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5/18/2020
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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
Controversies: Stroke prevention in CKDWei Ling Lau, MDDO N
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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
Controversies: Stroke prevention in CKDWei Ling Lau, MD
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
Controversies: Stroke prevention in CKDWei Ling Lau, MDDO N
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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
Controversies: Stroke prevention in CKDWei Ling Lau, MD
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
Controversies: Stroke prevention in CKDWei Ling Lau, MD
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
Controversies: Stroke prevention in CKDWei Ling Lau, MDDO N
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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
Controversies: Stroke prevention in CKDWei Ling Lau, MD
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
Controversies: Stroke prevention in CKDWei Ling Lau, MDDO N
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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
Controversies: Stroke prevention in CKDWei Ling Lau, MDDO N
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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
Controversies: Stroke prevention in CKDWei Ling Lau, MD
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%
Controversies: Stroke prevention in CKDWei Ling Lau, MD
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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
Controversies: Stroke prevention in CKDWei Ling Lau, MDDO N
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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
Controversies: Stroke prevention in CKDWei Ling Lau, MDDO N
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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
Controversies: Stroke prevention in CKDWei Ling Lau, MD
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
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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
Controversies: Stroke prevention in CKDWei Ling Lau, MD
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.
Controversies: Stroke prevention in CKDWei Ling Lau, MDDO N
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