the results of the study of heart and renal protection (sharp) colin baigent, martin landray on...

The results of the Study of Heart and Renal Protection (SHARP)

The results of the Study of Heart and Renal Protection (SHARP)

Colin Baigent, Martin Landray

on behalf of the SHARP Investigators

Disclosure: SHARP was sponsored, designed, run, and analysed by the University of Oxford. Funding was received from Merck, the UK MRC,

British Heart Foundation, and Australian NHMRC.

Colin Baigent, Martin Landray

on behalf of the SHARP Investigators

Disclosure: SHARP was sponsored, designed, run, and analysed by the University of Oxford. Funding was received from Merck, the UK MRC,

British Heart Foundation, and Australian NHMRC.

Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010 Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

SHARP: RationaleSHARP: Rationale

Risk of vascular events is high among patients with chronic kidney disease

Lack of clear association between cholesterol level and vascular disease risk

Pattern of vascular disease is atypical, with a large proportion being non-atherosclerotic

Previous trials of LDL-lowering therapy in chronic kidney disease are inconclusive

Risk of vascular events is high among patients with chronic kidney disease

Lack of clear association between cholesterol level and vascular disease risk

Pattern of vascular disease is atypical, with a large proportion being non-atherosclerotic

Previous trials of LDL-lowering therapy in chronic kidney disease are inconclusive


SHARP: EligibilitySHARP: Eligibility History of chronic kidney disease

• Not on dialysis: elevated creatinine on 2 occasions

► Men: ≥1.7 mg/dL (150 µmol/L)

► Women: ≥1.5 mg/dL (130 µmol/L)

• On dialysis: haemodialysis or peritoneal dialysis

Age ≥40 years

No history of myocardial infarction or coronary revascularization

Uncertainty: LDL-lowering treatment not definitely indicated or contraindicated

History of chronic kidney disease

• Not on dialysis: elevated creatinine on 2 occasions

► Men: ≥1.7 mg/dL (150 µmol/L)

► Women: ≥1.5 mg/dL (130 µmol/L)

• On dialysis: haemodialysis or peritoneal dialysis

Age ≥40 years

No history of myocardial infarction or coronary revascularization

Uncertainty: LDL-lowering treatment not definitely indicated or contraindicated


SHARP: Assessment of LDL-loweringSHARP: Assessment of LDL-lowering

SHARP: Baseline characteristicsSHARP: Baseline characteristics

Age (years) 62 ± 12Men 63%Systolic BP (mmHg) 139 ± 22Diastolic BP (mmHg) 79 ± 13Body mass index (kg/m2) 27 ± 6Current smoker 13%Vascular disease 15%Diabetes mellitus 23%

Non-dialysis patients only (n=6247)eGFR (ml/min/1.73m2) 27 ±

13Albuminuria 80%

Age (years) 62 ± 12Men 63%Systolic BP (mmHg) 139 ± 22Diastolic BP (mmHg) 79 ± 13Body mass index (kg/m2) 27 ± 6Current smoker 13%Vascular disease 15%Diabetes mellitus 23%

Non-dialysis patients only (n=6247)eGFR (ml/min/1.73m2) 27 ±

13Albuminuria 80%


SHARP: Compliance and LDL-C reduction at study midpoint

SHARP: Compliance and LDL-C reduction at study midpoint

~2/3 compliance~2/3 compliance

LDL-C reduction of 32 mg/dL with 2/3 compliance, equivalent to 50 mg/dL with full compliance

LDL-C reduction of 32 mg/dL with 2/3 compliance, equivalent to 50 mg/dL with full compliance

Eze/simva Placebo

Compliant 66% 64%

Non-study statin 5% 8%

Any lipid-lowering 71% 8%

Eze/simva Placebo

Compliant 66% 64%

Non-study statin 5% 8%

Any lipid-lowering 71% 8%


SHARP: Baseline paperand data analysis plan

SHARP: Baseline paperand data analysis plan

1-year LDL-C reduction of 30 mg/dL with simvastatin 20 mg alone and of 43 mg/dL with eze/simva 10/20 mg

