Caring for Australians with Renal Impairment

Medical Management of CAD in CKD(excluding lipid-lowering therapy)

Sharan Dogra

Background

• 40-50% mortality in CKD attributed to CVD• Post AMI 61% 1 yr and 75% 2 yr mortality

• “Therapeutic Nihilism” and “Renalism” (Fox CS, Circulation 2010;121:357-365; Rifkin DE Nat Rev Nephrology 2010;6:449-450)

• Medical management of CAD and ACS well

established and investigated in the general

population but often patients with mod-severe

renal disease excluded.

CARI Guidelines: Levels of Evidence

• Level I: Evidence obtained from a systematic review of all relevant RCTs (GUIDELINE)

• Level II: Evidence obtained from at least one properly designed RCT (GUIDELINE)

• Level III: Evidence obtained from well-designed pseudo-RCTs or comparative studies (i.e cohort studies, case control studies) (Suggestion for clinical care)

• Level IV: Evidence obtained from case series (Suggestion for clinical care)

POST HOC ANALYSIS???

• To assess the benefits and harms of medical management of chronic stable CAD and ACS in patients with CKD, including the dialysis and transplant populations.

• Specifically anti-platelet and anticoagulant therapies, beta-blocker therapy, and ACEi/ARB therapy (but excluding lipid-lowering therapy).

Aim

The benefits of the medical therapies in ACS and CAD are examined in relation to myocardial infarction and cardiovascular death as outcome measures, as well as revascularisation in the case of medical therapies used during PCI.

The harms examined relate to serious adverse events reported in the literature in relation to the aforementioned medical therapies.

Benefits and Harms

Guidelines (Level I/II) – Benefit of therapy in ACS

• Anti-platelet therapy– No recommendations are possible regarding aspirin,

clopidogrel or combination aspirin/clopidogrel therapy

• Anticoagulant therapy (UFH, LMWH, GPIIb/IIIa inhibitors and Thrombin Inhibitors) – No recommendations possible

• Beta-blockers and ACE-inhibitors– No recommendations possible

Guidelines (Level I/II) – Safety of therapy in ACS

• Patients with CKD, specifically those with an eGFR <30mL/min, are at increased risk of bleeding with antiplatelet or anticoagulant therapy compared with those with an eGFR>30mL/min (Level 1)

• In CKD eGFR <30mL/min, caution should be exercised when using enoxaparin for ACS, with a preference for (empirical or based on anti-Xa levels) dose adjustment in an effort to lower bleeding risk. (Level I)

• In haemodialysis patients combination anti-platelet therapy with high-dose aspirin (325mg) and clopidogrel or warfarin is associated with an increased risk of significant bleeding requiring hospitalisation or transfusion, and should be avoided. (Level I/II)

• Low-dose aspirin (100mg daily) as a single anti-platelet agent can be used safely in patients with a serum creatinine ≥ 150 µmol/L through to those on haemodialysis or peritoneal dialysis, or in patients with a functioning renal transplant (level II)

Suggestions for Clinical Care: ACSLevel III/IV

• All CKD patients, including haemodialysis and peritoneal dialysis patients and transplant patients should be treated as the general population when presenting with an ACS with regards to reperfusion therapy, anti-platelet and anticoagulant therapies (Heparins, Thrombin Inhibitors, GPIIb/IIIa inhibitors), beta-blockers and ACE-inhibitors.

• Caution should be exercised when using drugs with altered clearance in CKD and dialysis patients, specifically LMWH and GPIIb/IIIa inhibitors.

Management of patients with STEMI

Reperfusion – Primary PCI or fibrinolysis

Adjuvant therapy associated with reperfusion

Antiplatelet therapy: Give aspirin and clopidogrel unless contraindicated.

Antithrombin therapy: Give in combination with PCI or fibrinolytic therapy with fibrin-specific fibrinolytic agents.

Glycoprotein IIb/IIIa inhibitors Reasonable to use abciximab with primary PCI, but GP IIb/IIIa inhibitors should generally be avoided with fibrinolytic therapy.

