ACC/SCAI 2008 : Disclosures

Funding for ASTRAL

• Medtronic

• MRC

• KR-UK

No members of the ASTRAL TMC or collaborators have any pecuniary or advisory affiliation with Medtronic

Philip A Kalra

Lead Nephrologist for ASTRAL, Hope Hospital, Salford, UK,

On behalf of the ASTRAL TMC and collaborators

UK MULTI-CENTRE TRIAL IN ATHEROSCLEROTIC RENOVASCULAR DISEASE

ASTRAL Angioplasty and STent for Renal Artery Lesions

Rationale for RCTs in ARVD

• Very common condition : annual rate of ARVD diagnosis ↑3x between 1992-2004

• High level of associated co-morbidity and mortality• Revascularization procedures frequently performed (eg

16% of newly diagnosed Medicare patients : Kidney Int 2005; 68 : 293-301)

• Revascularization not without some risk • 4 previous RCTs investigating revascularization – all

small (largest 106 patients) and inconclusive• Uncertainty regarding renal functional, CVS events and

mortality outcomes

Main questions asked within ASTRAL

What is the effect of renal revascularization upon

Renal functional outcome (rate of change of renal function over follow-up – reciprocal creatinine plot; 750 patients for 80% power to show 20% difference)

Secondary end-points• Survival• Other (CVS) macrovascular events• Blood pressure control• Cardiac function and structure (sub-study)

ASTRAL Trial Schema

Diagnosis of significant ARVD (Unilateral or Bilateral)

Revascularization not contraindicated

Uncertain whether to revascularizeRandomisation

No revascularization

Medical Treatment only

Revascularization

with angioplasty and/or stent

(and medical treatment)

RECRUITMENTRECRUITMENT

• ASTRAL opened to recruitment in September 2000

• September 2000 - October 2007, 806 patients randomised into the trial from 58 centres (4 in Australasia)

– 403 revascularization (+ medical therapy)– 403 medical management

• Current mean follow-up 27 months

49 55 5885

106

806

0

200

400

600

800

Plouin Webster Weibull van de Ven van J aarsveld ASTRAL (now)

No

. of P

atie

nts

Trial ComparisonOver 7x bigger than the next largest trial (van Jaarsveld (n=106)

PATIENT CHARACTERISTICS BY PATIENT CHARACTERISTICS BY RANDOMISED TREATMENTRANDOMISED TREATMENT

Revasc. Medical P-value

Mean age (range) 70 (42 – 86) 71 (43 – 88) 0.7

Male 63% 63% 0.9

Ex-smoker 52% 55% 0.3

Current smoker 20% 22% 0.5

Diabetes 31% 29% 0.5

CHD 49% 48% 0.2

PVD 41% 40% 0.7

Stroke 18% 19% 0.4

Dialysis 0% 0.3% 0.5

LABORATORY and BP DATA BY LABORATORY and BP DATA BY RANDOMISED TREATMENTRANDOMISED TREATMENT

Revasc. Medical P-value

SCr (μmol/l)

88 μmol/l = 1 mg/dl

179

(66 – 551)

178

(64 – 750)

0.9

Rapid increase in SCr 12% 12% 0.9

GFR (ml/min) 40.3

(5.4 – 124.5)

39.8

(7.1 – 121.7)

0.7

Albumin:Creatinine ratio 70.2

(0 – 2740)

71.7

(0 – 2466)

0.9

Systolic BP (mm Hg) 149

(87 – 270)

152

(90 – 241)

0.07

Diastolic BP (mm Hg) 76

(45 – 120)

76

(46 – 130)

0.6

Cholesterol (mmol/l) 4.68

(0.1 – 14.8)

4.71

(1.9 – 9.6)

0.8

PATIENT CHARACTERISTICS – PATIENT CHARACTERISTICS – GFRGFR

Mean = 40 ml/min (Range: 5.4 – 124.5)

0

50

100

150

200

250

300

<=20 20-30 30-40 40-50 >50

GFR (ml/min)

No

. o

f p

atie

nts

ANGIOGRAPHIC DATA BY ANGIOGRAPHIC DATA BY RANDOMISED TREATMENTRANDOMISED TREATMENT

Revasc. Medical P-value

% Stenosis 76% (40 – 100%) 75% (20 – 100%) 0.3

Renal length 9.7cm (6 – 14) 9.7cm (6 – 20) 0.5

Location of ostial/distal ARVD lesion

Left kidney 24% 20% 0.2

Right kidney 18% 17%

Both 50% 57%

Missing data 8% 6%

PATIENT CHARACTERISTICS – PATIENT CHARACTERISTICS – Percent StenosisPercent Stenosis

