Secondary Prevention of Stroke (aka the Homer Talk) Roland Halil, BSc(Hon), BSc(Pharm), ACPR, PharmD Bruyere Academic Family Health Team Jan 2014

Secondary Prevention Secondary Prevention ofof

StrokeStroke(aka the Homer Talk)(aka the Homer Talk)

Roland Halil, Roland Halil, BSc(Hon), BSc(Pharm), ACPR, BSc(Hon), BSc(Pharm), ACPR, PharmDPharmD

Bruyere Academic Family Health TeamBruyere Academic Family Health Team

Jan 2014Jan 2014

Stroke CaseStroke CaseMr. HS (54 y.o. Mr. HS (54 y.o.

male) - 5 weeks male) - 5 weeks ago he awoke at ago he awoke at noon with right noon with right facial weakness, facial weakness, numbness, & numbness, & slurred speech. slurred speech. He had been He had been diagnosed with a diagnosed with a stroke (CT Head). stroke (CT Head). At the time of his At the time of his appointment he is appointment he is left with no left with no residual deficits.residual deficits.

PMHx: 6 MPMHx: 6 MII’’s over past s over past 10 TV seasons10 TV seasons

Hypertension Hypertension Type 2 Diabetes X 3 yrsType 2 Diabetes X 3 yrs SHx: SHx: 12 beers 4 times/ 12 beers 4 times/

week week – Lives w/ wife & 3 kids Lives w/ wife & 3 kids

Current Medications:Current Medications:– EC-ASA 81 mg po ODEC-ASA 81 mg po OD– Metformin 500 mg po Metformin 500 mg po

TIDTID– Glyburide 2.5 mg po Glyburide 2.5 mg po

BIDBID– Diltiazem 240 (CD) mg Diltiazem 240 (CD) mg

po ODpo OD– Maalox prn for Maalox prn for

““heartburnheartburn””

ObjectivesObjectives Describe CVA Describe CVA

subtypessubtypes Identify CVA Risk Identify CVA Risk

FactorsFactors Identify Signs & Identify Signs &

Symptoms of Symptoms of Acute StrokeAcute Stroke

Describe Describe management management strategies for CVA strategies for CVA subtypessubtypes

Describe outcomes Describe outcomes of secondary of secondary prevention trialsprevention trials – AntiplateletsAntiplatelets– Combo therapiesCombo therapies– Warfarin & Warfarin &

anticoagulantsanticoagulants– Statins Statins – Blood Pressure Blood Pressure

ControlControl

– The Bottom Line!The Bottom Line!

Stroke SubtypesStroke Subtypes

From: Kirshner, H, Bottorff, MB. Opportunities and Guidelines for Aggressive Prevention of Secondary Stroke http://www.princetoncme.com/pdf/programs/2006-174.pdf Accessed May 8/07.

http://www.princetoncme.com/pdf/programs/2006-174.pdf

This is your brain….This is your brain….

This is your brain on This is your brain on stroke…stroke…

Non-Modifiable Risk FactorsNon-Modifiable Risk Factors

AgeAge (Doubling rate (Doubling rate

each decade > 55 each decade > 55 y.o.)y.o.)

Prior CVAPrior CVA FHxFHx

Race Race (Blacks/Hispanics > (Blacks/Hispanics >

Whites)Whites)

Low Birth Low Birth WeightWeight(RR ~2) (RR ~2)

(Wt < 2.5kg (Wt < 2.5kg

vs > 4 kg)vs > 4 kg)

MaleMale

Modifiable Risk FactorsModifiable Risk Factors

HypertensionHypertension– The Biggest Risk The Biggest Risk

Factor!Factor!

– ~ 28-38% Risk ~ 28-38% Risk Reduction with Reduction with TreatmentTreatment


Ischemic Ischemic Heart DiseaseHeart Disease ((IHDIHD))– CAD, CHF, LVHCAD, CHF, LVH– Major Risk Major Risk

Factor!Factor!


SmokingSmoking– 50% Risk 50% Risk

Reduction w/i 1 yrReduction w/i 1 yr– Baseline > 5 yrsBaseline > 5 yrs– Major Risk Factor!Major Risk Factor!


DiabetesDiabetes– Major Risk Factor!Major Risk Factor!– BP Control is KEYBP Control is KEY– Mortality benefit Mortality benefit

with statinswith statins– ** No evidence that No evidence that

tight sugar control tight sugar control reduces risk of CVAreduces risk of CVA

Modifiable Risk Factors - Modifiable Risk Factors - AFibAFib

CHADS-2 model CHADS-2 model score from 0 to score from 0 to

6, based on:6, based on:– CCHF = 1 HF = 1 – HHigh BP = 1igh BP = 1– AAge > 75y.o. = ge > 75y.o. =

11– DDiabetes = 1 iabetes = 1 – SStroke Hx = troke Hx = 22

Yearly risk of stroke Yearly risk of stroke due to AFib based due to AFib based on on CHADS-2 CHADS-2 Score:Score:

0 - 1.9%0 - 1.9%

1 - 2.8%1 - 2.8%

2 - 4.0%2 - 4.0%

3 - 5.9%3 - 5.9%

4 - 8.5%4 - 8.5%

5 - 12.5%5 - 12.5%

6 - 18.2%6 - 18.2%Snow V et al. Ann Int Med 2003;139(12):1009-1017


DyslipidemiDyslipidemiaa– 25-30% Risk 25-30% Risk

Reduction with Reduction with statin usestatin use


Physical Physical InactivityInactivity

Heavy Alcohol Heavy Alcohol useuse • > 5 drinks /day> 5 drinks /day

ObesityObesity


High Dose High Dose EstrogenEstrogen• > 50 mcg /day> 50 mcg /day


Asymptomatic Asymptomatic Carotid Carotid StenosisStenosis– 50% Risk Reduction 50% Risk Reduction

with endarterectomywith endarterectomy

SXS of Stroke SXS of Stroke

Among U.S. Among U.S. adults > 50 yrs adults > 50 yrs oldold::– Only 57% could Only 57% could

identify a identify a SINGLE stroke SINGLE stroke symptom!symptom!

