Stroke Prevention in Chronic Kidney Disease Disclosures

5/18/2020

Controversies: Stroke Prevention in Chronic Kidney Disease

Wei Ling Lau, MD FASN FAHA FACP Assistant Professor, Nephrology University of California, Irvine Visiting Fellow at OptumLabsCOPY

Disclosures

• Prior or current research funding from NIH, AHA, Sanofi, ZS Pharma, and Hub Therapeutics. • Associate Medical Director for home peritoneal dialysis at Fresenius University Dialysis Center of Orange. • Has beenNOT on Fresenius medical advisory board for Velphoro. • No conflicts of interest relevant to the current talk.

Controversies: Stroke prevention in CKD Wei Ling Lau, MD DO 1 5/18/2020

Stroke Prevention in CKD

• Blood pressure targets • Antiplatelet agents • Statins • Anticoagulation

Controversies: Stroke prevention in CKD Wei Ling Lau, MD COPY

BP TARGETS Data is limited, as patients with CKD were historically excluded from clinical trials NOT

Whelton 2017 ACC/AHA hypertension guidelines [Hypertension 2018]

Controversies: Stroke prevention in CKD Wei Ling Lau, MD DO 2 5/18/2020

Systolic Blood Pressure Intervention Trial 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 CKD The SPRINT Research Group. N Engl J Med 2015 p2103 Wei Ling Lau, MD COPY

SPRINT subgroup analysis: CKD • 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 outcomeNOT – but did not impact stroke

Controversies: Stroke prevention in CKD Cheung 2017 J Am Soc Nephrol p2812 Wei Ling Lau, MD DO 3 5/18/2020

The hazard of incident stroke associated with systolic BP (SBP) and chronic kidney disease (CKD)BP using and an unadjusted stroke model risk: that contained J‐shaped dummy variables association for CKD and BP groups (A) and a fully adjusted model that contained dummy variables for CKD and BP grou... Secondary analysis of CKD patients Unadjusted in 2 longitudinal studies: • Atherosclerosis Risk in Communities Study (ARIC) • Cardiovascular Health Study (CHS)

CKD patients on antihypertensives in SBP <120 group had significantly increased Multivariate adjusted risk for incident stroke HR 2.62 model [95% CI 1.22 to 5.66]

Reference group: CKD patients with SBP 120 to 129 mmHg

Controversies: Stroke prevention in CKD Weiner J Am Soc Nephrol 2007 p960 Wei Ling Lau, MD COPY

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.NOT • 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.

Controversies: Stroke prevention in CKD Tonelli 2004 Circulation p1557 Wei Ling Lau, MD DO 4 5/18/2020

Controversies: Stroke prevention in CKD Wei Ling Lau, MD 3 major statin RCTs in ESKD

Where n Median f/u intervention Stroke outcomes German Diabetes and Dialysis Study (4D) Germany 1255 dialysis 4 years Atorvastatin 20 mg Higher stroke mortality pts with type RR 2.03 [95% CO 1.05‐3.93] 2 DM P=0.04 AURORA (An Assessment of Survival and Cardiovascular Events) 280 centers 2776 dialysis 3.8 years Rosuvastatin 10 mg Same stroke incidence 1.2 vs 25 countries pts 1.1 per 100 patient‐years P=0.42 **lacked sufficient power to assess SHARP (Study of Heart and Renal Protection) effects separately in dialysis patients 380 hospitals 9270 which 4.9 years Simvastatin 20 mg + Less ischemic stroke 18 countries included 3023 ezetimibe 10 mg RR 0.72 [95% CI 0.57‐0.92] dialysis pts P=0.007

“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.” CochraneCOPY review 2013

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

Controversies: Palmer 2013 Cochrane Database Syst Rev Stroke prevention in CKD Wei Ling Lau, MD Tanios 2015 Seminars in Dialysis p276 DO 5 5/18/2020

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

Controversies: Stroke prevention in CKD Wei Ling Lau, MD Fored 2001COPY 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.

Example: Aspirin AHA/ASA stroke guidelines 2014 Kidney Disease Improving Global NOTOutcomes (KDIGO) 2012 Aspirin recommended for stroke Suggest prescribing aspirin to CKD prevention in CKD stage 3 but no patients “at risk for atherosclerotic recommendation for CKD stages 4 and 5 events” only for secondary prevention, if (eGFR <30) no increased bleeding risk

Meschia 2014 Stroke p3754 Controversies: Stevens 2013 Ann Intern Med p825 Stroke prevention in CKD Wei Ling Lau, MD Kim & Bang 2013 Contrib Nephrol p119 DO 6 5/18/2020

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 2010COPY 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  preventNOT 16 ischemic strokes  prevent 75 MIs  cause 19 intracranial bleeds and 53 serious extracranial bleeds

Controversies: Antithrombotic Trialists’ collaboration BMJ 2002 p71 Stroke prevention in CKD Herrington 2015 Seminars in Dialysis p35 Wei Ling Lau, MD DO 7 5/18/2020

Clopidogrel: no benefits in CKD

Possibly due to high prevalence of clopidogrel resistance (up to 50‐80% in ESRD)

