New ACC/AHA Guidelines on Lipids: Are PCSK9 Inhibitors...

New ACC/AHA Guidelines on Lipids:

Are PCSK9 Inhibitors

Poised for a Breakthrough?

Sidney C. Smith, Jr. MD, FACC, FAHA

Professor of Medicine/Cardiology University of North Carolina at Chapel Hill

Immediate Past President

World Heart Federation

Nothing to Disclose

]

“In its current form, habits, and environment, American health care is incapable of providing the public with the quality health care it expects and deserves.”

Design Rule 5: Current: Decision making is based on training and experience. New: Decision making is based on evidence. Patients should receive care based on the best available scientific knowledge. Care should not vary illogically form clinician to clinician or from place to place.

Institute of Medicine, Crossing the Quality Chasm: A New Health System for the Twenty-first Century.

Washington: National Academy Press, 2001

Institute of Medicine Report: Quality Chasm

Development of clinical practice guidelines

was a key role for NHLBI in those years

Joint National Committee on

Prevention, Detection,

Evaluation, & Treatment of

High Blood Pressure (JNC)

JNC 7: 2003

JNC 6: 1997

JNC 5: 1992

JNC 4: 1988

JNC 3: 1984

JNC 2: 1980

JNC 1: 1976

Detection, Evaluation, and

Treatment of High Blood

Cholesterol in Adults (ATP,

Adult Treatment Panel)

ATP III Update: 2004

ATP III: 2002

ATP II: 1993

ATP I: 1988

Clinical Guidelines on the

Identification, Evaluation, &

Treatment of Overweight

and Obesity in Adults

Obesity 1: 1998

5

Correlation Between CHD Events and LDL-C Levels

S = Statin treated; P = Placebo treated

25

20

15

10

5

0

50 70 90 110 130 150 170 190 210

?

CARE-S

LIPID-S

4S-S

CARE-P

LIPID-P

4S-P

CH

D e

ven

t (%

)

LDL-C (mg/dL)

Statin Trials and Goals of Cholesterol-Lowering Therapy

The quantitative relation between the magnitude of cholesterol lowering and CHD reduction has not been precisely defined

3 models

a) Linear b) Threshold c) Curvilinear

210

Correlation Between CHD Events,

LDL-C Levels, and Risk

Opie et al.,Lancet 2006; 367: 69–78

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

Heart Protection Study (HPS)

Risk ratio and 95% CI

Simva 40

better

Placebo

better

24% SE 2.6

reduction

(2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4 Patients 40–80 years old; CAD, CVD, PVD,

diabetes or HTN; TC >135.

LDL Statin

(10,269) Placebo (10,267)

< 100 ATP III - No RX

285 360

> 100 < 130 ATPIII - Diet or Rx 670 881

> 130 ATP III - Rx

1087 1365

All patients

2042 (19.9%)

2606 (25.4%)

© 2003 American Heart Association

Het2 = 0.8 c2

PROVE IT–TIMI 22: Primary Endpoint*

* Total mortality, NFMI, rehosp with UA, revasc-PCI, CABG ≥ 30 d, stroke

Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.

Atorvastatin 80 mg

LDL-C = 62 mg/dL

(22.4%)

Pravastatin 40 mg

LDL-C = 95 mg/dL

(26.3%)

16% RRR

P = 0.005

0 6 12 18 24 30 0

5

10

15

20

25

30

Months of follow-up

Death

or

majo

r C

V e

ven

t (%

)

No. at risk

Pravastatin 2,063 1,688 1,536 1,423 810 138

Atorvastatin 2,099 1,736 1,591 1,485 842 133

CTT Meta-analysis 26 Trials

0.4 0.6 0.8 1 1.2 1.4

Nonfatal MI

CHD death

Any major coronary event

CABG

PTCA

Unspecified

Any coronary revascularisation

Ischaemic stroke

Haemorrhagic stroke

Unknown stroke

Any stroke

Any major vascular event

1175 (1.3%)

