The overwhelming case for LDL-C lowering

Prof Kausik Ray, BSc (hons), MBChB, FRCP, MD, MPhil (Cantab), FACC, FESC

Professor of Cardiovascular Disease Prevention

St Georges University of London

Honorary Consultant Cardiologist St Georges Hospital

4S Primary Endpoint: Total Mortality

Scandinavian Simvastatin Survival Study Group. Lancet. 1994 ;344:1383-1389.

Years Since Randomization

ProportionAlive

Simvastatin

Placebo

0 1 2 3 4 5 60.00

0.80

0.85

0.90

0.95

1.00

30% RiskReduction(P=0.0003)

HPS: Effects of Simvastatin on First Major Vascular Event According to Baseline LDL-C

STATIN PLACEBO(n=10269) (n=10267)

ALL PATIENTS 2033 2585 (19.8%) (25.2%)

Risk ratio and 95% CI

0.4 0.6 0.8 1.0 1.2 1.4

LDL-C (mg/dL)

139 951/4331 1183/4349

< 116 598/3389 756/3404

484/2549 646/2514 116 - 139

STATIN better STATIN worse

24% reductionp<0.0001

Heart Protection Study Collaborative Group. Lancet 2002; 360:7-22.

ASCOT-LLA: Primary Prevention in HTN Nonfatal MI and Fatal CHD

0

1

2

3

4

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Years

Cum

ulati

ve In

cide

nce

(%)

36% reduction

HR = 0.64 (0.50-0.83)

Atorvastatin 10 mg Number of events 100Placebo Number of events 154

p=0.0005

Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58.

3.0%

1.9%

Baseline LDL 132 mg/dl

CARDS-Cumulative Hazard for Primary Endpoint

Relative Risk -37% (95% CI: -52, -17)

Years

328305

694651

10741022

13611306

13921351

AtorvaPlacebo

14281410

Placebo127 events

Atorvastatin10mg83 events

Cum

ulati

ve H

azar

d (%

)

0

5

10

15

0 1 2 3 4 4.75

P=0.001

CTT Collaboration Effects on Major Coronary Events per mmol/L LDL Cholesterol Reduction Subdivided by Baseline Lipid Values

Groups (mmol/L) Events (%)Treatment Control

RR & CI(Treatment : Control)

Total cholesterol:≤5.2 748 (6·9) 940 (8·6)5.2-6.5 1678 (7·0) 2246 (9·4)>6.5 896 (8·8) 1220 (12·1)

LDL cholesterol:≤3.5 1130 (6·8) 1443 (8·7)3.5-4.5 1374 (7·3) 1814 (9·6)>4.5 801 (9·3) 1120 (12·9)

HDL cholesterol:≤0.9 1167 (9·3) 1538 (12·1)0.9-1.1 939 (7·4) 1270 (10·2)>1.1 1207 (6·2) 1595 (8·1)

Triglycerides:≤1.4 1162 (7·3) 1521 (9·6)1.4-2.0 937 (7·1) 1304 (9·8)>2.0 1217 (7·9) 1564 (10·2)

Overall 3337 (7·4) 4420 (9·8)0·77 (0·74 – 0·80)

0·5 1·0 1·5Treatment Control

better better

p < 0·00001

Heterogeneity/trendp-value

p = 0·7

p = 0·5

p = 0·8

p = 0·6

CTT Collaborators. Lancet. 2005; 366:1267-78

Cholesterol Trialist Collaboration Meta-Analysis of Dyslipidemia Trials

50%

40%

30%

20%

10%

0%

-10%

0.5 1.0 1.5 2.0

Reduction in LDL Cholesterol (mmol/L)

Major Vascular Events

Prop

ortio

nal R

educ

tion

in E

vent

Rat

e (S

E)

Adapted from CTT Collaborators. Lancet. 2005; 366:1267-78

Death/Nonfatal MI

(%)

Months Of Follow-Up

16

12

8

4

00 2 4 6 4 5 6

Stable CAD

ACS

PROVE IT-TIMI 22/ A to Z/ IDEAL

Years

4SCARE

LIPID/ HPS/IDEAL

Only high dose statins have been tested immediately after ACS

All-Cause Death or Major CV Events in All Randomized Subjects

0 3 18 21 24 27 306 9 12 15

% with Event

Months of Follow-up

Pravastatin 40mg(26.3%)

Atorvastatin 80mg(22.4%)

16% RR(P = 0.005)

30

25

20

15

10

5

0

Cannon CP, et al. NEJM 2004;350:1495-504.