Management of ACS 2006 GuidelinesNational Heart Foundation of Australia and Cardiac

Society of Australia and New Zealand

Management of patients with NSTEACS

High-risk NSTEACSAggressive medical management and coronary angiography and revascularisation

Intermediate-risk NSTEACS Further observation and risk stratificationReclassification into either high risk or low risk

Low-risk NSTEACSDischarge on upgraded medical therapy with urgent cardiac follow- up

Management of ACS 2006 GuidelinesNational Heart Foundation of Australia and

Cardiac Society of Australia and New Zealand

Early medical management of NSTEACS

Low-risk and intermediate- risk NSTEACSAspirin

High-risk NSTEACSAspirinClopidogrel (unless immediate angiography planned, or patient at high-risk of requiring surgery)Unfractionated heparin or subcutaneous enoxaparinIntravenous tirofiban or eptifibatideBeta-blocker

Management of ACS 2006 GuidelinesNational Heart Foundation of Australia and

Cardiac Society of Australia and New Zealand

Summary – ACS Management in CKDTherapy Patients Data Safety

Reperfusion CKD only No RCTRetrospective cohort OR 0.7 (0.6,0.9) for death

Thrombolysis may be a/winc.bleeding risk

Aspirin and Clopidogrel added for USA

CKD onlyN=12253 CUREn-=2002 CREDO

Post Hoc CURE and CREDOTrend to benefit, less so in lowest tertile of GFR <64mL/min

Major bleeding probablytrend to increase with treatment in CKD group but more variable response

LMWH vs UFH CKD onlyN=20,479

N=6969

N=11,881

Post Hoc EXTRACT-TIMI 25 6-26% enoxaparin benefit across all CrCl strata

Post Hoc ESSENCE and TIMI 11B. Trend to favouring enoxaparin

Propsective GRACE registry shows worse outcomes with UFH

Major bleeding increased esp. eGFR<30 so no net benefit in this group

No significant increase in bleed risk

More bleeding with UFH

GPIIb/IIIa CKD onlyN=1537 PRISM-PLUSN=2044 ESPRIT

Post hoc PRISM-PLUS and ESPRIT suggest a 22-48% RRR with tirofiban and eptifibatide

Abciximab data only from prospective and retrospective registries suggests benefit

Probable increase bleeding risk

Increase bleeding risk

Summary – ACS Management in CKDTherapy Patients Data Safety

Bivalirudin CKDN=5035

N=2469

Meta-analysis of Post hoc analyses of 3 studies (Hirulog, REPLACE-1, CACHET) 20-25% benefit across all strata of GFR

Post hoc ACUITY –Bivalirudin alone no different to heparin/GPI

Reduced bleeding risk across all strata except GFR <30 – no events

Reduced bleeding SO NET BENEFIT

Beta-blockers CKD and HD No RCT data

Retrospective studies suggest 60-80% RRR with aspirin and beta-blocker use post MIProspective registry data RRR 22%

ACEi CKDN=2183

CKD and HD

SAVE Post hocRRR31% with captopril in CKD eGFR <60 group but treatment interaction not significant

Retrospective studies suggest 37% RRR with ACEiuse post MIProspective registry data RRR 42%

Aspirin and Clopidogrel Safety Study Design Outcome SafetyUK-HARP-1Baigent AJKD 2005;45(3):p473

RCT aspirin aloneCreat ≥150µmol/L, HD, PD or txp1yr treatment

Major BleedMinor Bleed20% increase creat

RR 0.66(0.19,2.31)RR 2.81(1.49,5.28)RR 1.13(0.84,0.52)

Kaufman JS, JASN 2003;14:p2313

RCT of clopidogrel75mg and aspirin 325mg to prevent AVG thrombosis

HD patients

Stopped early due to SAEStudy ran for 10mth

Increased Major BleedingHR 1.98(1.19,3.28)

Hiremath S, cJASN2009;4:p1347

Systematic review on safety of anti-plateletagents in HD patients

Major and minor bleeds not always clearly defined in studies

Combination anti-platelet therapy increases risk for major bleeding in HD patients

Safety of LMWH for ACS in CKD and Dialysis

Study Design Outcome SafetyLim W, JASN 2004;15:p3192

Safety and Efficacy of LMWH for HD patients for preventing circuit thrombosis

Meta-analysis RCTs comparing LMWH to UFH

HD patients

All Bleeding events

Access compression time

Circuit thrombosis

RR0.96(0.27, 3.43)