645 (0.7%)

1725 (1.9%)

637 (0.7%)

1166 (1.3%)

447 (0.5%)

2250 (2.6%)

440 (0.5%)

69 (0.1%)

63 (0.1%)

572 (0.6%)

3837 (4.5%)

1380 (1.5%)

694 (0.7%)

1973 (2.2%)

731 (0.9%)

1508 (1.8%)

502 (0.6%)

2741 (3.2%)

526 (0.6%)

57 (0.1%)

80 (0.1%)

663 (0.7%)

4416 (5.3%)

0.71 (0.58 - 0.87)

0.85 (0.63 - 1.15)

0.74 (0.65 - 0.85)

0.72 (0.55 - 0.95)

0.60 (0.50 - 0.71)

0.78 (0.58 - 1.04)

0.66 (0.60 - 0.73)

0.69 (0.50 - 0.95)

1.39 (0.57 - 3.39)

0.63 (0.24 - 1.66)

0.74 (0.59 - 0.92)

0.72 (0.66 - 0.78)

10

No. of events (% pa) Relative risk (CI) per

mmol/L LDL-C reduction More statin Less statin

More statin better Less statin better

99% or 95% CI

MORE VS LESS STATIN – Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction

( 1 mmol/L = ~ 39 mg/dL)

CTT Collaborators Lancet 2010: 376: 1670 - 81

0.5 0.75 1 1.25 1.5

Statin/more better Control/less better

<2.0

2,<2.5

2.5,<3.0

3,<3.5

3.5

Total

910 (14.7%)

1528 (14.0%)

1866 (12.4%)

2007 (12.3%)

4508 (13.0%)

10973 (13.0%)

1012 (16.4%)

1729 (15.9%)

2225 (14.7%)

2454 (15.2%)

5736 (16.5%)

13350 (15.8%)

0.78 (0.61 - 0.99)

0.77 (0.67 - 0.89)

0.77 (0.70 - 0.85)

0.76 (0.70 - 0.82)

0.80 (0.76 - 0.83)

0.78 (0.76 - 0.80)

11

No. of events (% pa)

Statin/more Control/less

<2.0

2,<2.5

2.5,<3.0

3,<3.5

3.5

Total

704 (17.9%)

1189 (18.4%)

1065 (20.1%)

517 (20.4%)

303 (23.9%)

3837 (19.4%)

795 (20.2%)

1317 (20.8%)

1203 (22.2%)

633 (25.8%)

398 (31.2%)

4416 (22.3%)

0.71 (0.52 - 0.98)

0.77 (0.64 - 0.94)

0.81 (0.67 - 0.97)

0.61 (0.46 - 0.81)

0.64 (0.47 - 0.86)

0.72 (0.66 - 0.78)

<2.0

2,<2.5

2.5,<3.0

3,<3.5

3.5

Total

206 (9.0%)

339 (7.7%)

801 (8.2%)

1490 (10.8%)

4205 (12.6%)

7136 (11.0%)

217 (9.7%)

412 (9.1%)

1022 (10.5%)

1821 (13.3%)

5338 (15.9%)

8934 (13.8%)

0.87 (0.60 - 1.28)

0.77 (0.62 - 0.97)

0.76 (0.67 - 0.86)

0.77 (0.71 - 0.84)

0.80 (0.77 - 0.84)

0.79 (0.77 - 0.81)

More vs less statin

Statin vs control

All trials

Relative risk (CI) per

mmol/L LDL-C reduction

99% or 95% CI

Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction, by baseline LDL-C


Previous coronary disease: CHD

Non-CHD vascular

None

Diabetes: Type 1 diabetes

Type 2 diabetes

No diabetes

Sex: Male

Female

Age (years) 65

>65, 75

>75

Body mass index (kg/m2): <25 25,< 30

30

Smoking status: Current smokers

Non-smokers

8395 (4.5%) 674 (3.1%)

1904 (1.4%)

145 (4.5%)