Is there benefit from an LDL of 2 mmol/L vs 2.6mmol/L in stable CAD?

LaRosa JC, et al. NEJM. 2005; 352:1425-1435Pedersen TR, et al. JAMA. 2005; 294:2437-2445

*CHD death, nonfatal non-procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke.

Years Since Randomization

MCV

E Cu

mul

ative

Haz

ard

(%)

0 1 2 3 4 50

4

8

12

16

HR = 0.87, P=.02

Simvastatin 20/40

Atorvastatin 80

HR = 0.78, P<.0010

5

10

15 Atorvastatin 10 mg

Atorvastatin 80 mg

Maj

or C

V Ev

ent*

(%)

0 1 2 3 4 5 6Time (years)

IDEALIDEAL TNTTNT

-13% RRR

-22% RRR

Cholesterol Trialist Collaboration Meta-Analysis of Dyslipidemia Trials

50%

40%

30%

20%

10%

0%

-10%

0.5 1.0 1.5 2.0

Reduction in LDL Cholesterol (mmol/L)

Major Vascular Events

Prop

ortio

nal R

educ

tion

in E

vent

Rat

e (S

E)

Adapted from CTT Collaborators. Lancet. 2005; 366:1267-78

TNT

IDEAL

Meta-Analysis of Intensive Statin Therapy LDL Cholesterol by Trial

40

60

80

100

120

140

160

LDL-CTIMI 22

A-to-Z TNT IDEAL Pooled

.

BaselineStandardIntensive

ACS Stable CAD Pooled

4162 4497 10001 8888 27548

25.2% 0% 0% 75.5% 28.2%

Patients

n

Prior Statin Use

Baseline* 108.4 112.9 152 121.5 129.6 (3.32)

Standard* 97.1 101 101 104 101.4 (2.6)

Intensive* 65.5 69.1 77 81 75.4 (1.93)

LDL-

C (m

g/dL

)

Cannon CP, et al. JACC 2006; 48: 438 - 445.

PROVE IT-

High-dose statin better High-dose statin worse

Odds Reduction

Event RatesNo./Total (%)

High Dose Std Dose

-16% 3972/13798 (28.8)

4445/13750 (32.3)

-16% 1097/13798 (8.0)

1288/13750 (9.4)

-12%462/13798

(3.3)520/13750

(3.8)

+3%340/13798

(2.5)331/13750

(2.4)

-6%808/13798

(5.9)857/13750

(6.2)

-18%316/13798

(2.3)381/13750

(2.8)

Coronary Death or Any Cardiovascular Event

Coronary Death or MI

Cardiovascular Death

Non-Cardiovascular Death

Total Mortality

Stroke

0.5 1 2.5

OR 0.8295% CI, 0.71-0.96p=0.012

Odds Ratio (95% CI)

Meta-Analysis of Intensive Statin Therapy - All Endpoints

OR, 0.9495% CI, 0.85-1.04P=0.20

OR, 1.0395% CI, 0.88-1.20p=0.73

OR, 0.8895% CI, 0.78-1.00p=.054

OR, 0.8495% CI, 0.77-0.91p=0.00003

OR, 0.8495% CI, 0.80-0.89P=.0000000000006

Cannon CP, et al. JACC 2006; 48: 438 - 445.

PROVE IT-TIMI 22: Relationship Between Month 4 LDL and Long-Term Risk of Death or Major CV Event

*Adjusted for age, gender, DM, prior MI, baseline LDL

0.80 (0.59, 1.07)

0.67 (0.50, 0.92)

0.61 (0.40, 0.91)

Hazard Ratio

Lower Better Higher Better

Referent

Wiviott SD, Cannon, Ray et al. JACC. 2005

0 1 2

<1.03

> 1.03 -1.54

>1.54 – 2.05

>2.05 – 2.56

0

2

4

6

8

10

12

14

Major CV events CHD death Nonfatal MI Stroke

<1.64 1.64- <1.97 1.97- <2.3 2.3- <2.7 >=2.7

P < 0.0001*

P < 0.01*

P < 0.0001*

P < 0.05*

*P-value for trend across LDL-C

TNT: Incidence of First Major Cardiovascular Events Across Quintiles

LaRosa JC. AJC. 2007, 100, 747-52

% p

atien

ts

Event rates by achieved LDL-C in trials

% with CHD event

Mean LDL-C level at follow-up (mmol/L)