-0.87(-2.75, 1.02)

1.15 (0.70, 1.91)

Lim W, Ann Intern Med 2006;144:p673

LMWH and Bleeding in Patients with Severe Renal Insufficiency (GFR < 30mL/min but not on dialysis)

Meta-analysis RCTs comparing bleeding risks with therapeutic, prophylactic and adjusted doses of LMWH

12 studies n=4971

Bleeding with all LMWH CrCl≤30 compared with >30

Subgroup:Therapeutic enoxaparin

CrCl≤30 compared with >30

Adjusted enoxaparinCrCl≤30 compared with >30

OR2.25(1.19, 4.27)

OR3.88(1.78, 8.45)

OR0.58(0.09, 3.78)

Guidelines (Level I/II) – Chronic stable CAD Benefits and Safety

• Anti-platelet therapy– No recommendations are possible regarding aspirin

or clopidogrel therapy

• Beta-blockers, ACE-inhibitor and ARB • No recommendations possible• For BP lowering effects refer to Guidelines on

Cardiovascular Effects of BP Lowering• Safety

– Low-dose aspirin (100mg daily) as a single anti-platelet agent can be used safely in patients with a serum creatinine ≥ 150 µmol/L through to those on haemodialysis or peritoneal dialysis, or in patients with a functioning renal transplant (level II)

• All CKD patients, including haemodialysis and peritoneal dialysis patients and transplant patients should be treated for chronic stable CAD as the general population with regards to anti-platelet therapies, beta-blockers, ACE-inhibitors and angiotensin receptor blockers.

Suggestions for clinical care (Level III/IV) –Chronic stable CAD

Aspirin +/or Clopidogrel for Stable CAD – HaemodialysisStudy Design Outcome SafetyATT Meta-analysisBMJ 2002;324:p71

Meta-analysis subgroupHDn= 2,632 12-18mth

CV death/MI/CVA%Odds reduction (SE):

41%(16)

Major bleedsAntiplatelet 2%Control 2.3%

DOPPS Ethier J, AJKD 2005;50: p602

Prospective observational n=16,471 HDAspirin prescription

All-cause mortalityRR0.99(0.93,1.05)Any cardiac eventRR1.08(1.02,1.14)

MIRR1.21(1.06,1.38)

CVARR0.82(0.69,0.98)

GI Bleeding1.01(0.88,1.17)

SDH0.56(0.30,1.07)

Chan KE JASN 2009;20(4):p872

Retrospective observational n= 41,425 HDAspirin, clopidogrel or warfarin prescription

All-cause mortalityAspirin

1.06(1.01,1.11)Clopidogrel

1.24(1.13,1.35)

Bleeding a/w:Mortality

Asp:HR 0.90(0.51,1.59)Clop:HR 2.74(1.26,6.00)

HospitalisationAsp:HR 1.05(0.91,1.20)Clop:HR 1.39(1.08,1.80)

No Data for PD or Txp; No RCTs

Aspirin alone or with Clopidogrel for Stable CAD - CKDStudy Design Outcome SafetyHOT post hoc (1) Zanchetti A, J Hypertens2002;20:p2301

RCT CKD n= 1,367Creat 115-177µmol/L1º prevention 75mg aspirin

Major CV event (CV death/MI/CVA)

RR 0.595 (0.387, 0.913)Prevent 12.9 events at cost of 2

bleeds per 1000 pt years

Major bleedsRR 1.50 (0.67, 3.34)

HOT post hoc (2) Jardine MJ, JACC 2010;56:p956

RCT CKD n= 3,619eGFR <60mL/min 1º prevention75mg aspirin

Major CV event (CV death/MI/CVA)

eGFR RR≥60: 0.91(0.76,1.09)45-59: 0.85(0.61,1.17)<45: 0.34(0.17,0.67)

Prevent 76 events at cost of 27 bleeds per 1000 pts treated for

3.8 years

Major BleedingeGFR RR≥60: 1.52(1.11, 2.08)45-59: 1.7(0.74,3.88)<45: 2.81(0.92,8.84)

CHARISMA post hocDasgupta A, Am J Cardiol2009;103:p1359

RCT Clopidogrel 75mg or placebo added to aspirin (75-162mg)N= 2009 with diabetic nephropathy but no creatinine2º prevention