5 Cardinal Symptoms of Stroke5 Cardinal Symptoms of Stroke

1.1. SuddenSudden one-sided one-sided weaknessweakness, , numbness, or paralysis of face, numbness, or paralysis of face, arm or leg.arm or leg.

2.2. SuddenSudden blurryblurry or or vision. vision.3.3. SuddenSudden difficulty difficulty speakingspeaking or or

understanding simple understanding simple statements.statements.

4.4. SuddenSudden dizzy, loss of dizzy, loss of balancebalance or or coordination.coordination.

5.5. SuddenSudden severe, unexplainable severe, unexplainable headacheheadache – – ““worst …worst …””..

Break!Break!

Treatment OptionsTreatment OptionsIschemic CVA - Trial Ischemic CVA - Trial

EvidenceEvidence Anti-plateletsAnti-platelets

– ASAASA– ClopidogrelClopidogrel– Combo StrategiesCombo Strategies

Clopidogrel + ASAClopidogrel + ASA ASA + ER-ASA + ER-

Dipyridamole Dipyridamole (Aggrenox™) (Aggrenox™)

– TicagrelorTicagrelor– Prasugrel Prasugrel

Anti-coagulantsAnti-coagulants

Anti-Anti-dyslipidemicsdyslipidemics– (Statins)(Statins)

Anti-Anti-hypertensiveshypertensives

ASA – ASA – Bottom LineBottom Line

~23% RRR ASA over placebo ~23% RRR ASA over placebo NNT ~ 50-100 for 1 year to NNT ~ 50-100 for 1 year to

prevent any vascular event. prevent any vascular event. – at a dose range of 50-325mg at a dose range of 50-325mg

ASAASANNH ~ 1 to 2 major extra-NNH ~ 1 to 2 major extra-

cranial bleeds per 1000 peoplecranial bleeds per 1000 people

Anti-platelets - ASAAnti-platelets - ASA

Antiplatelet TrialistsAntiplatelet Trialists– large meta-analysis (~70% ASA large meta-analysis (~70% ASA

trials) trials) – ASA 75-150mg - beneficial in all high ASA 75-150mg - beneficial in all high

risk patients except for those with risk patients except for those with hemorrhagic stroke. hemorrhagic stroke.

– No added benefit of ASA 500 – 1300 No added benefit of ASA 500 – 1300 mgmg

– BMJ 2002;324:71-86BMJ 2002;324:71-86

Anti-platelets - Anti-platelets - ASAASA

CAST/IST TrialsCAST/IST Trials – ASA w/i 48h of CVAASA w/i 48h of CVA– Combined analysis - significant Combined analysis - significant

reduction of 9 fewer deaths or nonfatal reduction of 9 fewer deaths or nonfatal strokes per 1000 treated patients w/ strokes per 1000 treated patients w/ ASA (160-325 mg/d)ASA (160-325 mg/d)

– Absolute risk reduction Absolute risk reduction (ARR) = 0.9%;(ARR) = 0.9%; – Number needed to treat Number needed to treat (NNT) = 111(NNT) = 111 – BMJ 1988; 296:313-16BMJ 1988; 296:313-16


SALTSALT Trial – ASA 75mg vs placebo Trial – ASA 75mg vs placebo– Bottom lineBottom line - Low dose ASA - Low dose ASA

significantly reduces risk of stroke significantly reduces risk of stroke and death in patients with ischemic and death in patients with ischemic stroke when used for ~ 32 monthsstroke when used for ~ 32 months

– ARR = 4.6%ARR = 4.6%– NNT = 22NNT = 22 – Lancet 1991;338:1345-9Lancet 1991;338:1345-9


DUTCH TIADUTCH TIA Trial: Trial: – 30mg ASA is no less effective than 30mg ASA is no less effective than

283 mg for prevention of vascular 283 mg for prevention of vascular events in pts w/ TIA/minor CVA events in pts w/ TIA/minor CVA

– 30mg ASA resulted in fewer minor 30mg ASA resulted in fewer minor bleeds then 283mg (bleeds then 283mg (NNH = 50NNH = 50))

– NEJM 1991;325(18):1261-6NEJM 1991;325(18):1261-6

Ticlopidine - Ticlopidine - Bottom LineBottom Line

More effective than ASA in secondary More effective than ASA in secondary prevention of CVAprevention of CVA

NNTNNT = 28-34 = 28-34 – (with 250mg po bid ticlopidine for 2-6 years to (with 250mg po bid ticlopidine for 2-6 years to

prevent a stroke)prevent a stroke) ButBut - risk serious ADRs + monitoring costs - risk serious ADRs + monitoring costs

– NeutropeniaNeutropenia CBC q 2 wks – baseline till 3CBC q 2 wks – baseline till 3rdrd month; further only if month; further only if

infection is suspectedinfection is suspected

– RashRash may preclude the onset of thrombotic may preclude the onset of thrombotic

thrombocytopenic purpura (TTP) thrombocytopenic purpura (TTP)

Anti-platelets - Anti-platelets - TiclopidineTiclopidine CATS trialCATS trial: Ticlopidine vs placebo : Ticlopidine vs placebo

– Lancet 1989;1:1215-20Lancet 1989;1:1215-20 TASS trialTASS trial: Ticlopidine vs ASA (650mg bid): : Ticlopidine vs ASA (650mg bid):

– Stroke 1989;321: 501-507Stroke 1989;321: 501-507 BOTH trialsBOTH trials: :

– Ticlopidine - more effectiveTiclopidine - more effective– ButBut - greater risk of ADRs (even with high dose ASA) - greater risk of ADRs (even with high dose ASA)

– In TASSIn TASS: Stroke/death – : Stroke/death – ARR = 2%;ARR = 2%; NNT = 50NNT = 50 in in favour of ticlid. (driven by nonfatal stroke) favour of ticlid. (driven by nonfatal stroke)

– Secondary endpoint of stroke – Secondary endpoint of stroke – ARR 3%; NNT = 34ARR 3%; NNT = 34. .

