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Cardiovascular and All-Cause Mortality Outcomes Among Hypertensive Patients With Moderate Renal Dysfunction in the ASCOT-LLA, and its Extended Follow-up. Dr Ajay K Gupta International Centre for Circulatory Health, ICTU, Imperial College London, UK.

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Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Cardiovascular and All-Cause Mortality Outcomes Among Hypertensive Patients With Moderate Renal Dysfunction in the ASCOT-LLA, and its Extended Follow-up

Dr Ajay K Gupta

International Centre for Circulatory Health, ICTU, Imperial College London, UK

Presented on Behalf of the ASCOT Investigators


Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Background: CKD and Cardiovascular morbidity and mortality

An eGFR less than 60 mL/min/1・73 m2 is an independent

predictor of all-cause mortality and cardiovascular

mortality in the general population.

The Lancet, Vol 375, Pages 2073 - 2081, 12 June 2010


Trial evidence statin use among those with ckd

Trial evidence: statin use among those with CKD

In clinical trials on chronic kidney disease (CKD) patients on haemodialysis, the use of statins was not associated with any cardiovascular (CV) benefits (AURORA trial & 4D study).

Among non-dialysis CKD patients, the use of statins also failed to show any extra CV benefits (PREVEND-IT & ALERT).

Among hypertensive patients with renal dysfunction in the lipid-lowering arm of the ALLHAT trial, the use of pravastatin had no added CV benefits, beyond that of usual care.


Statin among those with ckd

Statin among those with CKD

In contrast, in post-hoc secondary analyses of the JUPITER trial , CARDS & TNT, allocation to the statin therapy was found to have protective effects on some, but not all, CV outcomes among patients with renal dysfunction.

In the SHARP trial, among CKD patients, the use of ezetimibe/simvastatin combination was associated with:

17% and 19% (significant) reduction in major vascular events and stroke, respectively.

No significant impact on total coronary events or all-cause mortality.


Comparison of the impact of statin on non fatal mi in the renal and non renal trials

Comparison of the impact of statin on non-fatal MI in the Renal and non-Renal trials

Events (% pa)

Allocated

Allocated

Risk ratio (RR) per

p

Trial

LDL-C reduction

control

mmol/L LDL-C reduction

LDL-C reduction

Control better

better

33 (1.91)

35 (2.02)

4D

c

2

ALERT

54 (1.03)

65 (1.24)

=

0.3

3

(p = 0.96)

91 (1.97)

107 (2.33)

AURORA

134 (0.71)

159 (0.85)

SHARP

312 (1.02)

366 (1.21)

0.83 (0.70 - 0.98)

0.03

Subtotal: 4 renal trials

23 other trials

3307 (0.97)

4386 (1.29)

0.73 (0.70 - 0.76)

<0.0001

3619 (0.97)

4752 (1.29)

0.74 (0.70 - 0.77)

All trials

<0.0001

2

c

2.2 (p = 0.14)

=

Difference between renal and non-renal trials:

1

99% or

95% CI

0.5

0.75

1

1.5

2

*modified from the SHARP presentation


Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Comparison of impact of statin on Vascular death in the Renal vs Non-Renal trials

Events (% pa)

Allocated

Allocated

Risk ratio (RR) per

p

Trial

LDL-C reduction

control

mmol/L LDL-C reduction

LDL-C reduction

Control better

better

4D

151 (8.52)

167 (9.36)

2

c

66 (1.23)

73 (1.36)

ALERT

=

0.9

3

(p = 0.82)

324 (6.87)

324 (6.86)

AURORA

361 (1.82)

388 (1.97)

SHARP

Subtotal: 4 renal trials

902 (2.85)

952 (3.01)

0.94 (0.85 - 1.04)

0.27

3679 (1.05)

4230 (1.21)

0.85 (0.81 - 0.89)

23 other trials

<0.0001

4581 (1.20)

5182 (1.36)

0.86 (0.83 - 0.90)

All trials

<0.0001

c

2

=

3.8 (p = 0.05)

Difference between renal and non-renal trials:

1

99% or

95% CI

0.5

0.75

1

1.5

2

*modified from the SHARP presentation


Ascot lla extension

ASCOT-LLA-Extension

  • Early closure of ASCOT-LLA

  • Median follow-up 3.3 years

  • Atorvastatin versus placebo:

  • 36% reduction in the primary endpoint

  • 27% reduction in stroke

  • ASCOT-LLA-extended

  • Offering atorvastatin 10 mg daily to all patients in LLA

  • Continued for a further 2.2 years until the closure of ASCOT-BPLA

  • Statin usage at the end of LLA-extended

Values are n (%)

*Also the end of LLA-extension


Methods

Methods

  • Based on mean estimated glomerular filtration rate (eGFR) (MDRD-method), patients at baseline were allocated to have a moderate renal damage (CKD) (eGFR 30-60 mL/min/1.73 m2) or not.

  • Outcomes:

    • Non-fatal myocardial infarction (MI) plus fatal CHD plus revascularisation .