2494 (4.2%)

8272 (3.2%)

8712 (3.5%)

2261 (2.5%)

6056 (2.9%)

4032 (3.7%)

885 (4.8%)

3030 (3.0%)

5033 (3.3%)

2732 (3.3%)

2268 (3.6%)

8703 (3.1%)

10123 (5.6%) 802 (3.7%)

2425 (1.8%)

192 (6.0%)

2920 (5.1%)

10163 (4.0%)

10725 (4.4%)

2625 (2.9%)

7455 (3.6%)

4908 (4.6%)

987 (5.4%)

3688 (3.7%)

6125 (4.1%)

3331 (4.1%)

2896 (4.7%)

10452 (3.9%)

0.79 (0.76 - 0.82) 0.81 (0.71 - 0.92)

0.75 (0.69 - 0.82)

0.77 (0.58 - 1.01)

0.80 (0.74 - 0.86)

0.78 (0.75 - 0.81)

0.77 (0.74 - 0.80)

0.83 (0.76 - 0.90)

0.78 (0.75 - 0.82)

0.78 (0.74 - 0.83)

0.84 (0.73 - 0.97)

0.79 (0.74 - 0.84)

0.78 (0.74 - 0.82)

0.78 (0.73 - 0.84)

0.78 (0.73 - 0.84)

0.78 (0.75 - 0.82)

0.4 0.6 0.8 1 1.2 1.4 99% or 95% CI

12

No. of patients (% pa)

Statin/more Control/less

Relative risk (CI) per

mmol/l LDL-C reduction

Statin/more

better

Control/less

better

Total 10973 (13.0%) 13350 (15.8%) 0.78 (0.76 - 0.80)

Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction, by baseline prognostic factors


New Onset DM and MACE in Patients

treated with Statins for ACS or CHD

Preiss et al, JAMA. 2011;305(24):2556-2564

Drug Interactions with Simvastatin

Egan, A & Colman,E NEJM 2011

Simvastatin:

Key components of label change 1. Restrict 80 mg to >12 mos users

2. Switch 80 mg users to alternate

drug for drug –drug interaction

3. If LDL-C goal not achieved with 40 mg use another more potent statin i.e. atorvastatin or rosuvastatin.

CTT 2012 Meta-analysis of statins in those at lower risk of major CVD*

* Major CVD = first nonfatal MI, coronary death, stroke, or coronary revascularization

(27 trials, >134,000 participants)

CTT Collaborators. Lancet 2012; 380: 581-590

Primary prevention 5 to <10% 5-year major CVD risk Per 1 mmol reduction LDL-C with a statin*

*1 mmol/L (39 mg/dl) LDL-C reduction was the average in the primary prevention RCTs excluding JUPITER CTT Collaborators. Lancet 2012; 380: 581-590

• Significantly greater 34% reduction in relative risk of major CVD than higher risk groups

• 17% reduction in total mortality

Primary prevention <5% 5-year major CVD risk Per 1 mmol reduction LDL-C with a statin*

*1 mmol/L LDL-C reduction was the average in the primary prevention RCTs CTT Collaborators. Lancet 2012; 380: 581-590

• 39% reduction in relative risk of major CVD • No reduction in total mortality • 88% of MEGA, 63% of JUPITER, 45% of AFCAPS/TexCAPS participants (92% of

n=23,034)

CTT 2012

Meta-analysis of statins in those at lower risk of major CVD* * Major CVD = first nonfatal MI, coronary death, stroke, or coronary revascularization

(27 trials, >134,000 participants)