Clopidogrel – Clopidogrel – Bottom LineBottom LineCAPRIE trial – nada!CAPRIE trial – nada!

All All PatientsPatients

Stroke Stroke SubgroupSubgroup EndpoiEndpoi

ntntASAASAn=958n=958

66

ClopidogrClopidogrelel

n=9599n=9599

ASAASAn=319n=319

88

ClopidogrelClopidogreln=3233n=3233

99 99 1919 1717Ischemic Ischemic StrokeStroke

1010 1010 1919 1919 TIA / TIA / RINDRIND

Anti-Platelets – Anti-Platelets – ClopidogrelClopidogrel CAPRIECAPRIE trial: ASA 325mg vs Clopidogrel trial: ASA 325mg vs Clopidogrel

75mg75mg > 19000 pts! (1 in 3 had ischemic > 19000 pts! (1 in 3 had ischemic

stroke)stroke) Ischemic Ischemic stroke/MI/Vascular deathstroke/MI/Vascular death

– 5.32%(CLOP) vs 5.83%(ASA) event rate/yr 5.32%(CLOP) vs 5.83%(ASA) event rate/yr – RRR = ~9%; ARR = 0.51; NNT = 196RRR = ~9%; ARR = 0.51; NNT = 196

Benefit seen only in Benefit seen only in multiplemultiple groups with groups with multiplemultiple composite endpoints.composite endpoints.

No benefit of clopidrogel over ASANo benefit of clopidrogel over ASA to to reduce reduce recurrent strokerecurrent stroke events. events.

Lancet 1996;348(9038):1329-39Lancet 1996;348(9038):1329-39

Anti-Platelet COMBO: Anti-Platelet COMBO: ASA+PlavixASA+Plavix

MATCHMATCH trial trial– Increase in life-threatening bleedsIncrease in life-threatening bleeds

CHARISMACHARISMA trial (n = 15603) trial (n = 15603)– Increase in moderate bleedsIncrease in moderate bleeds– N Engl J Med 2006;354.N Engl J Med 2006;354.

Both trials showed NO improvement Both trials showed NO improvement in secondary prevention of CVA with in secondary prevention of CVA with an increase in bleed risk.an increase in bleed risk.

CHARISMA trialCHARISMA trial

No No benefit benefit seen with seen with combo txcombo tx

Increase Increase in in moderate moderate bleeds!bleeds!

Anti-Platelet COMBO: ASA+PlavixAnti-Platelet COMBO: ASA+Plavix

CHANCE CHANCE trial – trial – A + C w/i 24h of CVA/TIA x21d then CA + C w/i 24h of CVA/TIA x21d then C

– Reduction in CVA in first 90 daysReduction in CVA in first 90 days– Clopidogrel + ASA = 8.2%; ASA alone = 11.7% Clopidogrel + ASA = 8.2%; ASA alone = 11.7%

90 day stroke free HR = 0.68; (95%C.I. 0.57 - 0.81); 90 day stroke free HR = 0.68; (95%C.I. 0.57 - 0.81); P<0.001P<0.001

No increase in hemorrhagic stroke or severe bleedingNo increase in hemorrhagic stroke or severe bleeding Increase in mild bleedingIncrease in mild bleeding

– N.B. ** Exclusively in China **N.B. ** Exclusively in China ** Being repeated in USA as Being repeated in USA as POINTPOINT trial trial

N Engl J Med 2013; 369:11-19N Engl J Med 2013; 369:11-19

Anti-Platelet COMBO: Anti-Platelet COMBO: AggrenoxAggrenox™™

ESPS-2 TrialESPS-2 Trial – 6602 pts – 6602 pts – ASA 25mg bid vs placebo vs dipyridamole MR ASA 25mg bid vs placebo vs dipyridamole MR

200mg bid vs ASA-dipyridamole (Aggrenox) bid200mg bid vs ASA-dipyridamole (Aggrenox) bid (Non)fatal stroke:(Non)fatal stroke:

– Aggrenox > ASA or DP alone (p<0.006, p<0.002 Aggrenox > ASA or DP alone (p<0.006, p<0.002 respectively) respectively)

– ARR = 3%; NNT = 34 (DP-ASA vs ASA)ARR = 3%; NNT = 34 (DP-ASA vs ASA) Other vascular events (PE/DVT/peripheral Other vascular events (PE/DVT/peripheral

artery obstruction/retinal artery occlusion)artery obstruction/retinal artery occlusion)– DP-ASA - 14%;DP-ASA - 14%; ASA - 26%; DP - 24%; Placebo - ASA - 26%; DP - 24%; Placebo -

36%; p<0.0136%; p<0.01 J Neuro Sci 1996;143:1-13J Neuro Sci 1996;143:1-13

ESPRITESPRIT trial – 2739 pts w trial – 2739 pts w// prior CVA prior CVA– ASA 30-235mg (median 75mg) +/- ASA 30-235mg (median 75mg) +/-

dipyridamole MR 200mg BIDdipyridamole MR 200mg BID Composite of vascular Composite of vascular

death/stroke/MI/major bleeding death/stroke/MI/major bleeding complicationcomplication– ASA + dipyridamole (13%) vs ASA (16%)ASA + dipyridamole (13%) vs ASA (16%)– HR = 0.80, 95% CI 0.66–0.98; HR = 0.80, 95% CI 0.66–0.98; – ARR = 1.0%/yr (95% CI 0.1–1.8))ARR = 1.0%/yr (95% CI 0.1–1.8))

