Statins in CVD management : Is just lipid lowering enough?

Dr Vivek BaligaConsultant Internal Medicine

Director, HeartSenseTM

www.heartsense.in

Preamble• Statins were originally introduced as lipid lowering drugs, but

today they are recommended in many high risk patient groups irrespective of baseline lipid levels.

• This suggests that benefits of statins are beyond and independent of lipid lowering effects.

• So Choice of statin should be based on evidence of CV benefits rather than lipid lowering

Primary Prevention of CVD• As per AHA 2013, guidelines all T2DM patients of age 40-75

require either moderate or high dose statin therapy

2016 ADA guidelines for statins in DM

Diabetes Care 2016;39(supple 1): S1-S112

All DM patients with> 1 CV risk factor require moderate to high dose statin

But what is the evidence that statins reduce CV events in T2DM patients without high LDL-C?

MI Risk in Diabetics Without Prior MI Equivalent to Nondiabetic With MI

Haffner SM et al. N Engl J Med. 1998;339:229-234.

Numbers in bars represent number of persons in category at baseline.

Finnish population study (7-year follow-up)

3.5

20.218.8

45

0

10

20

30

40

50

60

Patients without diabetes Patients with diabetes

Inci

denc

e of

fata

l/non

fata

l MI

durin

g 7-

year

follo

w-u

p (%

)

No prior MI

Prior MI

P<0.001

P<0.001

P<0.001 for diabetes vs no diabetes

890130469 169

Diabetes is CHD equivalent

RM Parikh et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 4 (2010) 10–12

85.5%

Dyslipidemia

97.8 %

Dyslipidemia

85.5 %

Prevalence of Dyslipidemia (%) in Male T2 DM

Prevalence of Dyslipidemia (%) in Female T2DM

In India, 90% diabetics have dyslipidemia

Study Patients Follow up Results

ASCOT LLA * 2532 Atorvastatin 10 mg

3.3 yrs 23% risk reduction

CARDS 2838 Atorvastatin 10 mg

3.9 yrs 37% risk reduction

HPS * 2912 Simvastatin 40 mg

5 yrs 33% risk reduction

Major Statin Primary Prevention Trials In DM

* sub-analysis

Only Atorvastatin and Simvastatin have evidence that statin reduce CV events in Primary prevention.

OTHERS DO NOT HAVE SUCH EVIDENCE!

4-year follow-up

CARDS: primary prevention in T2DM Atorvastatin 10 mg/day

(n=1428)

Placebo(n=1410)

2838 patients

Primary end point: Incidence of major cardiovascular events:

– Cardiovascular-related death– Nonfatal MI– Stroke– Resuscitated cardiac arrest– Unstable angina– Coronary revascularization procedures

Patient population: Age: 40-75 years LDL-C 160 mg/dL Triglycerides 600 mg/dL Type 2 diabetes No prior MI or CHD 1+ CHD risk factor

C o l h o u n H M e t a l . L a n c e t . 2 0 0 4 ; 3 6 4 : 6 8 5 - 6 9 6 .CARDS: Collaborative Atorvastatin Diabetes Study

At Baseline,LDL-C: 120 mg/dlHDL-C: 54.5 mg/dlNon-HDL-C: 153 mg/dl

CARDS: Atorvastatin reduces CV events by 37%

*Acute CHD event, coronary revascularization, stroke. RRR: Relative risk reduction

Colhoun HM et al. Lancet. 2004;364:685-696.

0

5

10

15

0 1 2 3 4 5 6

RRR=37% p=0.001

Cum

ulati

ve in

cide

nce

of e

vent

s (%

of p

atien

ts)

127 events

83 events

Time (years)

Atorvastatin 10 mg (n=1428)Placebo (n=1410)

median follow-up 3.9 years

0

1

2

3

4

5

6

0 1 2 3 4 5 6

CARDS: Atorvastatin Reduces Stroke by 48% in T2DM

Newman C et al. American Heart Association 78th Scientific Sessions, 2005.

RRR= 48% (95% CI: 31%-89%)P=0.016

Cum

ulati

ve in

cide

nce

of e

vent

s (%

of p

atien

ts)

39 events

21 events

Time (years)

Atorvastatin 10 mg (n=1428)Placebo (n=1410) Median follow-up 3.9 years

Stroke was a component of the primary endpoint, evaluated individually as a secondary survival analysis.

AHA and ADA guidelines for statin therapy in T2DM for primary prevention are based on

Atorvastatin’s CARDS trial

Atorvastatin for Primary Prevention in High risk patients: ASCOT-LLA

A double-blind, placebo-controlled trial of atorvastatin 10 mg Vs Placebo in 10305 hypertensive patients studied

Median follow up: 3.3 years

Study end pointsPrimary: Combined nonfatal MI (including silent MI) and fatal CHD

Secondary: Fatal and nonfatal stroke

Total cardiovascular events and procedures

Total coronary events

Atorvastatin 10 mg Number of events 89Placebo Number of events 121

0

1

2

3

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Years

Cum

ulati

ve In

cide

nce

(%)

HR = 0.73 (0.56-0.96)P = .0236

27% reduction

ASCOT-LLA

Primary Endpoint:Nonfatal MI and Fatal CHD

Secondary Endpoint:Fatal and Nonfatal Stroke

0

1

2

3

4

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5Years

Cum

ulat

ive

Inci

denc

e (%

)

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

36% reduction

HR = 0.64 (0.50-0.83)P = .0005

Sever PS, et al. Lancet. 2003;361:1149-1158.