    • Secondary outcomes: total coronary events, fatal and non-fatal stroke, CV mortality & all-cause mortality.


Statistical methods

Statistical Methods

  • For each of these outcomes, a separate Cox model was developed to assess the effect of statin therapy, after adjusting for a priori confounders: age, sex, race, socio-economic status (age at leaving education), systolic BP and allocated BP treatment, among those with and without CKD at baseline.

  • Heterogeneity in the treatment effect between those with or without CKD was assessed using an appropriate interaction test

  • These analyses were repeated using time to first event during the extended follow-up in the ASCOT-LLA-extended.


Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Trial Profile: patients with CKD in the ASCOT-lipid lowering arm

10,305 randomised

65 excluded because of protocol violations

5 excluded as serum creatinine at baseline > 200 μ mol/L

10,235 evaluable

5,103 in placebo arm

5,132 in statin arm

1,002(19.5%)

with CKD

4,083(80.0%) without CKD

1,020(20.0 %) with CKD

4,130 (80.5%) without CKD


Lipids levels during ascot lla and lla extended

Lipids Levels During ASCOT-LLA and LLA-extended

Atorvastatin

Placebo

*Lipid closeout visit (end of ASCOT-LLA)


Mean ldl cholesterol among those with ckd stratified by treatment

Mean LDL-cholesterol among those with CKD, stratified by treatment

CKD & Atorvastatin

CKD & Placebo

dif=0.9 P<0.0001

dif=mean difference in change in LDL-C from baseline to year 3 between atorvastatin (-1.2) and placebo (-0.3)

LDL-C: low-density lipoprotein cholesterol; CKD: chronic kidney disease; Ator: atorvastatin


Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Event rates of cardiovascular outcomes and death, among those with and without presence of CKD


Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Cardiovascular events and deaths associated with statin therapy among those with and without CKD (ASCOT-LLA)

Placebo

Total events

Atorvastatin

Interaction Test

NF MI+F CHD+ Revas

Non-CKD

264

161

103

p=0.26

CKD

69

37

32

NF MI+NF Stroke +CV Death

Non-CKD

405

240

165

p=0.10

CKD

121

62

59

CV Death

Non-CKD

112

59

53

p=0.70

CKD

39

22

17

Total Stroke

Non-CKD

153

90

63

p=0.35

CKD

52

27

25

All Cause Mortality

Non-CKD

281

152

129

p=0.89

CKD

105

56

49

Total Coronary Events

Non-CKD

328

190

138

p=0.97

CKD

90

52

38

0.5

0.6

0.7

0.8

0.9

1

1.2

1.5

Favors atorvastatin Favors placebo

Hazard ratio and 95% CI (log scale)

Adjusted for age, sex, baseline SBP, ethnicity, socio-economic status, randomised BP treatment


Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Cardiovascular events and deaths associated with statin therapy, after 2 years of further follow-up (LLA-extended)

Placebo

Interaction Test

Total events

Atorvastatin

NF MI+F CHD+ Revas

Non-CKD

437

170

267

p=0.09

CKD

114

54

60

NF MI+NF Stroke+CV Death

Non-CKD

615

250

365

p=0.06

CKD

205

98

107

CV Death

Non-CKD

210

93

117

p=0.59

CKD

84

40

44

Total Stroke

Non-CKD

263

110

153

p=0.18

CKD

108

53

55

All Cause Mortality

Non-CKD

590

269

321

p=0.58

CKD

222

107

115

Total Coronary Events

Non-CKD

569

240

329

p=0.49

CKD

156

70

86

0.5

0.6

0.7

0.8

0.9

1

1.2

1.5

Favors atorvastatin Favors placebo

Hazard ratio and 95% CI (log scale)

Adjusted for age, sex, baseline SBP, ethnicity, socio-economic status , randomised BP treatment


Conclusions

Conclusions

  • Hypertensive patients with CKD are at a higher risk of cardiovascular events and death.

  • In the ASCOT LLA

    • Among those without CKD, allocation to atorvastatin therapy was associated with a significant reduction in coronary and stroke outcomes, but not for death.

    • There was no difference (statistically) in the effect of statin therapy among those with and without renal damage.

  • In ASCOT-LLA extended:

    • Statin therapy was associated with significant reduction in CV outcomes and death among those without CKD, and similar trends were noted among those with CKD.

    • The benefits of statin therapy remained unchanged, 2 years after the ASCOT-LLA closure. This was despite similar lipid levels at the end of LLA-extended.

  • .