Lancet 2006; 367: 1665–73Lancet 2006; 367: 1665–73

Anti-Platelet COMBO: Anti-Platelet COMBO: AggrenoxAggrenox™™

Anti-Platelets – Anti-Platelets – AggrenoxAggrenox

ESPRIT trial - Lancet 2006; 367: 1665–73

Aggrenox™ vs Plavix™ Aggrenox™ vs Plavix™ PRoFESS trialPRoFESS trial

Double blind RCT, n = 20,332Double blind RCT, n = 20,332 2x2 factorial2x2 factorial

– Axis 1:Axis 1: ASA 25 mg + ER-dipyridamole 200 mg ASA 25 mg + ER-dipyridamole 200 mg

BID versus 75 mg of clopidogrel dailyBID versus 75 mg of clopidogrel daily

– Axis 2: Axis 2: Telmisartan 80mg versus placeboTelmisartan 80mg versus placebo

– Not discussed hereNot discussed here

N Engl J Med 2008;359

Aggrenox™ vs Plavix™Aggrenox™ vs Plavix™

Primary outcome: Primary outcome: – First recurrence of strokeFirst recurrence of stroke

Secondary outcome: Secondary outcome: – Composite of stroke, myocardial Composite of stroke, myocardial

infarction, or death from vascular infarction, or death from vascular causescauses

Statistical testing of non-inferiority, Statistical testing of non-inferiority, followed by superiority testing, was followed by superiority testing, was planned. planned.

PRoFESS – Results - EfficacyPRoFESS – Results - Efficacy After 2.5 years (mean) of follow-upAfter 2.5 years (mean) of follow-up No difference in: No difference in:

– First recurrence of strokeFirst recurrence of stroke

OutcomeOutcomeASA–ASA–ERDP ERDP

(n = 10,181) (n = 10,181) # (%)# (%)

ClopidogClopidogrel rel

(n = 10,151) (n = 10,151) # (%)# (%)

Hazard Hazard Ratio for Ratio for ASA-ERDPASA-ERDP (95% CI)(95% CI)

Recurrent Recurrent strokestroke

916 916 (9.0) (9.0)

898 898 (8.8) (8.8)

1.01 1.01 (0.92-(0.92-1.11) 1.11)


– Composite stroke / MI / vascular deathComposite stroke / MI / vascular death

OutcomeOutcome

ASA–ASA–ERDP ERDP

(n = 10,181) (n = 10,181) # (%)# (%)


(n = 10,151) (n = 10,151) # (%)# (%)

Hazard Hazard Ratio for Ratio for

ASA-ERDP ASA-ERDP (95% CI)(95% CI)

Composite Composite of stroke, of stroke, MI, or MI, or vascular vascular deathdeath

1333 (13.1) 1333 (13.1) 1333 (13.1)1333 (13.1) 0.99 (0.92–0.99 (0.92–1.07)1.07)


– Myocardial infarction Myocardial infarction (i.e. no need for ASA (i.e. no need for ASA 81mg!)81mg!)


(n = 10,181) (n = 10,181) # (%)# (%)


(n = 10,151) (n = 10,151) # (%)# (%)


M.I.M.I. 178 (1.7)178 (1.7) 197 (1.9)197 (1.9)0.90 0.90 (0.73–(0.73–1.10)1.10)

PRoFESS – Results - EfficacyPRoFESS – Results - Efficacy After 2.5 years (mean) of follow-upAfter 2.5 years (mean) of follow-up Significant difference in: Significant difference in:

– New or worsening CHF New or worsening CHF (hypothesis (hypothesis generating)generating)


(n = 10,181) (n = 10,181) # (%)# (%)


(n = 10,151) (n = 10,151) # (%)# (%)


New or New or worsening worsening CHFCHF

144 (1.4)144 (1.4) 182 (1.8)182 (1.8)0.780.78 ((0.62–0.62–0.960.96) )

PRoFESS – Results - ToxicityPRoFESS – Results - ToxicityOutcomeOutcome

ASA–ERDP ASA–ERDP (n = 10,181) (n = 10,181)

# (%)# (%)

ClopidogrelClopidogrel (n = 10,151) (n = 10,151)

# (%)# (%)

Hazard Ratio for Hazard Ratio for ASA-ERDP (95% ASA-ERDP (95%

CI)CI)

Major hemorrhagic eventMajor hemorrhagic event 419 (4.1)419 (4.1) 365 (3.6)365 (3.6) 1.15 (1.15 (1.001.00––1.32)1.32)

Life-threateningLife-threatening 128 (1.3)128 (1.3) 116 (1.1) 116 (1.1)

Non–life-threateningNon–life-threatening 291 (2.9)291 (2.9) 249 (2.5)249 (2.5)

Hemorrhagic event Hemorrhagic event (minor or major)(minor or major)

535 (5.3)535 (5.3) 494 (4.9)494 (4.9) 1.08 (0.96–1.08 (0.96–1.22) 1.22)

Intracranial hemorrhageIntracranial hemorrhage 147 (1.4)147 (1.4) 103 (1.0)103 (1.0) 1.42 (1.11–1.42 (1.11–1.83)1.83)

Hemorrhagic strokeHemorrhagic stroke 90 (0.9)90 (0.9) 55 (0.5) 55 (0.5)

FatalFatal 28 (0.3)28 (0.3) 29 (0.3)29 (0.3)