0

5

10

15

20

25

30

2.3 2.8 3.3 3.8 4.4

2° PreventionStable CHD

1° Prevention

1.8

JBS2 ESC GMSATP III

Ray IJCP 2007, 61, 1608-11

Optimal standard

Minimum audit standard

PROVE IT Safety Results: Side Effects

Atorvastatin 80 mg LDL (mmmol/L)

p valueEvent* 2.07-2.59

1.55-2.07

1.04-1.55 <1.04

Myositis or Myalgia (AE) 1.6 3.1 3.2 2.8 NS

CK > 3x ULN 2.3 0.7 1.9 1.0 NS

CK > 10x ULN 0.3 0 0.3 0 NS

Rhabdomyolysis 0 0 0 0 NS

ALT > 3X ULN 3.1 3.0 3.2 3.6 NS

Wiviott, et al. JACC. 2005

Adverse Event Profiles Across Quintiles- TNT

Number (%) of patients

Quintile 1<64 mg/dL(114/1722)

*

Quintile 264-<77 mg/dL

(529/1403)*

Quintile 377-<90 mg/dL

(1019/968)*

Quintile 490-<106 mg/dL

(1515/515)*

Quintile 5≥106

mg/dL(1718/266)*

Withdrawals due to treatment-associated AEs

122 (6.6) 107 (5.5) 100 (5.0) 106 (5.2) 143 (7.2)

Treatment-associated myalgia

84 (4.6) 85 (4.4) 93 (4.7) 96 (4.7) 104 (5.2)

Persistent† CPK >10 ULN

0 0 0 0 0

Persistent† ALT and/or AST >3 ULN

20 (1.1) 15 (0.8) 18 (0.9) 8 (0.4) 10 (0.5)

*Number of patients: Atorvastatin 10 mg/atorvastatin 80 mg†Occurring twice within 4-10 days

CTT Lancet 2012

Statins increase risk of Dysglycaemia

Sattar N, ……Ray. Lancet 2010; 375: 735-42

Statins and DYSGLYCAEMIA vs CVD Risk

Preiss .... Ray. JAMA 2011;305:2556-64

Prognosis of Patients withNew-Onset T2DM

Waters DD et al. JACC. 2011;

TNT, IDEAL and SPARCL TNT, IDEAL and SPARCL Atorvastatin 80 mg groups

With new-onset T2DM

Without new-onset T2DM

Diabetes at baseline*

With new-onset T2DM

Without new-onset T2DM

Diabetes at baseline*

Incidence of MCVE

n / N (%)

157 / 1,387 (11.3%)

1,884/ 17,472 (10.8%)

832 / 4,761 (17.5%)

76 / 756 (10.1%)

867 / 8,684(10.0%)

358 / 2,359 (15.2%)

Univariate analysis**

(HR=1.03, 95% CI 0.78-1.35, p=0.83)

– – (HR=0.90, 95% CI 0.60-1.34, p=0.59)

– –

Multivariate analysis**

(HR=1.02, 95% CI 0.77-1.35, p=0.69)

– – (HR=0.87, 95% CI 0.58-1.30, p=0.49)

– –

*Patients were excluded from the new-onset T2DM study**MCVEs in patients with and without new-onset T2DM were assessed with an extensive time-dependent Cox proportional hazard analysis

The Evidence for Clinical Benefit of Statin Therapy for the prevention of CAD

• ACS

•Pravastatin

– L-CAD

– PACT

•Simvastatin

– A to Z

•Atorvastatin

– MIRACL

– PROVE IT-TIMI 22

•Primary Prev

•Pravastatin

– WOSCOPS

– PROSPER

•Simvastatin

– HPS

•Atorvastatin

– ASCOT

– CARDS

Rosuvastatin

– JUPITER

Lovastatin

– TEXCAPS/AFCAPS

Secondary Prev

Pravastatin CARE LIPID PROSPER

Simvastatin 4S HPS SEARCH

Atorvastatin AVERT TNT IDEAL

Summary

•LDL-C lowering offers similar proportional reductions among those with and without vascular disease

•The magnitude of benefit is related to the degree of LDL-C reduction

•LDL-C lowering is safe in general

•The greatest benefit are in those with the greatest absolute risk