Confirmation of safety of ezetimibe when added to simvastatin (1-year results)

Revised data analysis plan published as an appendix before unblinding of main results

1-year LDL-C reduction of 30 mg/dL with simvastatin 20 mg alone and of 43 mg/dL with eze/simva 10/20 mg

Confirmation of safety of ezetimibe when added to simvastatin (1-year results)

Revised data analysis plan published as an appendix before unblinding of main results

Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among9,438 patients with chronic kidney disease

Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among9,438 patients with chronic kidney disease

SHARP Collaborative Group. Am Heart J 2010 (in press)SHARP Collaborative Group. Am Heart J 2010 (in press)

SHARP: Main outcomesSHARP: Main outcomes

Key outcome• Major atherosclerotic events (coronary death,

MI, non-haemorrhagic stroke, or any revascularization)

Subsidiary outcomes• Major vascular events (cardiac death, MI, any

stroke, or any revascularization)• Components of major atherosclerotic events

Main renal outcome• End-stage renal disease (dialysis or transplant)

Key outcome• Major atherosclerotic events (coronary death,

MI, non-haemorrhagic stroke, or any revascularization)

Subsidiary outcomes• Major vascular events (cardiac death, MI, any

stroke, or any revascularization)• Components of major atherosclerotic events

Main renal outcome• End-stage renal disease (dialysis or transplant)


SHARP: Major atherosclerotic eventsSHARP: Major atherosclerotic events

0 0 1 1 2 2 3 3 4 4 5 5

Years of follow-up Years of follow-up

0 0

5 5

10 10

15 15

20 20

25 25

Pro

port

ion

su

fferi

ng

eve

nt (

%)

Pro

port

ion

su

fferi

ng

eve

nt (

%)

Risk ratio 0.83 (0.74-0.94)Logrank 2P=0.0022

Placebo

Eze/simva


Pro

port

ion

al r

edu

ctio

n in

ath

ero

scle

rotic

eve

nt r

ate

(95

% C

I)P

ropo

rtio

na

l re

duct

ion

ina

the

rosc

lero

tic e

vent

ra

te (

95%

CI)

00

55

1010

1515

2020

2525

3030Statin vs. control(21 trials)

Mean LDL-C difference between treatment groups (mg/dL)

More vs. less(5 trials)

SHARP32 mg/dL

2020 40401010 3030

CTT: Effects on major atherosclerotic eventsCTT: Effects on major atherosclerotic events

00


SHARP17% risk reduction

SHARP: Major atheroscleroticand vascular events

SHARP: Major atheroscleroticand vascular events

Risk ratio (95% CI)Risk ratio (95% CI)Placebo(n=4620)Placebo(n=4620)

Eze/simva(n=4650)

Eze/simva(n=4650)

Major coronary eventNon-haemorrhagic strokeAny revascularizationMajor atherosclerotic event

Other cardiac deathHaemorrhagic stroke

Other major vascular events

Major vascular event

Major coronary eventNon-haemorrhagic strokeAny revascularizationMajor atherosclerotic event

Other cardiac deathHaemorrhagic stroke

Other major vascular events

Major vascular event

213131284526

16245

207

701

213131284526

16245

207

701

(4.6%)(2.8%)(6.1%)

(11.3%)

(3.5%)(1.0%)

(4.5%)

(15.1%)

(4.6%)(2.8%)(6.1%)

(11.3%)

(3.5%)(1.0%)

(4.5%)

(15.1%)

230174352619

18237

218

814

230174352619

18237

218

814

(5.0%)(3.8%)(7.6%)

(13.4%)

(3.9%)(0.8%)

(4.7%)

(17.6%)

(5.0%)(3.8%)(7.6%)

(13.4%)

(3.9%)(0.8%)

(4.7%)

(17.6%)

16.5% SE 5.4 (P=0.0022)