NonfatalNonfatal 62 (0.6)62 (0.6) 26 (0.3) 26 (0.3)

Intraocular hemorrhageIntraocular hemorrhage 22 (0.2)22 (0.2) 22 (0.2)22 (0.2)

Nonstroke intracranial Nonstroke intracranial hemorrhagehemorrhage 35 (0.3)35 (0.3) 26 (0.3) 26 (0.3)

PRoFESS – Results - ToxicityPRoFESS – Results - ToxicityOutcomeOutcome

ASA–ERDP ASA–ERDP 10,055 (100.0) 10,055 (100.0)

# (%)# (%)

ClopidogrelClopidogrel (n= 10,040 (n= 10,040

(100.0) # (%)(100.0) # (%)

Adverse events leading Adverse events leading to discontinuationto discontinuation

1,650 1,650 (16.4)(16.4)

1,069 1,069 (10.6) (10.6)

HeadacheHeadache 593 (5.9)593 (5.9) 87 (0.9)87 (0.9)

VomitingVomiting 158 (1.6)158 (1.6) 37 (0.4)37 (0.4)

NauseaNausea 155 (1.5)155 (1.5) 58 (0.6)58 (0.6)

DizzinessDizziness 134 (1.3)134 (1.3) 52 (0.5)52 (0.5)Atrial fibrillationAtrial fibrillation 122 (1.2)122 (1.2) 143 (1.4)143 (1.4)

DiarrheaDiarrhea 102 (1.0)102 (1.0) 42 (0.4)42 (0.4)HypotensionHypotension 54 (0.5)54 (0.5) 35 (0.3) 35 (0.3)

Potential LimitationsPotential Limitations

52% entered PRoFESS with lacunar 52% entered PRoFESS with lacunar strokes strokes • = fewer recurrences vs large artery CVA= fewer recurrences vs large artery CVA’’ss

Only 2.5 yrs follow-up – shortOnly 2.5 yrs follow-up – short

– ?enough to see a difference in efficacy??enough to see a difference in efficacy?

~ 32% asian population~ 32% asian population– Increased risk of bleeding vs non-asians?Increased risk of bleeding vs non-asians?

StrengthsStrengths

Large, DB-RCTLarge, DB-RCT DirectDirect comparison of anti-platelet comparison of anti-platelet

regimensregimens Very generalizable – international Very generalizable – international

trialtrial More choices in stroke therapy for More choices in stroke therapy for

practitionerspractitioners

Ticagrelor and PrasugrelTicagrelor and Prasugrel

Ticagrelor – no improvement vs Ticagrelor – no improvement vs clopidogrel and possible increase in clopidogrel and possible increase in harm in stroke patientsharm in stroke patients– PLATO studyPLATO study

Prasugrel – possible improvement vs Prasugrel – possible improvement vs clopidogrel in ACS, but more clopidogrel in ACS, but more intracranial bleeding.intracranial bleeding.– esp. in pts with previous stroke! esp. in pts with previous stroke! – TRITON-TIMI 38 studyTRITON-TIMI 38 study

Secondary Prevention – CVA1) Efficacy

Agent Monotherapy Combo w/ ASAASA ASA ~23% RRR > placebo

NNT ~ 50-100 x1 year to prevent any vascular event. (50-325mg)

(CAST, IST, SALT, Dutch-TIA trials)

--

Ticlopidine Superior to ASA (CATS & TASS trials)

unknown

Clopidogrel Equivalent to ASA (extremely small absolute improvement per CAPRIE trial)

Possible improvement for 1st 21 days post CVA (CHANCE trial)No benefit long term (CHARISMA, MATCH trials)

Aggrenox® Superior to ASA (ESPRIT & ESPS2 trials), but Equivalent to Clopidogrel (PRoFESS trial) whaa?

--

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013From: Antiplatelet treatment http://cks.nice.org.uk/antiplatelet-treatment#!management Accessed Apr 4/13From: http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf Accessed Apr 4/13.

http://www.Rxfiles.ca/

http://cks.nice.org.uk/antiplatelet-treatment#!management

http://www.nice.org.uk/nicemedia/live/13588/56819/56819.pdf

Secondary Prevention – CVA2) Toxicity

Agent Monotherapy Combo w/ ASA

ASA Low, but look at additive bleeding risk factors: (Age >75 yrs, DM, elevated INR warfarin, female, ↓

hematocrit, HF/MI, ↑HR, length of antithrombotic tx, liver dx, ↑↓ systolic BP, medications (e.g.

anticoagulants, antiplatelets, NSAIDs), previous GI bleed or stroke noncardioembolic, ↑Scr, ↓ wt.)

--

Clopidogrel ~ equivalent in absolute senseSlightly less GI bleed & GI events except diarrhea; More Rash

More bleeding vs ASA alone(CHARISMA & MATCH trials)

Aggrenox® More headache, diarrhea, GI upset, dizziness, & early D/C vs ASA or Clopidogrel

More intracranial bleed vs Clopidogrel--

Secondary Prevention – CVASecondary Prevention – CVA

3) 3) CostCost– ASAASA

Pennies!Pennies!

– ClopidogrelClopidogrel ~ $95/mo~ $95/mo LU code for ASA LU code for ASA

intolerance onlyintolerance only

– Aggrenox®Aggrenox® ~ $61/mo~ $61/mo LU code for CVALU code for CVA

4) 4) ConvenienceConvenience– ASAASA

75-325mg once 75-325mg once daily daily

– ClopidogrelClopidogrel 75mg once daily75mg once daily

– Aggrenox®Aggrenox® 200/25mg 200/25mg BIDBID

popo

From: www.Rxfiles.ca ORAL ANTIPLATELET & ANTITHROMBOTIC AGENTS Comparison Table; Feb 2013

http://www.Rxfiles.ca/

Bottom Line 2Bottom Line 2oo Prevention Prevention CVACVA

ASAASA or or ClopidogrelClopidogrel or or AggrenoxAggrenox®®– Any will do, until tie breaker trial Any will do, until tie breaker trial

between these agents. between these agents. – Aggrenox® might be more efficacious, Aggrenox® might be more efficacious,

but with more side effects and less but with more side effects and less convenience. convenience.