Mean = 76% (Range: 20% – 100%)

0

50

100

150

200

250

300

<50 50-59 60-69 70-79 80-89 >=90

Stenosis (%)

No

. o

f p

ati

en

ts

CONCOMITANT MEDICINE BY CONCOMITANT MEDICINE BY RANDOMISED TREATMENTRANDOMISED TREATMENT

Revasc. Medical P-value

Anti-hypertensives 97% 99% 0.2

Diuretic 70% 67%

Ca2 antagonist 61% 68%

Beta-blocker 46% 52%

ACE-I, A-II antagonist 47% 38%

Alpha-blocker 40% 37%

Mean no. anti-hypertensives 2.8 (1 - 6) 2.8 (1 - 6) 0.9

CONCOMITANT MEDICINE BY CONCOMITANT MEDICINE BY RANDOMISED TREATMENTRANDOMISED TREATMENT

Revasc. Medical P-value

Anti-platelets 76% 78% 0.5

Aspirin 91% 93%

Cholesterol lowering 80% 80% 1.0

Statin 96% 95%

Warfarin 11% 11% 1.0

COMPLIANCE WITH COMPLIANCE WITH RANDOMISED TREATMENTRANDOMISED TREATMENT

N Revasc. Successful

Attempted but Failed

Not Attempted

Revasc. 403 308 (82%)* 17 44

Medical 403 18 (4.4%) 1 1

*Revascularization forms not yet returned for 34 patients who were randomised to revascularization

REVASCULARIZATION PROCEDUREREVASCULARIZATION PROCEDURE

Revasc. Medical

Intervention Performed N=308 N=13

Angioplasty plus stent 201 (65%) 8 (62%)

Stent only 86 (28%) 5 (38%)

Balloon angioplasty 21 (7%) 0 (-)

Unilateral 259 (84%) 11 (85%)

Bilateral 49 (16%) 2 (15%)

SAFETY – IMMEDIATE POST-OP SAFETY – IMMEDIATE POST-OP COMPLICATIONSCOMPLICATIONS (in 24 (7%) patients) (in 24 (7%) patients)

Complication N=321

Stent misplacement requiring additional stent 10 (3%)

Renal arterial perforation or dissection 4 (1%)

Renal artery thrombosis or occlusion 1 (0.3%)

Renal embolisation 2 (0.6%)

Non-renal embolisation 1 (0.3%)

Stent embolisation 3 (1%)

Distal stent retrieval or deployment 1 (0.3%)

Balloon rupture 1 (0.3%)

Need for surgical rescue 0 (-)

Access vessel damage 6 (2%)

SAFETY – POST-OP COMPLICATIONSSAFETY – POST-OP COMPLICATIONS >24 HRS AFTER REVASCULARIZATION>24 HRS AFTER REVASCULARIZATION

Complication Revasc.

(N=254)

Local infection at puncture site 1 (0.4%)

Groin haemorrhage or haematoma 25 (10%)

Pseudoaneurysm 2 (0.8%)

Deterioration in renal function 26 (10%)

If deterioration in renal function – maximum SCr whilst in hospital

N=24

Mean (SD) 319 (145)

Range 148 - 632

PLOT OF SCr OVER TIMEPLOT OF SCr OVER TIME

MEAN CHANGE IN SCr BETWEEN MEAN CHANGE IN SCr BETWEEN BASELINE AND 1 YEARBASELINE AND 1 YEAR

0

50

100

150

< -70

-70 to

-51

-50 to

-31

-30 to

-11

-10 to

10

10 to

30

31 to

50

51 to

70

71 to

90

91 to

110

111

to 1

30

131

to 1

50>15

0

No

. of

pa

tie

nts

Revasc. Medical

Negative change = Improvement in SCr (i.e. reduction in SCr)