CURE and CREDO Clopidogrel did not decrease combined CV secondary analysis primary outcome in pre‐dialysis CKD

CHARISMA secondary Increased mortality in patients with analysis diabetic nephropathy compared to placebo

Dialysis Outcomes and Clopidogrel was associated with increased Practice Patterns Study stroke and mortality compared to aspirin (DOPPS)

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

Tanios 2015 Sem Dialysis p276 Sood 2013 Kidney Int p600 Dasgupta 2009 Am J Cardiol p1359 ChenCOPY 2014 Int J Stroke p580

Anticoagulation

Unfractionated Low molecular weight heparins heparin (factor Xa inhibitors) Enoxaparin Fondaparinux

Direct thrombin inhibitors Factor Xa inhibitors Argatroban Bivalirudin Apixaban NOT Rivaroxaban Edoxaban

Direct thrombin Inhibitor Dabigatran Vitamin K antagonist Warfarin DO 8 5/18/2020

Intrinsic pathway Extrinsic pathway

Controversies: Stroke prevention in CKD Wei Ling Lau, MD http://www.neurology.org/content/78/7/501/F2.large.jpgCOPY

Controversies: Stroke prevention in CKD General population: Wei Ling Lau, MD warfarin reduces stroke risk

with a‐fib by 64% Hart Ann Intern Med 2007

1954-2010: Warfarin was the only oral anticoagulantNOT available in the US ESKD population: warfarin has no effect or may increase stroke risk; increases major bleeding;

no mortality benefit Dahal Chest 2016 Tan BMC Nephrology 2016 DO 9 5/18/2020

Off-target effects: warfarin and vascular calcification

warfarin

Calcific uremic Tantisattamo 2015 ATVB p237 arteriolopathy Lau, Ix 2013 Semin Nephrol p93 MeissnerCOPY 2007 Dermatology p278

NOT

Controversies: Stroke prevention in CKD Wei Ling Lau, MD Lin 2017 Am J Nephrol p249 DO 10 5/18/2020

Lin 2017 Am J Nephrol p249

Warfarin therapy: • Higher mortality • Higher rates of MI • Higher rates of bleeding requiring transfusion or hospitalization • No difference in ischemic stroke rate COPY

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

• 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 NOTWarfarin use and associated Risks Mortality Ischemic Hemorrhagic Major stroke stroke bleeding

HR 0.95 HR 0.96 HR 1.49 HR 1.20 95% CI 0.83-1.09 (0.82-1.13) (1.03-1.94) (0.99-1.47)

Controversies: Stroke prevention in CKD Wei Ling Lau, MD DO 11 5/18/2020

Apixaban in ESKD FDA-approved 2014 ! Limited Evidence !

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 excluded RE‐LY (dabigatran) Apixaban was ROCKET‐AF (rivaroxaban) FDA‐approved for use in ARISTOTLE (apixaban) dialysis patients based on ENGAGE AF‐TIMI 48 (edoxaban) a single‐dose pharmacokinetic study in 8 hemodialysis patients

Controversies: Pelliccia 2016 Int J Cardiology Stroke prevention in CKD Wei Ling Lau, MD Wang 2016COPY J Clin Pharm p628

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 toNOT 218 ng/ml (P=0.03), above the 90th percentile for the 5‐mg dose in patients with normal kidney function.

Controversies: Stroke prevention in CKD Mavrakanas 2017 J Am Soc Neph p2241 Wei Ling Lau, MD DO 12 5/18/2020

…however apixaban 5 mg BID may be more effective for stroke prevention

• 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 COPY

Incident Rate Ratio for Ischemic Stroke in 340,732 patients: Warfarin vs. DOACs unpublished data 3

Across all strata, patients receiving 2.5 warfarin had a faster time to first stroke and a higher incidence of stroke event

2 1.5NOT 1 Non-CKD CKD 3-4 CKD 5 / ESKD Upper 95% CI 1.66 1.32 2.44 Lower 95% CI 1.63 1.25 1.99 IRR after multivariate 1.64 1.29 2.21 adjustment

ASN Kidney Week 2018 abstract 3023067: Edgett… Lau et al. "Direct Oral Anticoagulants vs. Warfarin: Stroke Outcomes in CKD Patients" DO 13 5/18/2020

Hazard ratio for mortality in 27,787 US veterans: DOACs vs Warfarin unpublished 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" COPY

NOT

Nigwekar & Thadhani 2018 Circulation (editorial) p1530 DO 14 5/18/2020

What do we do at the dialysis unit?

Discuss with D/C heparin, our patients re-introduce initial Monitor for clotting of bolus if circuit (Kecn, drip necessary chambers, venous and arterial pressures, Discuss with dialyzer streaks) prescribing doc ?? Optimal apixaban dose: 2.5 or 5 mg BID Alert RN and technicians Decrease dose to 2.5 mg BID if weight <60 kg or age ≥80 y/o

Controversies: Stroke prevention in CKD Wei Ling Lau, MD COPY

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 overNOT 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 CKD Wei Ling Lau, MD DO 15