Lau 5.8.20 Stroke Prevention BrainKidney2020 · 2020-06-11 · COPY. 5/18/2020 4 The hazard of incident stroke associated with systolic BP (SBP) and chronic kidney disease (CKD) using

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Controversies:

Stroke Preventionin Chronic Kidney Disease

Wei Ling Lau, MDFASN FAHA FACPAssistant Professor, NephrologyUniversity of California, IrvineVisiting Fellow at OptumLabs

Disclosures

• Prior or current research funding from NIH, AHA,Sanofi, ZS Pharma, and Hub Therapeutics.

• Associate Medical Director for home peritonealdialysis at Fresenius University Dialysis Center ofOrange.

• Has been on Fresenius medical advisory board forVelphoro.

• No conflicts of interest relevant to the current talk.

Controversies: Stroke prevention in CKDWei Ling Lau, MDDO N

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Stroke Prevention in CKD

• Blood pressure targets

• Statins

Controversies: Stroke prevention in CKDWei Ling Lau, MD

• Antiplatelet agents

• Anticoagulation

Data is limited, as patients with CKD were historically excluded from clinical trials

Whelton 2017 ACC/AHA hypertension guidelines [Hypertension 2018]

BP TARGETS


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The SPRINT Research Group. N Engl J Med 2015 p2103

SPRINT: BP lowering to <120 vs<140 mmHg significantly lowered rate of CVD composite primary outcome; no clear effect on stroke


Systolic Blood Pressure Intervention Trial

SPRINT subgroup analysis: CKD

Cheung 2017 J Am Soc Nephrol p2812

• Patients with CKD stage 3‐4 (eGFR of 20 to <60) comprised 28% of the SPRINT study population

• Intensive BP management seemed to provide the same benefits for reduction in the CVD composite primary outcome – but did not impact stroke


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The hazard of incident stroke associated with systolic BP (SBP) and chronic kidney disease (CKD) using an unadjusted model that contained dummy variables for CKD and BP groups

(A) and a fully adjusted model that contained dummy variables for CKD and BP grou...

Weiner J Am Soc Nephrol 2007 p960

Secondary analysis of CKD patients in 2 longitudinal studies: • Atherosclerosis Risk in Communities Study (ARIC)

• Cardiovascular Health Study (CHS)

BP and stroke risk: J‐shaped association

CKD patients on antihypertensives in SBP <120

group had significantly increased risk for incident stroke HR 2.62

[95% CI 1.22 to 5.66]

Reference group: CKD patients with SBP 120 to 129 mmHg


Unadjusted

Multivariate adjusted model

STATINS• No benefit on stroke or mortality outcomes in the CKD population.

• Pravachol Pooling Project combined data from three placebo‐control RCTs and included 4491 patients with CKD stage 3 and coronary heart disease.

• There was benefit with primary end‐point of time to MI, coronary death, or coronary revascularization but no benefit in regard to stroke or mortality.

Tonelli 2004 Circulation p1557Controversies: Stroke prevention in CKDWei Ling Lau, MDDO N

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3 major statin RCTs in ESKD

“Statins have little or no beneficial effects on mortality or cardiovascular events and uncertain adverse effects in adults treated with dialysis despite clinically

relevant reductions in serum cholesterol levels.” Cochrane review 2013

Where n Median f/u intervention Stroke outcomes

German Diabetes and Dialysis Study (4D)

Germany 1255 dialysispts with type 2 DM

4 years Atorvastatin 20 mg Higher stroke mortalityRR 2.03 [95% CO 1.05‐3.93]P=0.04

AURORA (An Assessment of Survival and Cardiovascular Events)

280 centers25 countries

2776 dialysis pts

3.8 years Rosuvastatin 10 mg Same stroke incidence 1.2 vs1.1 per 100 patient‐yearsP=0.42

SHARP (Study of Heart and Renal Protection)

380 hospitals18 countries

9270 which included 3023 dialysis pts

4.9 years Simvastatin 20 mg + ezetimibe 10 mg

Less ischemic strokeRR 0.72 [95% CI 0.57‐0.92] P=0.007

**lacked sufficient power to assess effects separately in dialysis patients


Antiplatelet therapy

Cochrane systematic review:“ Antiplatelet drugs increase the risk for major and minor bleeding (by 33 and 49%, respectively) but do not significantly reduce the risk for stroke, all‐cause and cardiovascular mortality in CKD ”

Palmer 2013 Cochrane Database Syst RevTanios 2015 Seminars in Dialysis p276


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ASA and CKD progression

• Long‐term aspirin use has been debated due its association with CKD risk

• Population‐based study in Sweden (NEJM 2001):

Regular use of aspirin or acetaminophen was associated with a 2.5x increased risk of CKD compared with non‐users

Fored 2001 N Engl J Med p1801


Antiplatelets in CKD: Limited evidence for primary prevention

Aspirin, combined aspirin and dipyridamole or clopidogrel are options for initial therapy. May consider cilostazol or triflusal as an alternative if anticipate high‐risk for bleeding.