Break!Break!

AnticoagulantsAnticoagulants

WarfarinWarfarin– Vitamin K antagonist Vitamin K antagonist – (clotting factors (clotting factors

2,7,9,10, protein C & 2,7,9,10, protein C & S)S)

DabigatranDabigatran– Direct thrombin Direct thrombin

inhibitor (factor 2)inhibitor (factor 2)

RivaroRivaroxaxabanban– Factor Factor XaXa inhibitor inhibitor

ApiApixaxabanban– Factor Factor XaXa inhibitor inhibitor

Bottom Line – WarfarinBottom Line – Warfarin

At least as good as ASA in At least as good as ASA in prevention of prevention of thromboticthrombotic CVA CVA– But why bother?But why bother?

Warfarin is superior to ASA in Warfarin is superior to ASA in cardioembolic stroke (AFib)cardioembolic stroke (AFib)– At least twice as good as ASAAt least twice as good as ASA

What about newer oral What about newer oral anticoagulants? (NOACs)anticoagulants? (NOACs)

Anticoagulants (VTE, Afib, Valve disease)

Agent Efficacy Toxicity

Warfarin Excellent vs placebo or ASA1.3% - 3.5% -- major bleed

< 0.25% - 0.5%/yr – ICHVit K reversal agent (< 24h)

Dabigatran~ same

N.B. (~1% absolute difference)(RE-LY trial - industry funded)

Less intracranial bleedingMore GI bleeds; ?More MI?Untested > 79y.o. or CrCL < 30NO reversal agent

Rivaroxaban~ same

N.B. (<1% absolute difference)(ROCKET-AF trial – industry funded)

Less intracranial bleedingMore GI bleedsUntested > 79y.o. or CrCL < 30NO reversal agent

Apixaban~ same

N.B. (<1% absolute difference)(ARISTOTLE trial – industry funded)

Less intracranial bleedingGI bleeding – no differenceUntested > 77y.o. or CrCL < 30NO reversal agent

AnticoagulantsAnticoagulants (VTE, Afib, Valve disease) (VTE, Afib, Valve disease)

Agent Cost Convenience

Warfarin ~ $40/mo (with INR monitoring)

QD poINR q3d – q1mo

(ODB covered)

Dabigatran $110/moBID po

(ODB w/ LU code 431 for AFib)

Rivaroxaban $100/moQD with food

(ODB w/ LU codes for Afib or VTE)

Apixaban $140/moBID po

(ODB w/ LU code 448 for Afib)

Rxfile

s.ca

Com

pari

son o

f W

arf

ari

n &

New

Ora

l A

nti

coagula

nts

(N

OA

Cs)

in

Non-V

alv

ula

r A

tria

l Fi

bri

llati

on 0

7/0

3/2

01

3

SummarySummary AntiplateletsAntiplatelets

– Small differences in efficacy or toxicity, dictate Small differences in efficacy or toxicity, dictate that cost will drive selection. that cost will drive selection.

– = ASA= ASA– Combination therapy where indicated Combination therapy where indicated

AnticoagulantsAnticoagulants– Small differences in efficacySmall differences in efficacy– Important unknowns in toxicity w/ newer agents Important unknowns in toxicity w/ newer agents

(age effects, renal dysfunction, lack of antidotes) (age effects, renal dysfunction, lack of antidotes)

– Use warfarin except for carefully selected patients Use warfarin except for carefully selected patients with with significantsignificant compliance barriers due to the compliance barriers due to the inconvenience of INR testing. inconvenience of INR testing.

Anti-coagulants - Anti-coagulants - WarfarinWarfarin WARSS trial WARSS trial – 2200 minor-moderate – 2200 minor-moderate

CVAsCVAs ASA 325mg vs Warfarin (ASA 325mg vs Warfarin (INR 1.4 - 2.8INR 1.4 - 2.8)) Primary - Primary - death or recurrent CVA - NSdeath or recurrent CVA - NS SecondarySecondary

– minor hemorrhage NNH = 13minor hemorrhage NNH = 13– major hemorrhage NSmajor hemorrhage NS

N.B.N.B.– 16.% INRs < 1.4 (mean 2.1; median was 1.9) 16.% INRs < 1.4 (mean 2.1; median was 1.9) – 14% INRs > 2.8 14% INRs > 2.8

NEJM 345(20); Nov 15/01, 1444-51NEJM 345(20); Nov 15/01, 1444-51

Anticoagulants – WarfarinAnticoagulants – Warfarin EAFT Trial - EAFT Trial - Afib pts w/in 3 months of Afib pts w/in 3 months of

minor CVA/TIAminor CVA/TIA Open-label warfarin (INR 2.5-4) vs ASA Open-label warfarin (INR 2.5-4) vs ASA

300mg vs placebo300mg vs placebo Vascular death/nonfatal CVA or Vascular death/nonfatal CVA or

MI/embolism: Warfarin vs ASA: MI/embolism: Warfarin vs ASA: – HR = 0.6; (95% CI 0.41-0.87) p = 0.008HR = 0.6; (95% CI 0.41-0.87) p = 0.008