CV death/MI/CVAMedian 28mth f/up

RR 1.1 (0.8, 1.6)

RR 0.93 (0.83, 1.05)

No increase in mod-severe bleeding

No RCT specifically in CKD population

• May be indicated for Aspirin allergy

• NO RCT in CKD examining 2º prevention benefits

• CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) Lancet 1996; 348:p1329

• Significant reduction (RRR 8.7%, 95% CI 0.3, 16.5%) in combined CAD,CVD and PVD outcome but severe renal insufficiency excluded and no post hoc analysis......yet

• Dember LM, JAMA 2008:299; p2164 – RCT of clopidogrel for AVF failure in HD. No reduction in atherosclerotic events 6mth f/up(secondary outcome)

Clopidogrel monotherapy for Stable CAD

Beta-Blockers in Chronic Stable CADStudy Design Outcome SafetyCice G, JACC 2003;41:p1438 Open label RCT of carvedilol

in 114 HD patients with dilated CMP – NYHA II-III with LVEF<35%. 2yr f/up

All cause mortality0.51(0.32,0.82)

CV deaths0.32(0.18,0.57)

Castagno DEur J Heart Fail 2010;12(6):p607Bisoprolol in patients with heart failure and renal impairment: (CIBIS II)

Post hoc analysis in CKDeGFR quartilesHeart failure 2º anyEF≤35% NYHA III/IVCreat <300.1.3 yr f/up

HR<1.0 for all cause mortality for all GFR categories.

No treatment by renal function interaction

Walli RKCirc Heart Fail 2011;4(1):p18Efficacy and Safety of Carvedilolin treatment of heart failure with CKD

Post hoc meta-analysis of CAPRICORN (Isch CMP) & COPERNICUS (2º anyaetiology)N=4217,GFR≤60 (CKD) n=2566

F/up mean 10.4 mth COPERNICUS1.3yrs CAPRICORN

All cause mortality0.75(0.63,0.93)CV mortality

0.76(0.62,0.94)HF mortality

0.68(0.52,0.88)Sudden cardiac death

0.76(0.56,1.05)eGFR<45: Carvedilol not

different to placebo

Transientincrease in creatininewithout need for dialysis

CIBIS II: Cardiac insufficiency bidoprolol study II CAPRICORN – Carvedilol Postinfarct Survival Control in Left Ventricular DysfunctionCOPERNICUS – Carvedilol Prospective Randomised Cumulative Survival Study

Beta-Blockers in Chronic Stable CAD• Ezekowitz J, JACC 2004;44(8):p1587: Prospective cohort study that examined

the effect of aspirin, beta-blocker, ACEi &statin use on 12 month mortality in CKD patients with heart failure and angiographically proven CAD. CKD =C-G CrCl < 60mL/min.

– 6,427 registry patients with heart failure and CAD, 2,047 had a CrCl 30-59 mL/min and 466 had a CrCl < 30mL/min, of which 192 were on dialysis.

– Users of beta-blockers in patients with CKD was associated with a lower 12 month mortality (OR 0.75 95% CI 0.62 to 0.90).

• Abbott KC, Arch Intern Med 2004;164(22):p2465: Retrospective cohort study of 2,550 haemodialysis patients

– Beta-blocker use in dialysis patients without heart failure (n = 1578) reduced the risk of heart failure and cardiac death

– RR 0.77 (95% CI 0.61 to 0.97)

• Nakao K, Nephron Clin Pract 2009;113:c132;. Beta-blocker prescription and outcomes in the haemodialysis patients from the Japan DOPPS

– N= 2,286 randomly selected patients; only 11.9% on beta-blockers– Patients on beta blockers had a higher prevalence of CAD and HTN, but beta

blockers independently associated with reduced all cause mortality– HR 0.48 (0.25, 0.88)

ACE inhibitors and ARBs in Chronic Stable CADRefer: Cardiovascular Effects of BP lowering in patients with CKD

• HOPE• PEACE• EUROPA• ADVANCE• PROGRESS• IDNT• RENAAL• VALHEFT• ONTARGET and TRANSCEND ANALYSIS, Circulation 2011 Epub• CANDESARTAN in HD patients, Takahashi, NDT 2006; 21: p2507• META-ANALYSES OF BP LOWERING IN DIALYSIS PATIENTS