Meschia 2014 Stroke p3754Stevens 2013 Ann Intern Med p825

Kim & Bang 2013 Contrib Nephrol p119

Example: Aspirin

AHA/ASA stroke guidelines 2014 Kidney Disease Improving Global Outcomes (KDIGO) 2012

Aspirin recommended for stroke prevention in CKD stage 3 but no recommendation for CKD stages 4 and 5 (eGFR <30)

Suggest prescribing aspirin to CKD patients “at risk for atherosclerotic events” only for secondary prevention, if no increased bleeding risk


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Hypertension Optimal Study: Aspirin in hypertensive CKD stage 3b

• HOT study supports aspirin for primary prevention of composite CV outcomes in hypertensive CKD 3 patients

• Participants aged 50‐80 years from 26 countries in Europe, North and South America, and Asia randomized to aspirin 75 mg daily (n = 9,399) or placebo (n = 9,391)

• “Among every 1,000 persons with eGFR <45 treated for 3.8 years, 76 major cardiovascular events and 54 all‐cause deaths will be prevented while 27 excess major bleeds will occur”

Jardine 2010 J Am Coll Cardiol p956

ASA and secondary stroke prevention

• No good RCT data

• DOPPS: aspirin did not decrease CV events

• Antithrombotic Trialists’ collaboration meta‐analysis: aspirin reduced composite CV events in hemodialysis patients by 41% but increased bleeding events

• ATT meta‐analysis: If 1,000 dialysis patients with vascular disease are treated with aspirin for 5 years

prevent 16 ischemic strokes

prevent 75 MIs

cause 19 intracranial bleeds and

53 serious extracranial bleeds

Antithrombotic Trialists’ collaboration BMJ 2002 p71Herrington 2015 Seminars in Dialysis p35


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Clopidogrel: no benefits in CKDPossibly due to high prevalence of clopidogrel resistance (up to 50‐80% in ESRD)

Tanios 2015 Sem Dialysis p276 Sood 2013 Kidney Int p600Dasgupta 2009 Am J Cardiol p1359 Chen 2014 Int J Stroke p580

CURE and CREDO secondary analysis

Clopidogrel did not decrease combined CVprimary outcome in pre‐dialysis CKD

CHARISMA secondary analysis

Increased mortality in patients with diabetic nephropathy compared to placebo

Dialysis Outcomes and Practice Patterns Study (DOPPS)

Clopidogrel was associated with increased stroke and mortality compared to aspirin

Taiwan dialysis cohortClopidogrel did not alter stroke or mortality risk but increased risk of MI

Unfractionated heparin

Direct thrombin InhibitorDabigatran

Factor Xa inhibitorsApixabanRivaroxabanEdoxaban

Low molecular weight heparins(factor Xa inhibitors)

EnoxaparinFondaparinux

Vitamin K antagonistWarfarin

Direct thrombin inhibitorsArgatrobanBivalirudin

Anticoagulation

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http://www.neurology.org/content/78/7/501/F2.large.jpg

Intrinsic pathway Extrinsic pathway


ESKD population:warfarin has no effect or may increasestroke risk; increases major bleeding; no mortality benefit Dahal Chest 2016

Tan BMC Nephrology 2016

1954-2010: Warfarin was the only oral anticoagulant available in the US

Hart Ann Intern Med 2007

General population:warfarin reduces stroke risk with a‐fib by 64%


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Off-target effects: warfarin and vascular calcification

warfarin

Tantisattamo 2015 ATVB p237Lau, Ix 2013 Semin Nephrol p93

Meissner 2007 Dermatology p278

Calcific uremic arteriolopathy

Lin 2017 Am J Nephrol p249


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Warfarin therapy:• Higher mortality• Higher rates of MI• Higher rates of bleeding requiring

transfusion or hospitalization• No difference in ischemic stroke

rate

Lin 2017Am J Nephrol p249

• 15 studies published between 2008‐2019• 47,480 patients with a‐fib and ESRD; 10,445 (22%) were on warfarin• Mean follow‐up period 2.6 years

Warfarin use and associated Risks

Mortality

HR 0.9595% CI 0.83-1.09

Ischemic stroke

HR 0.96(0.82-1.13)

Hemorrhagic stroke

HR 1.49(1.03-1.94)

Major bleeding

HR 1.20(0.99-1.47)

Randhawa et al. JAMA Network Open. 2020;3(4):e202175


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Since 2009 there have been 4 large Phase III trials comparing NOACs with warfarin in a‐fib (over 71,000 patients); CKD 4/5 patients were excludedRE‐LY (dabigatran)ROCKET‐AF (rivaroxaban)ARISTOTLE (apixaban)ENGAGE AF‐TIMI 48 (edoxaban)

Pelliccia 2016 Int J CardiologyWang 2016 J Clin Pharm p628

Apixaban in ESKDFDA-approved 2014 ! Limited

Evidence !! Limited

Evidence !