Critical Question 1

Critical Question 2

New Perspective

on LDL–C & Non-HDL–C Goals

• Lack of RCT evidence to support titration of drug therapy

to specific LDL–C and/or non-HDL–C goals

• Strong evidence that appropriate intensity of statin

therapy should be used to reduce ASCVD risk in those

most likely to benefit

• Quantitative comparison of statin benefits with statin risk

• Nonstatin therapies – did not provide

ASCVD risk reduction benefits or safety profiles

comparable to statin therapy

2013 ACC/AHA Guidelines for Treating Hypercholesterolemia ( Summary)

Primary Prevention

Global Risk Assessment

• To estimate 10-year ASCVD risk

New Pooled Cohort Risk Equations

White and black men and women

• More accurately identifies higher risk individuals for statin

therapy

Focuses statin therapy on those most likely to benefit

You may wish to avoid initiating statin therapy in high-

risk groups found not to benefit (higher grades of

heart failure and hemodialysis)

ACC/AHA Risk Calculator

Lifetime risk estimator

• For age 20-59 years, it provides lifetime risk estimate

• This is intended to drive discussions of greater adherence to heart-healthy lifestyle

ASCVD Risk Calculator 55 yo AA and White Women

7.7

1.8

3.6

1.4

0

1

2

3

4

5

6

7

8

9

10

Your 10-Year ASCVD Risk

(%)

Optimal (%) Your 10-Year ASCVD Risk

(%)

Optimal (%)

10-Y

ear

AS

CV

D R

isk (

%)

African American

Women

White

Women

Individuals Not in a Statin Benefit Group

In those not clearly in a statin benefit group,

additional factors may inform treatment decision-

making:

• Family history of premature ASCVD

• Elevated lifetime risk of ASCVD

• LDL–C ≥160 mg/dL

• hs-CRP ≥2.0 mg/L

• Subclinical atherosclerosis

CAC score ≥300 or ABI<0.9

Discussion of potential for ASCVD risk reduction

benefit, potential for adverse effects, drug-drug

interactions, and patient preferences

• Thresholds for initiating statin therapy

derived from RCTs

• Before initiating statin therapy, clinicians

and patients engage in a discussion of

the potential for ASCVD risk reduction

benefits, potential for adverse effects, drug-

drug interactions, and patient preferences

Primary Prevention

Statin Therapy

Best

Scientific

Evidence Patient

preference

Clinical

Judgment

Primary Prevention- Risk Discussion Must Precede Statin Prescription

Computers do not practice Medicine Shared Decision Making is Essential

A. PCSK9 binds LDL

receptor leads to LDL

receptor degradation

B. PCSK9 Inhibition

restores LDL receptor to

hepatocyte wall causing

increased uptake of LDL

- C

PCSK9 Inhibition (Proprotein Convertase Subtilisin/Kexin type 9)

PCSK9

Mutation

LDL-C

Reduction

CHD

Reduction Population

Benn et al,

JACC 2010 R46L 12% 46%

1) Copenhagen City Heart

Study

2) Copenhagen General

Population Study

3) Copenhagen Ischemic Heart

Disease Study (DK)

Cohen et al,

NEJM 2006

R46L

Y142X or C679X

14%

28%

47%

88%

Atherosclerosis Risk

Community Study (US)

Population Studies:

PCSK9 Loss of Function Mutations • Patients with loss-of-function mutations in PCSK9 or total lack of PCSK9

– Have naturally low levels of LDL-C and reduced Coronary Heart Disease ( efficacy)

– Are not associated with other detectable abnormalities ( safety)

Benn, M. et al. J Am Coll Cardiol. 2010;55(25):2833–42; Cohen, JC. et al. N Engl J Med. 2006;354(12):1264–72.

PCSK9 Inhibitors Under Development

PCSK9 Inhibition (Proprotein Convertase Subtilisin/Kexin type 9)

PCSK9 enhances degradation of hepatic LDL receptors. Its Inhibition increases LDL receptors and decreases LDL-C

Recent Phase 2 trials

GAUSS – Statin intolerant pts due to muscle side effects

AMG 145 sc q 4 wk, -63% AMG+E vs. – 15 % E alone

• Rutherford – Heterozygous FH pts

AMG 145 420mg sc – 55% , 65% < 70mg LDL-C

• RN316 - primary hypercholesterolemia not goal on statin

RN 316 iv added to R/A/or S further – LDLC & + HDLC

Phase 3 trial

• ODYSSEY OUTCOMES - 18,000 patients with ACS compare statins to statins plus REGN 727