(Heerspink, Lancet 2009, Agarwal Hypertension 2009, Akbari Perit Dial Int 2009, Tai cJASN 2010)

• SECRET - Transplants

Discussion Points• The Post Hoc Analysis – what level of evidence?• Guidelines vs. Suggestions for Clinical Care• Therapies not addressed:

– GTN– CCB– Spironolactone– Smoking & Lifestyle factors (exercise, diet)– Timing of dialysis following ACS– Dry weight maintenance

Caring for Australians with Renal Impairment

Reperfusion therapy• Meta-analyses in the general population favour Primary PCI over

thrombolysis: combined criteria death or re-infarction (RRR = 46%; 95%CI=30%,58%). (Lancet 2003;361:13-20, Am Heart J 2003;145:47-57, Cochrane Database Syst Rev. 2003;(3):CD001560.)

• These data are not available for CKD. Both therapies are underutilised in CKD• Retrospective cohort showing that reperfusion therapy a/w decreased OR

death (0.7[0.6 to 0.9]) in CKD patients (Wright RS Ann Int Med 2002;137:p563)

• Perceived possible increased risk of bleeding with thrombolysis in CKD?

• Acute Coronary Syndromes Israeli Survey (ACSIS):observational prospective cohort study: thrombolysis (n=24) vs. PCI (n=35) vs. no perfusion (n=73) in 132 CKD patients of total 1,011 patients admitted with a STEMI (Dragu R, Am J Cardiol2006; 97: 1142-1145)

PCI relative to thrombolysis

Unadjusted OR Adjusted OR

30-day mortality 7.3 (1.8, 50.4) 8.1 (1.9, 50.4)1-yr mortality 3.2 (1.1, 10.5) 3.8 (1.2, 13.2)

Aspirin and Clopidogrel for ACS - CKDStudy Design Outcome SafetyCURE Post Hoc

N=12,253

RCT:CKD subgroups

Clopidogrel or placebo added to aspirin (75-325mg) in unstable angina

CVdeath/MI/Stroke 1yrRR(95%CI)

Tertiles of GFR<64: 0.89(0.76, 1.05)64-81.2: 0.68(0.56,0.84)>81.3: 0.74(0.60, 0.93)

0.80(0.72, 0.90)

Major Bleeding

Tertiles of GFRLow: 1.12(0.83, 1.51)Mid: 1.4(0.97, 2.02)

High: 1.83(1.23, 2.73)1.38(1.13, 1.67)

CREDO Post hoc

N=2002 (creat missing on 114)

RCT:CKD subgroups

Clopidogrel or placebo added to aspirin (81-325mg) in elective PCI

CVdeath/MI/Stroke 1yrHR(95% CI)

Tertiles of GFR<60 1.41(0..81, 2.45)60-89 0.80 (0.51, 1.25)>90 0.42(0.26, 0.69)

0.73(0.56, 0.96)

Major Bleeding 1yr

Tertiles of GFR<60 : 1.124(0..511, 2.476)60-89 1.595(0.970, 2.621)>90: 1.168(0.741, 1.841)

CURE – Clopidogrel in Unstable Angina to Prevent Recurrent Events, Keltai M Eur J Cardiovasc Prev Rehabil 2007 2007;14:p312CREDO – Clopidogrel for the Reduction of Events During Observation, Best PJ Am Heart J 2008;155:p687

No data for HD, PD or Txp; No RCT in CKD

Aspirin and Clopidogrel Safety Study Design Outcome SafetyUK-HARP-1Baigent AJKD 2005;45(3):p473

RCT aspirin aloneCreat ≥150µmol/L, HD, PD or txp1yr treatment

Major BleedMinor Bleed20% increase creat

RR 0.66(0.19,2.31)RR 2.81(1.49,5.28)RR 1.13(0.84,0.52)

Kaufman JS, JASN 2003;14:p2313

RCT of clopidogrel75mg and aspirin 325mg to prevent AVG thrombosis

HD patients

Stopped early due to SAEStudy ran for 10mth

Increased Major BleedingHR 1.98(1.19,3.28)