MEAN CHANGE IN SCrMEAN CHANGE IN SCr

PLOT OF RECIPROCAL SCr PLOT OF RECIPROCAL SCr OVER TIMEOVER TIME

PLOT OF SYSTOLIC BP OVER TIMEPLOT OF SYSTOLIC BP OVER TIME

MEAN CHANGE IN SYSTOLIC BPMEAN CHANGE IN SYSTOLIC BP

PLOT OF DIASTOLIC BP OVER TIMEPLOT OF DIASTOLIC BP OVER TIME

TIME TO FIRST RENAL EVENTTIME TO FIRST RENAL EVENT(ARF, Dialysis, Transplant, Nephrectomy, Renal Death)(ARF, Dialysis, Transplant, Nephrectomy, Renal Death)

HR=0.98, 95% CI=0.66 to 1.48

VASCULAR EVENTS - OVERALLVASCULAR EVENTS - OVERALLRevasc.

(N=369)

Medical

(N=380)

P-Value

Myocardial Infarction 22 (6%) 30 (8%) 0.3

Hospitalisation for Angina 24 (7%) 29 (8%) 0.5

Hospitalisation for Fluid Overload / Cardiac Failure

44 (12%) 55 (14%) 0.3

Stroke 19 (5%) 18 (5%) 0.8

Coronary Artery Procedure (CABG or PCTA)

9 (2%) 12 (3%) 0.6

Other Arterial Procedures 51 (14%) 38 (10%) 0.1

No. Events/No. Patients* 109 / 83 132 / 100 0.2

* Not including coronary or other arterial procedures

TIME TO FIRST OF MI, STROKE, VASCULAR DEATH TIME TO FIRST OF MI, STROKE, VASCULAR DEATH OR HOSPITALISATION FOR ANGINA, FLUID OR HOSPITALISATION FOR ANGINA, FLUID

OVERLOAD OR CARDIAC FAILUREOVERLOAD OR CARDIAC FAILURE

HR=0.90, 95% CI=0.66 to 1.15

MORTALITYMORTALITY

HR=0.92, 95% CI=0.68 to 1.26

MORTALITYMORTALITY

Cause of Death

(not mutually exclusive*)

Revasc.

(N=79)

Medical

(N=81)

Vascular (Heart Failure/MI/Stroke)

30 33

Renal Failure 6 14

Infection / Pneumonia 11 10

Cancer 11 9

Other 4 2

Not Stated/Not Known 23 26

* 14 patients’ have multiple causes of death

CONCOMITANT MEDICINE AT 1 YEAR CONCOMITANT MEDICINE AT 1 YEAR BY RANDOMISED TREATMENTBY RANDOMISED TREATMENT

Revasc. Medical P-value

Anti-hypertensives 98% 99% 0.2

Diuretic 67% 69%

Beta-blocker 47% 54%

ACE-I, ARB 48% (47%) 41% (37%)

Anti-platelet therapy 84% (76%) 81% (78%) 0.4

Warfarin 9% 9% 1.0

Cholesterol lowering 86% (80%) 88% (80%) 0.4

PRE-SPECIFIED SUBGROUP PRE-SPECIFIED SUBGROUP ANALYSESANALYSES

Subgroup Groups

SCr ≤150, 151-249, ≥250μmol/l

GFR <30, 30-45, >45ml/min

Stenosis ≤70%, 71-89%, ≥90%

Renal Length ≤9, 9-10, >10cm

Rapid increase in SCr

Yes, No, Not Known

MEAN CHANGE IN SCr AT 1 YEAR MEAN CHANGE IN SCr AT 1 YEAR STRATIFIED BY BASELINE SCrSTRATIFIED BY BASELINE SCr

MEAN CHANGE IN SCr AT 1 YEAR MEAN CHANGE IN SCr AT 1 YEAR STRATIFIED BY RAPID INCREASE IN SCrSTRATIFIED BY RAPID INCREASE IN SCr

ASTRAL Summary (1)ASTRAL Summary (1)

• Currently no evidence of a benefit for revascularization on renal function in the ARVD patients entered into ASTRAL – those in whom clinicians ‘uncertain’ of whether to revascularize

• Also no evidence of differences between the arms for any of the secondary endpoints (i.e. blood pressure, major events, mortality)

• No evidence of differences in treatment effect across the various subgroups – for renal functional end-point only

ASTRAL Summary (2)

• Minor differences in some parameters at 4 years (Creatinine, SBP, CVS events) but longer follow-up is needed to assess significance

• Some individuals do benefit – how can we identify these?

• Cardiac sub-studies (results due November 2008)