5.4% SE 9.4 (P=0.57)

15.3% SE 4.7 (P=0.0012)

0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4

Eze/simva better Eze/simva better Placebo better Placebo better


SHARP: Effects in subgroupsSHARP: Effects in subgroups

Among 8384 patients originally randomized to ezetimibe/simvastatin vs. placebo, major vascular events risk ratio = 0.84(95% CI 0.75-0.93; P=0.0010)

Similar reductions in major atherosclerotic events in all subgroups studied (includingnon-dialysis and dialysis patients)

Among 8384 patients originally randomized to ezetimibe/simvastatin vs. placebo, major vascular events risk ratio = 0.84(95% CI 0.75-0.93; P=0.0010)

Similar reductions in major atherosclerotic events in all subgroups studied (includingnon-dialysis and dialysis patients)


16.5% SE 5.4 (P=0.0022)

0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4


SHARP: Major atherosclerotic events by renal status at randomization

SHARP: Major atherosclerotic events by renal status at randomization


Non-dialysis (n=6247)

Dialysis (n=3023)

Major atherosclerotic event

Non-dialysis (n=6247)

Dialysis (n=3023)

Major atherosclerotic event

296

230

526

296

230

526

(9.5%)

(15.0%)

(11.3%)

(9.5%)

(15.0%)

(11.3%)

373

246

619

373

246

619

(11.9%)

(16.5%)

(13.4%)

(11.9%)

(16.5%)

(13.4%)

No significant heterogeneity between non-dialysis and dialysis patients

(P=0.25)

No significant heterogeneity between non-dialysis and dialysis patients

(P=0.25)


Eze/simva(n=4650)

Eze/simva(n=4650)


Eze/simva(n=4650)

Eze/simva(n=4650)

0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4



CoronaryOther cardiacSubtotal: Any cardiac StrokeOther vascularSubtotal: Any vascular

CancerRenalOther non-vascularSubtotal: Any non-vascular

Unknown cause

Total: Any death

CoronaryOther cardiacSubtotal: Any cardiac StrokeOther vascularSubtotal: Any vascular

CancerRenalOther non-vascularSubtotal: Any non-vascular

Unknown cause

Total: Any death

91162253

6840

361

150164354668

113

1142

91162253

6840

361

150164354668

113

1142

(2.0%)(3.5%)(5.4%)

(1.5%)(0.9%)(7.8%)

(3.2%)(3.5%)(7.6%)

(14.4%)

(2.4%)

(24.6%)

(2.0%)(3.5%)(5.4%)

(1.5%)(0.9%)(7.8%)

(3.2%)(3.5%)(7.6%)

(14.4%)

(2.4%)

(24.6%)

90182272

7838

388

128173311612

115

1115

90182272

7838

388

128173311612

115

1115

(1.9%)(3.9%)(5.9%)

(1.7%)(0.8%)(8.4%)

(2.8%)(3.7%)(6.7%)

(13.2%)

(2.5%)

(24.1%)

(1.9%)(3.9%)(5.9%)

(1.7%)(0.8%)(8.4%)

(2.8%)(3.7%)(6.7%)

(13.2%)

(2.5%)

(24.1%)

↓7.4% SE 8.4(P=0.38)

↓7.3% SE 7.0(P=0.30)

↑8.6% SE 5.8(P=0.14)

↑1.9% SE 4.2(P=0.65)

SHARP: Cause-specific mortalitySHARP: Cause-specific mortality

0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4


Main renal outcomeEnd-stage renal disease(ESRD)

Tertiary renal outcomesESRD or death

ESRD or 2 x creatinine

Main renal outcomeEnd-stage renal disease(ESRD)

Tertiary renal outcomesESRD or death

ESRD or 2 x creatinine

1057

1477

1190

1057

1477

1190

(33.9%)

(47.4%)

(38.2%)

(33.9%)

(47.4%)

(38.2%)

1084

1513

1257

1084

1513

1257

(34.6%)

(48.3%)

(40.2%)

