 days Atrial fibrillation

Deep vein thrombosis 21 days Deep vein thrombosis

Myocardial infarction 28 days Atrial fibrillation

Myocardial infarction 7 days Pulmonary embolism

Thrombotic events associated with prothrombin complex concentrates (PCC) therapy


Hematoma Growth

Significant hematoma growth despite INR correction with PCC.

This patient was treated with 1000 U of PCC and 10 mg vitamin K 98 minutes after baseline CT scan.

Repeat INR was 1.3, 42 minutes after PCC treatment and 1.2 the next day.

INR = international normalized ratio;

PCC = prothrombin complex concentrate


Poor Outcomes

Intracranial hemorrhage type Number In-hospital mortality*

Discharge mRS(Median IQR)†

Intraparenchymal 71 30 (42.3% 5 (3)‡

Subdural 61 21 (34.4% 3 (4)§

Epidural 1 0 3

Subarachnoid 8 1 (12.5%) 3 (3)

ICH = intracranial hemorrhage; mRS = modified Rankin Scale; IQR = interquartile range

*P = 0.3; †P=0.012; ‡mRS missing in 9; §mRS missing in 2

Outcome by anticoagulant-associated ICH


• Prothrombin complex concentrates (PCC) therapy rapidly corrected INR in the majority of patients with anticoagulant-associated ICH, yet mortality and morbidity rates remained high

• Outcomes after anticoagulant-associated ICH can be devastating even with a reversal strategy

Conclusion


Expected number of fatal hemorrhages, intracranial hemorrhages, strokes and deaths with different antithrombotic treatments

1. Eikelboom JW, et al. J Thromb Hemost 2012:10;966-968.

The potential role of antidotes

Agent Half life Antidote Use

Heparins 1 hr Protamine CABG

LMWH 3-6 hrs Protamine* Rare

New OAC 6-18 hrs Nil ??

Fonda 17-21 hrs Nil Rare

Warfarin 20-60 hrs K, PCC, FFP Common

DAPT 7-10 d Platelets† Common

*Protamine (partial). †Platelets (partial for clopidogrel)

Management of Bleeding in Patients Treated with Dabigatran

Mild bleeding

Delay next dose or discontinue treatment as

appropriate

1. van Ryn J, et al. Thromb Haemostat 2010;103:1116-11272. Hankey GJ & Eikelboom JW. Circulation 2011;123:1436-1450

Management of Bleeding in Patients Treated with Dabigatran

Moderate to severe bleeding

Life threatening bleeding

• Consider rFVIIa or PCC*

• Charcoal filtration* or hemodialysis

Bleeding continues

• Stop dabigatran• Monitor aPTT and TT• Oral charcoal (if within 2 hr

of drug ingestion)• Mechanical compression• Fluid replacement and

hemodynamic support• Blood product support• Surgical intervention

*Recommendation based only on non-clinical data (no experience in patients)aPTT = activated partial thromboplastin timeTT=thrombin timerFVIIa=recombinant factor VIIaPCC=prothrombin complex concentrates

Adapted from:1. van Ryn J, et al. Thromb Haemostat 2010;103:1116-1127 2. Hankey GJ & Eikelboom JW. Circulation 2011;123:1436-1450

3. Crowther MA & warkentin TE. J Thromb Hemostat 2009;7 (Suppl 1):107-1104. Pradax Monograph 2010, Boehringer Ingelheim Canada Ltd

• Bleeding is the most common complication of antithrombotic therapy

• Prevention is better than cure

• Careful management of interruption and general measures are foundation

• Specific measures (hemostatic agents, charcoal, dialysis) are available but will be rarely needed

• When considering anticoagulation, all AF patients should have appropriate assessment of both stroke and bleeding risk using validated risk assessment tools

• In cases of minor bleeding, hold 1 or 2 doses of the anticoagulant and eliminate any unnecessary concomitant medications that may increase bleeding risk

Summary/Conclusions

primary care education progam

Documents

ischemic stroke

gladstone stroke

effect of stroke

solomon stroke

stroke prophylaxis

stroke severity

cardioembolic stroke

stroke outcomes