Acknowledgements

Acknowledgements

All ASCOT patients and investigators

Professor Peter Sever, Professor Neil R Poulter, Bjorn Dahlof, C L Chang and staff at ICCH, Imperial College London, UK


Thank you for your attention

Thank you for your attention


Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Kaplan-Meier curve for total coronary events by CKD status

HR: adjusted for age, sex, baseline SBP, ethnicity, socio-economic status (education completion age) and randomised BP treatment


Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Kaplan-Meier curve for fatal and non-fatal stroke by CKD status

HR: adjusted for age, sex, baseline SBP, ethnicity, socio-economic status (education completion age) and randomised BP treatment


Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Kaplan-Meier curve for all-cause mortality by CKD status

HR: adjusted for age, sex, baseline SBP, ethnicity, socio-economic status (education completion age) and randomised BP treatment


Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Kaplan-Meier curve for non-fatal MI and fatal CHD and revascularisation by chronic kidney disease status

HR: adjusted for age, sex, baseline SBP, ethnicity, socio-economic status (education completion age) and randomised BP treatment


Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Kaplan-Meier curve for non-fatal MI, non-fatal stroke and CV deaths by chronic kidney disease status

HR: adjusted for age, sex, baseline SBP, ethnicity, socio-economic status (education completion age) and randomised BP treatment


Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Kaplan-Meier curve for cardiovascular deaths by chronic kidney disease status

HR: adjusted for age, sex, baseline SBP, ethnicity, socio-economic status (education completion age) and randomised BP treatment


Relationship between estimated gfr egfr and clinical outcomes

Relationship Between Estimated GFR (eGFR) and Clinical Outcomes

Death from Any CauseTotal Events = 51,424

Cardiovascular Events

Total Events = 139,011

Any Hospitalization

Total Events = 554,651

Age-Standardized Event Rate(per 100 Person-Yr)

60

45–59

30–44

15–29

<15

60

45–59

30–44

15–29

<15

60

45–59

30–44

15–29

<15

eGFR (mL/min/1.73 m2)

Go AS, et al. N Engl J Med. 2004;351:1296-305.


Ascot lla and lla extended overview

ASCOT-LLA and LLA-extended: overview

  • ASCOT-LLA : 10,305 hypertensive patients, with no pre-existing coronary heart disease (CHD), were randomised, using a 22 factorial design, to receive placebo or atorvastatin (10 mg/d).

    • Median follow-up: 3.3 years

  • ASCOT-LLA (extended): Patients were further followed up for an average of 2 years after closure of the LLA (as a part of the blood pressure lowering arm of the ASCOT trial [ASCOT-BPLA]).

    • Median follow-up: 5.5 years


Changes in ldl cholesterol until the end of lla extended

Changes in LDL cholesterol until the end of LLA extended

mmol/L

mg/Dl

Atorvastatin

Placebo


Dr ajay k gupta international centre for circulatory health ictu imperial college london uk

Effect of Statins Compared With Placebo or No Treatment on CV Events in Pre-Dialysis, Dialysis, and Transplant Patients

Study or subcategory

Statinn/N

Placebon/N

Relative risk(random) (95% CI)

Weight(%)

Relative risk(random) (95% CI)

Year

Pre-dialysis patientsFried 2001HPS 2003

PPP 2004PEVEND IT 2004

Lemos 2005

Subtotal (95% CI)Total events: 1391 (statin), 1806 (placebo)Test for heterogeneity: X2=5.78, df=4, P=0.22, I2=30.7%

Test for overall effect: z=4.58, P<0.001

Dialysis patients

4D trial 2005

Subtotal (95% CI)

Total events: 205 (statin), 246 (placebo)

Test for heterogeneity: not applicable

Test for overall effect: z=2.05, P=0.04

Transplant patients

Holdaas 2003

Subtotal (95% CI)

Total events: 46 (statin), 66 (placebo)

Test for heterogeneity: not applicable

Test for overall effect: z=1.92, P=0.05

Mixed population (pre-dialysis and dialysis patients)

Stegmayr 2005

Sub total (95% CI)

Total events: 6 (statin), 10 (placebo)

Test for heterogeneity: not applicable

Test for overall effect: z=0.96, P=0.34

Total (95% CI)

Total events: 1648 (statin), 2128 (placebo)

Test for heterogeneity: X2=7.68, df=7, P=0.36, I2=8.9%

Test for overall effect: z=6.72, P<0.001

0/17

182/646

1174/8376

15/433

20/150

9622

205/619

619

46/1050

1050

6/70

70

11 361

1/19

268/683

1474/8448

19/431

44/160

9741

246/636

636

66/1052

1052

10/73

73

11 502

0.37 (0.02 to 8.53)

0.72 (0.62 to 0.84)

0.80 (0.75 to 0.86)

0.79 (0.40 to 1.53)

0.48 (0.30 to 0.78)

0.75 (0.66 to 0.85)

0.86 (0.74 to 0.99)

0.86 (0.74 to 0.99)

0.70 (0.48 to 1.01)

0.70 (0.48 to 1.01)

0.63 (0.24 to 1.63)

0.63 (0.24 to 1.63)

0.78 (0.73 to 0.84)

2001

2003

2004

2004

2005

2005

2003

2005

0.05

18.12

54.92

1.15

2.18

76.43

19.33

19.33

3.69

3.69

0.56

0.56

100.00

Only studies with at least 1 event are included in the plot

0.01

0.1

1

10

100

Favors

statin

Favors

placebo

Giovanni FM. BMJ 2008;336;645-651.


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