Hiremath S, cJASN2009;4:p1347

Systematic review on safety of anti-plateletagents in HD patients

Major and minor bleeds not always clearly defined in studies

Combination anti-platelet therapy increases risk for major bleeding in HD patients

UFH and LMWH for STEMI in CKD

Study Design Outcome SafetyFox KAA JACC 2007;49(23):p2249

The Impact of Renal Dysfunction on Outcomes in the ExTRACT-TIMI 25 Trial

Creat >200 excluded

RCT enoxaparinvs UFH as an adjunct to fibrinolysis for STEMI

Post hoc analysis based on CrCl strataN=20,479

1º endpoint 30-day all cause mortality or non-fatal recurrent MI

CrCl mL/min OR

<30 0.74(0.38, 1.44)30-60 0.94(0.78, 1.12)>60-90 0.78(0.66, 0.92)>90 0.69(0.56, 0.84)

Major Bleed

OR

3.60(0.67,19.21)1.73(1.11,2.70)1.91(1.30,2.82)1.49(0.89,2.48)

*Not dose adjusted^Dose adjusted for CrCl; variable dosing and agents

ExTRACT-TIMI 25: Enoxaparin and Thrombolysis Reperfusion In Myocardial Infarction Treatment – Treatment in Myocardial Infarction 2550% Dose adjustment in enoxaparin if CrCl < 30mL/min

UFH and LMWH for ACS in CKDStudy Design Outcome Safety

Spinler SAAm Heart J 2003; 146:p33

ESSENCE & TIMI 11B trials

Retrospective analysis of RCT of enoxaparin* vs. UFH for ACS

2 subgroup s: CrCl≤30 n=143 CrCl>30 n=6826

Death/MI/revascularisation at 43 days

OR(95% CI)0.52(0.23, 1.19)

Major bleedOR(95% CI)

1.53 (0.37,6.32)

Any bleed1.04(0.42,2.59)

Collet JP Eur Heart J 2005;26:p2285Global Registry of Acute Coronary Events (GRACE)

Prospectiveobservational registryN=11,881 3709 UFH vs.4966 LMWH^

Absolute difference 30-daymortality

Tertiles of CrCl>60: 9.84(0.07,19.66)>30≤60: 34.97(13.96,56.09)≤30: 32.29(-29.57,94.46)

Major Bleeding

9.34(0.74, 17.99)23.32(7.69,39.03)33.90(-9.97,78.01)

*Not dose adjusted^Dose adjusted for CrCl; variable dosing and agents

Safety of LMWH for ACS in CKD and Dialysis

Study Design Outcome SafetyLim W, JASN 2004;15:p3192

Safety and Efficacy of LMWH for HD patients for preventing circuit thrombosis

Meta-analysis RCTs comparing LMWH to UFH

HD patients

All Bleeding events

Access compression time

Circuit thrombosis

RR0.96(0.27, 3.43)

-0.87(-2.75, 1.02)

1.15 (0.70, 1.91)

Lim W, Ann Intern Med 2006;144:p673

LMWH and Bleeding in Patients with Severe Renal Insufficiency (GFR < 30mL/min but not on dialysis)

Meta-analysis RCTs comparing bleeding risks with therapeutic, prophylactic and adjusted doses of LMWH

12 studies n=4971

Bleeding with all LMWH CrCl≤30 compared with >30

Subgroup:Therapeutic enoxaparin

CrCl≤30 compared with >30

Adjusted enoxaparinCrCl≤30 compared with >30

OR2.25(1.19, 4.27)

OR3.88(1.78, 8.45)

OR0.58(0.09, 3.78)

Enoxaprin vs Fondaparinux for ACS in CKD

Study Design Outcome SafetyJoyner CD, Am Heart J 2009;157:p502

N=20,0786% creat >14017% creat 106-14077% creat <106

Secondary analysis of OASIS-5, a RCT of fondaparinuxvs enoxaparinEnoxaparin dose reduced in CrCl<30

Death/MI/refractory ischaemia at 180 days by GRACE risk score

HRLow 0.90(0.75,1.08)Int 0.89(0.77,1.03)High 0.95(0.85,1.06)