(34.6%)

(48.3%)

(40.2%)

0.97 (0.89-1.05)

0.97 (0.90-1.04)

0.94 (0.86-1.01)

SHARP: Renal outcomesSHARP: Renal outcomes


Eze/simva(n=3117)

Eze/simva(n=3117)


SHARP: Cancer incidenceSHARP: Cancer incidence


0 0 1 1 2 2 3 3 4 4 5 5

Years of follow-up Years of follow-up

0 0

5 5

10 10

15 15

20 20

25 25

Pro

port

ion

su

fferi

ng

eve

nt (

%)

Pro

port

ion

su

fferi

ng

eve

nt (

%)

Placebo

Eze/simva

Risk ratio 0.99 (0.87-1.13)Logrank 2P=0.89

Oropharynx/oesophagusStomachBowelPancreasHepatobiliaryLungOther respiratory Skin cancer BreastProstateKidneyBladder & urinary tractGenitalHaematological Other known site Unspecified siteAny incident cancer

Oropharynx/oesophagusStomachBowelPancreasHepatobiliaryLungOther respiratory Skin cancer BreastProstateKidneyBladder & urinary tractGenitalHaematological Other known site Unspecified siteAny incident cancer

141153

98

423

136293931261226

913

438

141153

98

423

136293931261226

913

438

16143510

435

415321522332142712

7439

16143510

435

415321522332142712

7439

No significant differences

SHARP: Cancer incidence by siteSHARP: Cancer incidence by site


Eze/simva(n=4650)

Eze/simva(n=4650)

Placebo(n=4620)Placebo(n=4620)

(9.5%)(9.5%)(9.4%)(9.4%)

SHARP: SafetySHARP: Safety

Myopathy

• CK >10 x but ≤40 x ULN

• CK >40 x ULN

Hepatitis

Persistently elevated ALT/AST >3x ULN

Complications of gallstones

Other hospitalization for gallstones

Pancreatitis without gallstones

Myopathy

• CK >10 x but ≤40 x ULN

• CK >40 x ULN

Hepatitis

Persistently elevated ALT/AST >3x ULN

Complications of gallstones

Other hospitalization for gallstones

Pancreatitis without gallstones

16 (0.3%)

5 (0.1%)

18 (0.4%)

26 (0.6%)

76 (1.6%)

30 (0.6%)

17 (0.4%)

16 (0.3%)

5 (0.1%)

18 (0.4%)

26 (0.6%)

76 (1.6%)

30 (0.6%)

17 (0.4%)

17 (0.4%)

4 (0.1%)

21 (0.5%)

30 (0.6%)

85 (1.8%)

21 (0.5%)

12 (0.3%)

17 (0.4%)

4 (0.1%)

21 (0.5%)

30 (0.6%)

85 (1.8%)

21 (0.5%)

12 (0.3%)

Eze/simva(n=4650)

Eze/simva(n=4650)

Placebo(n=4620)Placebo(n=4620)


SHARP: ConclusionsSHARP: Conclusions

No increase in risk of myopathy, liver and biliary disorders, cancer, or non-vascular mortality

No substantial effect on kidney disease progression

Two-thirds compliance with eze/simva reduced the risk of major atherosclerotic events by 17% (consistent with meta-analysis of previous statin trials)

Similar proportional reductions in all subgroups (including among dialysis and non-dialysis patients)

Full compliance would reduce the risk of major atherosclerotic events by one quarter, avoiding 30-40 events per 1000 treated for 5 years

No increase in risk of myopathy, liver and biliary disorders, cancer, or non-vascular mortality

No substantial effect on kidney disease progression

Two-thirds compliance with eze/simva reduced the risk of major atherosclerotic events by 17% (consistent with meta-analysis of previous statin trials)

Similar proportional reductions in all subgroups (including among dialysis and non-dialysis patients)

Full compliance would reduce the risk of major atherosclerotic events by one quarter, avoiding 30-40 events per 1000 treated for 5 years


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