Lancet 1993; 342:1255–1262Lancet 1993; 342:1255–1262

Anticoagulants – WarfarinAnticoagulants – Warfarin SPAF-3 trial SPAF-3 trial – 1044 pts (stopped – 1044 pts (stopped

early)early) ASA + fixed dose warfarin ASA + fixed dose warfarin vsvs warfarin warfarin

(INR 2-3)(INR 2-3)– mean=2.4; median=3.9mg/d mean=2.4; median=3.9mg/d – 76% INRs between 1.8-3.276% INRs between 1.8-3.2

Ischemic stroke/systemic embolism:Ischemic stroke/systemic embolism:– ASA + Warf = 7.9% ASA + Warf = 7.9% – Warf = 1.9%; p<0.0001; Warf = 1.9%; p<0.0001; – ARR 6% [RRR=74% (95% CI 50-87%) p < ARR 6% [RRR=74% (95% CI 50-87%) p <

0.0001] 0.0001] – NNT = 17 for 1 yrNNT = 17 for 1 yr

Lancet 1996;348:633-36Lancet 1996;348:633-36

Review – Anti-thromboticsReview – Anti-thrombotics

Ischemic CVA – Aggrenox or Plavix or ASAIschemic CVA – Aggrenox or Plavix or ASA– If can’t tolerate one, change therapyIf can’t tolerate one, change therapy– If ASA allergy – clopidogrel 75mg qdIf ASA allergy – clopidogrel 75mg qd

Cardioembolic CVA – Warfarin Cardioembolic CVA – Warfarin (INR 2-3)(INR 2-3)– Good CrCL and poor INR control – consider ApixabanGood CrCL and poor INR control – consider Apixaban

Hemorrhagic CVA Hemorrhagic CVA – If ischemic or cardioembolic transformation: If ischemic or cardioembolic transformation:

treat as abovetreat as above

– If primary hemorrhage – usually due to HTNIf primary hemorrhage – usually due to HTN Add ASA once acute bleed resolved (primary Add ASA once acute bleed resolved (primary

prevention of ischemic event)prevention of ischemic event)

Anti-dyslipidemics - Anti-dyslipidemics - StatinsStatins

HPS trialHPS trial – 20,596 high risk pts – 20,596 high risk pts Simvastatin 40mg vs placeboSimvastatin 40mg vs placebo Stroke - 4.3% vs 5.7% (RRR Stroke - 4.3% vs 5.7% (RRR

25%)25%) Significant regardless of age Significant regardless of age

or cholesterol level!or cholesterol level! Lancet 2002; 360: 23–33Lancet 2002; 360: 23–33

From: Kirshner, H, Bottorff, MB. Opportunities and Guidelines for Aggressive Prevention of Secondary Stroke http://www.princetoncme.com/pdf/programs/2006-174.pdf Accessed May 8/07.

Anti-dyslipidemics - Anti-dyslipidemics - StatinsStatins

SPARCLSPARCL Trial - Trial - 4731 pts w/ 4731 pts w/ CVA/TIA, LDL 2.59-4.91 CVA/TIA, LDL 2.59-4.91 mmol/Lmmol/L

Atorvastatin 80mg vs Atorvastatin 80mg vs placeboplacebo

16% RRR for stroke (16% RRR for stroke (PP<.03)<.03) 23% reduction in CVA/TIA 23% reduction in CVA/TIA

((PP<.001)<.001) Slight increase in cerebral Slight increase in cerebral

hemorrhagehemorrhage N Engl J Med 2006;355(6):549-59 N Engl J Med 2006;355(6):549-59

For lucky best wash, use Mr SPARCL!

Bottom Line – Bottom Line – StatinsStatins

Statins are the only anti-Statins are the only anti-dyslipidemics proven to prevent dyslipidemics proven to prevent ischemic stroke and provide a ischemic stroke and provide a mortality benefit for secondary mortality benefit for secondary prevention of CVA.prevention of CVA.– SimvastatinSimvastatin– AtorvastatinAtorvastatin– ? Class effect?? Class effect?

Bottom Line - Bottom Line - Anti-Anti-hypertensiveshypertensives

BP reduction is key!BP reduction is key!– Aggressive reductionAggressive reduction

Up to 28% reduction of second CVAUp to 28% reduction of second CVA– Up to 40-50% reduction in first CVA!Up to 40-50% reduction in first CVA!

ACEinh or Thiazides – 1ACEinh or Thiazides – 1stst among among equals?equals?– Some evidence as well for ARBsSome evidence as well for ARBs

Strongly consider ACEinh + diuretic Strongly consider ACEinh + diuretic combocombo

Anti-hypertensives–Anti-hypertensives–ACE ACE inhibitorsinhibitors

HOPE trialHOPE trial - - ““high-riskhigh-risk”” pts pts– CAD (52%), stroke (11%), DM (39%), CAD (52%), stroke (11%), DM (39%),

PAD (42%) PAD (42%) Ramipril 10 mg vs placeboRamipril 10 mg vs placebo 22% less Stroke/MI/Vascular death22% less Stroke/MI/Vascular death Stroke alone Stroke alone 32%32% RRR RRR

– (subgroup analysis)(subgroup analysis) NNT = 67 (for stroke)NNT = 67 (for stroke) NEJM 2000;342:145-53NEJM 2000;342:145-53

Anti-hypertensives–Anti-hypertensives–ThiazidesThiazides

ALLHAT trialALLHAT trial - prospective, DB, MC- RCT - prospective, DB, MC- RCT– medium risk pts medium risk pts

36% DM2, average BMI 29, 90% on current BP meds36% DM2, average BMI 29, 90% on current BP meds Inclusion: ≥55y.o, stage 1 or 2 HTN with at least 1 risk Inclusion: ≥55y.o, stage 1 or 2 HTN with at least 1 risk

factor (previous MI >6mos., LVH, DMII, smoker, HDL<0.91, factor (previous MI >6mos., LVH, DMII, smoker, HDL<0.91, atherosclerotic CVD) atherosclerotic CVD)