Major bleed

HR0.55 (0.39,0.77)0.53 (0.40, 0.70)0.50(0.38, 0.64)

OASIS – Organisation to Assess Strategies in Ischaemic SyndromesGRACE – Global Registry of Acute Coronary EventsGRACE score – Killip Class, Age, SBP, HR and Serum Creatinine

Fondaparinux GSK Australia – Contraindicated if eGFR<30

GPIIb/IIIa Inhibitors -used as adjunctive therapy to heparin prior to or during PCI, and as additional therapy for progressive high-risk NSTEACS

Study Design Outcome SafetyJanuzzi JL, Circulation 2002;105:p2361PRISM-PLUSBenefits and safety of tirofiban among ACS patients with mild-mod renal insufficiency

RCTTirofiban plus heparin vs. Heparin.2º analysis adjusted for CrCl n=1537

death/MI/refractory ischaemia

adjusted for CrCl48hr 0.68(0.46,1.0)7d 0.68(0.52,0.88)30d 0.78(0.63,0.98)6m 0.81(0.68,0.98)

Incremental risk ofbleeding when tirofibanadded to heparin but not amplified in CKD patients

In original RCT, major bleeding was not

significantly different

Reddan DN, Am J Cardiol 2003;91:p17ESPRIT Treatment effects of Eptifibatide in Planned Coronary Stent Implantation in patients with CKD

RCT Eptifibatide vs. placebo for PCI with stent: 2º analysis CrCl<60

Dose adj. if creat >177Creat >354 excludedn=2044 / 289 CKD

Death/MI/urgent revasc/thrombotic bailout

48hr 0.52(0.33, 0.81)

30d 0.53(0.34, 0.83)

Major/minor bleed

0.99(0.87,1.13)Interaction p =0.791

GPIIb/IIIa InhibitorsStudy Design Outcome SafetyFrilling BAm J Cardiol2002;89:p450

Comparison of Efficacy and Complication rates after PCI in patients with and without renal insufficiency treated with abciximab

Prospective Observational Registry – Abciximabduring PCIN=1040, 44 with CKD (creatinine >115)

Procedural success and in-hospital

mortality not different between CKD and

non-CKD

Bleeding increased in CKD compared with non-CKDOR 5.1 (1.9, 13.8)

Freeman RVJACC 2003;41:p718

Influence of Concurrent Renal Dysfunction on Outcomes of Patients with ACS and Implications of the use of GP Iia/IIIb inhibitors

Retrospective observational study of patients receiving a GPIIb/IIIa inhibitor across a range of CrCl from >90 to dialysis. Total N=925

In-hospital MortalityOR 0.34(0.12,0.98)

after adjusting for CrCl

Major BleedingOR 2.13(1.39,3.27)After adjusting for CrCl

GPIIb/IIIa Inhibitors Study Design Outcome SafetyJeremias A Am J Cardiol2002;89:p1209

Abciximab duringPCI

Retrospective analysis 182 CKD patients (creatinine ≥177 to dialysis) abciximab vs. No abciximab

Death or MI

16% Abciximab23% Controls

P=0.31

Major bleeding

21% Abciximab, 15% Controls

P=0.39

Best PJ, Am Heart J 2003;146:p345

Abciximab during PCI

Prospective observational registryExamine abciximabassociated bleeding risk in PCI in patients based on their CrCl

Major BleedingInteraction with CrClin patients receivingabciximab

OR1.18(0.99,1.39)P=0.06

GPIIb/IIIa Inhibitors

Name Renal Clearance

Dose Adjust Adjustment

Abciximab None No NilTirofiban 65% Yes 50% in CrCl <30ml/minEptifibatide 50% Yes 50% infusion rate in creatinine 176-354µmol/L

No data for severe CKD

Thrombin Inhibitors in CKD• 1 meta-analysis of 3 randomized trials (n = 5,035) comparing bivalirudin with

heparin during PCI, with outcomes stratified by estimated C-G CrCl

• >90 [Normal n = 1,578], 90 to 60 [Mild n = 2,163], 59 to 30 [Moderate n = 1,255], and <30 ml/min [Severe n = 39]. Dialysis excluded.

• Composite end points of (1) death, myocardial infarction or revascularization, (2) haemorrhage, or (3) all 4 endpoints combined were assessed.