ASCOT-LLA: Primary prevention– DM Sub-analysis (yellow cells)

Highlighted boxes indicate diabetes patients enrolled in lipid-lowering arm.

-blocker ± diuretic CCB ± ACE inhibitor

TC >250 mg/dL (>6.5 mmol/L)

2532 TC 250 mg/dL(6.5 mmol/L)

TC >250 mg/dL (>6.5 mmol/L)

Open lipid lowering 1258 Atorvastatin 10 mg

1274Placebo Open lipid lowering

19,342 patients

Randomized

Randomized

Primary end point: Composite of fatal CHD and nonfatal MI

ASCOT: LLA: Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm Sever PS et al. J Hypertens. 2001;19:1139-1147. CCB: Calcium Channel Blocker ACE: Angiotension Convertase Inhibitor TC: Total Cholesterol

ASCOT-LLA :23% RRR for total CV events in DM patients with atorvastatin

Sever PS et al. Diabetes Care. 2005;28:1151-1157.

0

5

10

15

0 1 2 3 4 5 6

RRR=23% P=0.036

151 events

116 events

median follow-up 3.3 years

Cum

ulati

ve in

cide

nce

of e

vent

s (%

of p

atien

ts)

Time (years)

Atorvastatin 10 mgPlacebo

Statin in CKD patients

Alterations in Lipid Profiles in CKD

Clin J Am Soc Nephrol 2007; 2(4):766-85.

Triglycerides

HDL

Lipoprotein (a)

Normal or low LDL

Normal or low TC

VLDL remnants

Dose of statins in patients with CKD

• Atorvastatin: No dose adjustment required• Rosuvastatin: In patients severe CKD with creatinine

clearance < 30 ml/min (not on hemodialysis), Maximum dose: 10 mg/day

• Pitavastatin: in patients with moderate/severe CKD (GFR: 15-59 ml/min) Maximum dose: 2 mg/day,

GFR: Glomerular Filtration Rate

• Patients: 325 DM nephropathy patients urinary protein/creatinine ratios (UPCR): 500-5000 mg/g, LDL >90 mg/dL, and on ACEIs/ARBs for > 3 months.

• Patients divided in 3 groups: Rosuvastatin 10 mg, Rosuvastatin 40 mg and Atorvastatin 80 mg for duration of 52 weeks

• Baseline eGFR: 69-72 ml/min Baseline UPCR: 1160-1260 mg/g • The primary end point: Change in urinary protein/ creatinine ratio

from baseline to week 52

Atorvastatin vs Rosuvastatin in DM+ CKDPLANET I study

The Lancet Diabetes & Endocrinology 2015;3(3):181-90

PLANET I: % Change in UPCR and eGFR

UPCR Change (%)

-14

-12

-10

-8

-6

-4

-2

0

2

4

-13

2

-4

Atorvastatin 80 mg

Rosuvastatin 10 mg

Rosuvastatin 40 mg

p=0.033

p=0.83

p=0.53

The Lancet Diabetes & Endocrinology 2015;3(3):181-90

Change in eGFR

-8

-7

-6

-5

-4

-3

-2

-1

0

-1.61

-3.7

-7.29

Atorvastatin 80 mgRosuvastatin 10 mg Rosuvastatin 40 mg

Conclusion: Atorvastatin seems to have more renoprotective effects for the studied chronic kidney disease population.

de Zeeuw D. 2010European Renal Association-European Dialysis and Transplant Association Congress; June 27, 2010; Munich, Germany.

Atorvastatin vs Rosuvastatin for renal function PLANET I:

Adverse event

Rosuvastatin10 mg/day(n = 116)

Rosuvastatin 40 mg/day(n = 123)

Atorvastatin 80 mg/day(n = 110) p

Any renaladverse event

7.8 9.8 4.5 NS

Acute renal failure 0.0 4.1 0.9 <0.05

Serum creatininedoubling

0.0 4.9 0.0 <0.01

Serum creatininedoubling or acute

renal failure

0.0 7.3 0.9 <0.01

• A meta-analysis of 5 clinical trials head to head comparing atorvastatin vs rosuvastatin

Atorvastatin Vs Rosuvastatin For Proteinuria: A Meta-analysis

Circ J 2012;76:1259-66

Atorvastatin is safer than Rosuvastatin in DM patients with proteinuria

Atorvastatin is better than Rosuvastatin for reduction in proteinuria

2013 KDIGO Guidelines for dyslipidemia management in CKD

• In adults aged > 50 years with eGFR< 60 ml/min/1.73 m2 but not treated with chronic dialysis or kidney transplantation (GFR categories G3a-G5), we recommend treatment with a statin or statin/ezetimibe combination. (1A)