34

Ongoing PCSK9 inhibitor CVD outcomes trials (8 Reports on PCSK9 at ACC 2013)

All performed on background of high intensity or maximally tolerated statin therapy with > 50% further reduction LDL-C • LAPLACE-2 Evolocumab for 12 weeks 1117 pts Statin intolerant pts 63-75% LDLC vs. 20% with Ezetimibe • RUTHERFORD-2 Evolocumab 12 weeks with He FH 331 pts 80% Rx had LDL-C < 70 mg/dl vs. 2% control group • ODYSSEY OUTCOMES

– Alirocumab NCT01663402 – Acute coronary syndromes (N=18,000)

• FOURIER – Evolocumab NCT01764633 – Very high risk CVD (n=22,500)

• SPIRE 1 & 2 – Bococizumab NCT01975376 & NCT01975389 – High CVD risk (LDL-C >70 - <100 mg/dl n=>12,000; LDL-C >100 mg/dl

n=6300)

IMPROVE-IT

• A large scale (18,144 participants), multi-center RCT of high risk post Acute Coronary Syndrome (ACS) patients

• Intervention: ezetimibe 10 mg added to simvastatin 40*

• Comparator: simvastatin 40* Both groups achieved a mean LDL-C < 70 mg/dl

• Study took 9 years; f/u was 7 years

• No increase in side effects with the intervention *some uptitration allowed.

LDL-C and Lipid Changes in IMPROVE-IT

1 Yr Mean LDL-C TC TG HDL hsCRP

Simva 69.9 145.1 137.1 48.1 3.8

EZ/Simva 53.2 125.8 120.4 48.7 3.3

Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5

IMPROVE-IT slide set with permission

HR Simva* EZ/Simva* p-value

All-cause death 0.99 15.3 15.4 0.782

CVD 1.00 6.8 6.9 0.997

CHD 0.96 5.8 5.7 0.499 MI 0.87 14.8 13.1 0.002

Stroke 0.86 4.8 4.2 0.052

Ischemic stroke 0.79 4.1 3.4 0.008

Cor revasc ≥ 30d 0.95 23.4 21.8 0.107

UA 1.06 1.9 2.1 0.618

CVD/MI/stroke 0.90 22.2 20.4 0.003

Ezetimibe/Simva Better

Simva Better

Individual Cardiovascular Endpoints and CVD/MI/Stroke

0.6 1.0 1.4 *7-year event rates (%)

IMPROVE-IT slide set with permission

View from 35,000 Feet:

1) Study reaffirms the central role of intensive LDL reduction in the prevention of recurrent cardiac events (heart attack and stroke)

2) Results expand the options for additional “proven” * lipid lowering therapies *Shown to add incremental benefit and are safe when taken as directed

Does This Change the Guidelines?

2013 ACC-AHA Guidelines recommended high-intensity statin therapy for those with ACS, but expressly stated:

“Clinicians treating high risk patients who have a less than anticipated response to statins, who are unable to tolerate a less than recommended intensity of a statin or who are completely statin intolerant, may consider the addition of non-statin cholesterol lowering therapy”

New ACC/AHA Guidelines on Lipids:

Are PCSK9 Inhibitors

Poised for a

Breakthrough?

Sidney C. Smith, Jr. MD, FACC, FAHA

Professor of Medicine/Cardiology University of North Carolina at Chapel Hill

Immediate Past President


Nothing to Disclose

] YES !

If justified by outcomes and safety


Circulation June 29, 2004


Strategic Principles for Development

of National Clinical Guidelines

“Whereas the causes of CVD are common

to all parts of the world, the approaches

to its prevention at a societal or individual

level will differ between countries for

cultural, social, medical, and economic

reasons.”

Smith et al., Circulation June 29, 2004

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