DP Chew, Am J Cardiol 2003; 92: 919-923

Primary outcome OR (95%CI)

Major bleedOR (95% CI)

Total Group 0.75 (0.59, 0.94) 0.40 (0.26, 0.61)eGFR ≥ 90 0.79 (0.52, 1.18) 0.45 (0.21, 0.96)eGFR 60-89 0.73 (0.53, 0.99) 0.40 (0.90, 1.86)eGFR 30-58 0.77 (0.55, 1.07) 0.46 (0.30, 0.70)eGFR <30 0.81 (0.12, 5.23) No events

Thrombin Inhibitors vs. Heparin + GPI in CKD

• ACUITY – Open-label RCT of moderate-high risk ACS patients assigned to either Heparin/GPI, Bivalirudin/GPI or Bivalirudin monotherapy

• CKD defined as C-G CrCl < 60mL/min n=2469 out of 12939• CrCl <30 mL/min excluded• 1º endpoint = Composite Ischaemia=30day all cause death / MI / unplanned

revascularisation• Major bleeding• Net clinical outcome = Composite ischaemia + major bleeding

Post Hoc ACUITY. R Mehran J Am Coll Cardiol Intv 2009;2:748-757

Heparin/GPI vs. Bivalirudin monoTx

Risk ratio P value

Composite Ischaemia 1.18 (0.88,1.57) 0.27Major Bleeding 0.64 (0.45, 0.89) 0.008Net Clinical Outcome 0.95 (0.77,1.18) 0.65

Beta-Blockers in ACS• There are no RCTs examining the efficacy of beta-blocker therapy for

ACS in CKD patients.

• McCullough PA, Am Heart J 2002;144:p226– retrospective analysis of prospectively collected registry data to

examine the effect of combined aspirin and beta-blocker therapy after myocardial infarction in CKD and HD patients.

– CKD was defined using an abbreviated version of C-G formula as weight was not available in the database. 1724 patients, 731 had a CrCl< 63mL/min and 47 were on dialysis.

– Aspirin and beta-blocker use was associated with a significantly lower in-hospital mortality rate: Overall OR 0.18(0.12, 0.28) for beta blocker use

• RRR 78% on dialysis, • RRR 64.3% CrCl< 46 mL/min, • RRR 69% CrCl46-63 mL/min • RRR 75% CrCl 63 – 81.5 mL/min). • RRR 80% CrCl >81.5 mL/min

Beta-Blockers in ACS

• Berger AK, JACC 2003;42(2):p201 – prospectively collected registry data examining the effect of

aspirin, beta-blocker and ACEi therapy post acute myocardial infarction (AMI) in dialysis patients only.

– 145,740 patients without end-stage renal disease and 1025 patients on dialysis.

– The primary outcome examined was post-AMI 30-day mortality– Use of beta-blockers: RR 0.78 (95% CI 0.60 to 0.90)

ACEi in ACS• No RCTs in CKD• Tokmakova MP, Circulation 2004;110:p3667

– Post hoc analysis of SAVE (Survival and Ventricular Enlargement Trial)

– RCT of captopril post-AMI in patients with LVEF ≤ 40%– Of 2231, N= 2183 with creatinine; eGFR <60 in 719– Captopril prevented 12.4/100 events in CKD group vs. 5.5/100, – RRR CKD 31%(14-45%); No CKD 20%(4-33%)– Interaction between study drug and CKD was not significant (p=0.29)

ACEi in ACS• Berger AK, JACC 2003;42(2):p201

– prospectively collected registry data examining the effect of aspirin, beta-blocker and ACEi therapy post acute myocardial infarction (AMI) in dialysis patients only.

– 145,740 patients without end-stage renal disease and 1025 patients on dialysis.

– The primary outcome examined was post-AMI 30-day mortality– Use of ACEi: RR 0.58 (95% CI 0.42 to 0.77)

• Frances CD, Arch Intern Med 2000;160:p2645– Retrospective cohort n=20,902 of elderly patients with LVEF ≤40% post-AMI– Use of ACEi was associated with a 37% (16%-52%) lower mortality for patients

who had poor renal function (creat<265 micromol/L) and a 16% (8%-23%) lower mortality for patients who had better renal function