• In adults aged > 50 years with CKD and eGFR> 60 ml/min/1.73m2 (GFR categories G1-G2) we recommend treatment with a statin. (1B)

Rosuvastatin 20 mg (N=8901) MIStroke

Unstable Angina

CVD DeathCABG/PTCA

4-week run-in

Ridker PM et al, Circulation 2003;108:2292-2297

No Prior CVD/CKD/D

MMen >50, Women

>60 LDL <130 mg/dL hsCRP >2 mg/L

Placebo (N=8901)

Follow up: 1.9 yrs

Can we consider rosuvastatin for primary prevention in DM/CKD based on JUPITER?

Patients with DM and CKD were excluded from JUPITER, So there is no evidence for primary CV

prevention with rosuvastatin in DM/CKD!!!

Statin for secondary prevention• Current guidelines recommend moderate to high dose of

statins for secondary prevention.• Atorvastatin has multiple landmark trials for secondary

prevention

771 pts with NSTE-ACS sent to early coronary angiography (<48 hours)

Random

ization (N=191)

Atorvastatin 80 mg 12 hrs pre-angio;

further 40 mg 2 hrs before

N=96

Coronaryangiography

Placebo 12 hrs pre-angio;

further dose 2 hrs

before N=95

Primary end point:

30-day death, MI,

TVR

1st blood sample

(pre-PCI)

CK-MB, troponin-I, myoglobin, CRP

High dose Atorvastatin in ACSARMYDA-ACS trial

2nd and 3rd blood samples(8 and 24 hrs

post-PCI)

30 days

580 pts excluded for: - 451 statin therapy - 41 emergency angiography - 43 LVEF <30% - 30 contraindications to statins - 15 severe renal failure

PCI atorvastatin N=86

PCI placebo N=85

20 pts excluded for indication to: - medical therapy (N=8) - bypass surgery (N=12)

atorvast

ARMYDA-ACS: Secondary end point

Post-PCI percent increase of CRP levels from baseline

%

63

147

P=0.01

JACC 2007:49:1272-78

ARMYDA-ACS trialComposite primary end-point (30-day death, MI, TVR)

%

5

17

P=0.01

JACC 2007:49:1272-78

• 383 patients with stable angina (53%) or NST-ACS (47%) and on chronic statin therapy (55% atorvastatin) undergoing PCI were randomized to atorvastatin reload (80 mg 12 h before intervention, 40-mg pre-procedural dose or placebo (n=191).

• All patients received long-term atorvastatin treatment thereafter (40 mg/day).

• The primary end point was 30-day incidence of major adverse cardiac events (cardiac death, myocardial infarction, or unplanned revascularization).

Loading atorvastatin in patients already on statin ARMYDA-RECAPTURE

J. Am. Coll. Cardiol. 2009;54;558-565

ARMYDA-RECAPTURE: PRIMARY ENDPOINT

Series10

3

6

9

12

3.4

9.1

P=0.045

MA

CE

( %)

PlaceboAtorvastatin

Loading of Atorvastatin high dose before PCI can reduce the CV events

J. Am. Coll. Cardiol. 2009;54;558-565

Atorvastatin 80 mg n=4,995

Primary Endpoint: Major cardiovascular event defined as coronary heart death (CHD), nonfatal M, resuscitated cardiac arrest, and fatal or nonfatal stroke at a mean follow-up of 4.9 years.

Atorvastatin for stable CAD TNT Trial

Presented at ACC 2005

Atorvastatin 10 mg n=5,006

10,003 patients with stable coronary heart disease Age 35-75 years, LDL between 130 and 250 mg/dL, triglyceride ≤ 600 mg/dL

19% female, mean age 60.3 yearsAll received atorvastatin 10 mg during 8 week open-label run-in period

TNT Trial: Primary endpointHazard Ratio [HR]=0.78

p<0.001

Presented at ACC 2005

4,162 patients with an Acute Coronary Syndrome < 10 days

ASA + Standard Medical Therapy

“Standard Therapy”Pravastatin 40 mg

“Intensive Therapy”Atorvastatin 80 mg

Duration: Mean 2 year follow-up (>925 events)

Atorvastatin in ACS: PROVE IT - TIMI 22

2x2 Factorial: Gatifloxacin vs. placebo

Double-blind

Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke

CV events in PROVE IT study

Cannon et al. NEJM 2004 Ray et al. Am J Cardiol 2006

Death/MACEDeath/MI/Urg. Revascu.

↓33%↓16%

Intensive statin therapy provides more benefits than low/moderate Intensity statin

Take Home Message

• CV protection with statin is not completely dependent on lipid lowering.

• Though rosuvastatin is slightly more effective than atorvastatin for lipid lowering, Atorvastatin has stronger evidence for CV protection

• Atorvastatin is approved in both primary and secondary prevention, while rosuvastatin is approved only in primary prevention in patients with hsCRP > 2 mg/L WITHOUT DM/CKD