Apixaban wasFDA‐approved for use in dialysis patients based on

a single‐dosepharmacokinetic study in 8 hemodialysis patients


Apixaban in ESKD: What dose to give?

• Study in Canada that led to dose adjustment in ESKD trials.

• Dosed 2.5 mg BID, then 5‐day washout period and five patients received 5 mg apixaban BID for 8 days... trough levels increased to 218 ng/ml (P=0.03), above the 90th percentile for the 5‐mg dose in patients with normal kidney function.

Mavrakanas 2017 J Am Soc Neph p2241Controversies: Stroke prevention in CKDWei Ling Lau, MDDO N

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• Analysis of US Renal Data System (2010‐2015)• 25,523 patients with ESKD and atrial fibrillation (~10% on apixaban, others on warfarin)

• No difference in risk of stroke; apixaban was associated with less bleeding events

• Sensitivity analyses: standard‐dose apixaban (5 mg twice a day; n=1034) was associated with significantly lower risk of stroke/systemic embolism and death as compared with 2.5 mg BID dose or warfarin

…however apixaban5 mg BID may be more effective for stroke prevention

Non-CKD CKD 3-4 CKD 5 / ESKDUpper 95% CI 1.66 1.32 2.44Lower 95% CI 1.63 1.25 1.99IRR after multivariate

adjustment 1.64 1.29 2.21

1

1.5

2

2.5

3

Across all strata, patients receiving warfarin had a faster time to first stroke and a higher incidence of stroke event

Incident Rate Ratio for Ischemic Stroke in 340,732 patients: Warfarin vs. DOACsunpublished data

ASN Kidney Week 2018 abstract 3023067: Edgett… Lau et al. "Direct Oral Anticoagulants vs. Warfarin: Stroke Outcomes in CKD Patients"DO N

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Hazard ratio for mortality in 27,787 US veterans: DOACs vs Warfarinunpublished data

Patients on DOACs had a lower risk of death in non-CKD and CKD stage 3a groups; however associations became non-significant in later stage CKD (insufficient data in ESKD stage)

ASN Kidney Week 2018 Abstract 3023028: Dratch… Lau et al. "Direct Oral Anticoagulants vs. Warfarin across CKD Stages: Mortality Outcomes in US Veterans"

Nigwekar & Thadhani2018 Circulation (editorial) p1530

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Monitor for clotting of circuit (Kecn, drip

chambers, venous and arterial pressures, dialyzer streaks)

Monitor for clotting of circuit (Kecn, drip

chambers, venous and arterial pressures, dialyzer streaks)

Decrease dose to 2.5 mg BID if weight <60 kg or age

≥80 y/o

Discuss with our patientsDiscuss with our patients

Discuss with prescribing doc

Discuss with prescribing doc

?? Optimal apixaban dose: 2.5 or 5 mg BID

?? Optimal apixaban dose: 2.5 or 5 mg BID

D/C heparin, re-introduce initial

bolus if necessary

D/C heparin, re-introduce initial

bolus if necessary

What do we do at the dialysis unit?

Alert RN and technicians

Alert RN and technicians


Conclusions: Stroke Prevention and CKD

• Blood pressure: no benefit in lowering systolic BP <120 mmHg.

• Statins: no clear benefit.• Antiplatelets: no clear benefit for secondary prevention. Aspirin indicated for primary prevention in hypertensive CKD stage 3 patients.

• Anticoagulation: DOACs appear to have a favorable profile over warfarin. Apixaban 2.5 mg BID in hemodialysis patients resulted in drug exposure comparable with that of the standard 5 mg BID dose in non‐CKD patients – but observational data suggests that 5 mg BID dose is more effective at stroke prevention. RCTs testing apixaban in ESKD population are ongoing.


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Lau 5.8.20 Stroke Prevention BrainKidney2020 · 2020-06-11 · COPY. 5/18/2020 4 The hazard of incident stroke associated with systolic BP (SBP) and chronic kidney disease (CKD) using