Exclusion: symptomatic HF or LVEF<35%Exclusion: symptomatic HF or LVEF<35%

– chlorthalidone chlorthalidone (12.5-25mg/d) - (n = 15255)(12.5-25mg/d) - (n = 15255) vs vs – lisinopril lisinopril (10-40mg/d) - (n = 9054)(10-40mg/d) - (n = 9054) vs vs – amlodipine amlodipine (2.5-10 mg/d) - (n = 9048)(2.5-10 mg/d) - (n = 9048) vs vs – doxazocin doxazocin ((terminated due to terminated due to ↑↑CV eventsCV events) )

Open-label Step 2: atenolol, clonidine, reserpine - target Open-label Step 2: atenolol, clonidine, reserpine - target <140/90<140/90

JAMA 2002;288:2981JAMA 2002;288:2981

Anti-hypertensives–Anti-hypertensives–ThiazidesThiazides

Primary Endpoint: combined fatal CHD or Primary Endpoint: combined fatal CHD or nonfatal myocardial infarction (MI) nonfatal myocardial infarction (MI) – No differenceNo difference– All cause mortality – no differenceAll cause mortality – no difference

Secondary Endpoint: fatal and nonfatal Secondary Endpoint: fatal and nonfatal stroke: stroke: – chlorthalidone (5.6) vs chlorthalidone (5.6) vs – Amlodipine (5.4) Amlodipine (5.4) – Lisinopril (6.3) Lisinopril (6.3)

Lisinopril vs chlorthalidone Lisinopril vs chlorthalidone RR 1.15 (95% CI 1.02-1.30, p=.02RR 1.15 (95% CI 1.02-1.30, p=.02))

Chlorthalidone better than lisinopril in Chlorthalidone better than lisinopril in black subgroup for CVA, combined black subgroup for CVA, combined CVD/CHD, & CHFCVD/CHD, & CHF

Anti-hypertensivesAnti-hypertensivesACE inhibitors + ThiazidesACE inhibitors + Thiazides

PROGRESS Trial -PROGRESS Trial -TIA or stroke,TIA or stroke, Perindopril 4 mg +/- indapamide 2.5 Perindopril 4 mg +/- indapamide 2.5

mg vs placebomg vs placebo 28% RR in stroke over 4 years28% RR in stroke over 4 years N.B. Perindopril-indapamide combo N.B. Perindopril-indapamide combo

produced larger BP reduction and produced larger BP reduction and risk reductions than either drug risk reductions than either drug alonealone

Lancet 2001: 358:1033-41Lancet 2001: 358:1033-41

Anti-hypertensives – Anti-hypertensives – ARBsARBs

LIFELIFE trial: 9193 pts w/ HTN, losartan vs trial: 9193 pts w/ HTN, losartan vs atenolol atenolol – RRR 13% stroke/MI/death, RRR 13% stroke/MI/death, – RRR 25% stroke; RRR 25% stroke; – Losartan and atenolol ~ equal for preventing Losartan and atenolol ~ equal for preventing

MIMI SCOPESCOPE trial: 28% reduction in CVA over trial: 28% reduction in CVA over

placebo w/ candesartanplacebo w/ candesartan MOSESMOSES: Eprosartan vs nitrendipine: : Eprosartan vs nitrendipine:

– 21% RRR of events21% RRR of eventsFrom: Kirshner, H, Bottorff, MB. Opportunities and Guidelines for Aggressive Prevention of Secondary Stroke http://www.princetoncme.com/pdf/programs/2006-174.pdf Accessed May 8/07.

Feeling?Feeling?

Review – Secondary Review – Secondary PreventionPrevention

Cardioembolic CVACardioembolic CVA– Statin, ACEinh (since likely has CHD)Statin, ACEinh (since likely has CHD)– B-blockers (CHD, also for rate control)B-blockers (CHD, also for rate control)

Ischemic CVAIschemic CVA– Statin; ACEinh and/or diureticStatin; ACEinh and/or diuretic

Hemorrhagic CVAHemorrhagic CVA– If primary bleed - BP control!If primary bleed - BP control!– If transformation – treat as ischemic CVA If transformation – treat as ischemic CVA

once bleed resolvesonce bleed resolves

Stroke Case - revisitedStroke Case - revisited Mr. HS (54 y.o. Mr. HS (54 y.o.

male) - 5 weeks male) - 5 weeks prior he awoke at prior he awoke at noon with right noon with right facial weakness, facial weakness, numbness, & slurred numbness, & slurred speech. He had speech. He had been diagnosed with been diagnosed with a stroke (CT Head). a stroke (CT Head). At the time of his At the time of his appointment he is appointment he is left with no residual left with no residual deficits. deficits.

PMHx: PMHx: 6 MI6 MI’’s in 10 s in 10 seasonsseasons

HTN HTN DM-2 x 3 yrsDM-2 x 3 yrs SHx: SHx: 48 beers / week 48 beers / week

– Lives w/ wife & 3 Lives w/ wife & 3 kids kids

Current Meds:Current Meds:– EC-ASA 81 mg ODEC-ASA 81 mg OD– Metformin 500 mg TIDMetformin 500 mg TID– Glyburide 2.5 mg BIDGlyburide 2.5 mg BID– Diltiazem 240 mg ODDiltiazem 240 mg OD– Maalox prn for Maalox prn for

““heartburnheartburn””

What to do?What to do?

Questions?Questions?

Documents

Secondary Prevention of Stroke (aka the Homer Talk) Roland Halil, BSc(Hon), BSc(Pharm), ACPR, PharmD Bruyere Academic Family Health Team Jan 2014