Northwestern University Feinberg School of Medicine

Fixed Targets Don’t Add Incremental

Benefit to ASCVD Risk Reduction

Neil J. Stone MD, MACP, FACC, FAHA

Bonow Professor of Medicine

Feinberg School of Medicine

Dr. Stone has no disclosures

Dr. Stone doesn’t accept honoraria

from industry

Paradigm Shift

3

Prior cholesterol guidelines focused on LDL-C levels as

targets for intervention.

The new 2013 ACC-AHA guidelines endorse:

1) Increased focus on defining atrisk clinical groups

who benefit from statin therapy

2) Prioritizing interventions supported by strong

evidence

3) Endorsing clinicianpatient risk discussions for

primary prevention before statins are prescribed

& for those where RCT evidence is lacking

ACC-AHA GUIDELINES ASK THESE QUESTIONS:

a) Who merits consideration for statin treatment?

b) Does patient belong to a group that benefits?

c) Does therapy need to be adjusted based on

1) adequacy of effect

2) adherence

This requires follow-up lipids as indicated by

the guidelines

d) Non-statins: considered if a high risk group?

Why Choose RCTs for Guidelines?

2) Quantitative weighing of absolute risk reduction vs. adverse effects in defined populations a) Statins first choice as studied in RCTs b) Included many subgroups

1) Durability Class I Cardiology Guideline

Recommendations

91% retained if Level of Evidence A:

Multiple RCTs or meta-analyses JAMA 2014:311 (20);2092-2100.

2013 ACC-AHA Guidelines

Statins: Strong evidence first line drugs

to reduce ASCVD risk In groups that benefit:

Three high risk groups that benefit:

1) Clinical ASCVD

2) Diabetes 40-75 years with LDL-C ≥ 70 mg/dL

3) Severely elevated LDL-C ≥ 190 mg/dl

Two high risk groups with statin RCTs that do not benefit:

• Hemodialysis

• Higher grades of heart failure

2013 ACC-AHA Guidelines Fourth Group:

A lower risk primary prevention group

• No diabetes, LDL-C 70-190

• 10 year “hard” ASCVD risk ≥ 7.5%

• This selects 92% of those ≥ 50 with CKD

for statin treatment (Colantonio LD et al J Am Soc Nephrol. 2015;26(5):1173-80

But ASCVD risk doesn’t mean that statin

assignment is automatic!

Need clinician-patient risk discussion

Constant Relative Risk Reduction in

Multiple Subgroups Per-person RCT meta-analysis

Lancet 2010; 376: 1670-81

In all subgroups, about a 22% reduction in relative risk; so the higher the absolute risk, the greater the absolute risk reduction. You multiple absolute risk times fixed relative risk for approximate absolute risk reduction

Major difficulties with fixed targets 1) Accuracy of LDL-C

a) Fasting LDL-C (calc), non fasting LDL-C (calc) and

direct LDL-C accuracy don’t agree precisely:

b) What if you are at goal with one, but not the other?

2) Targets can result in additional therapy added but 1) Net benefit lacking

a) NNT is large: (NNT = number needed to treat)

b) Ezetemibe showed low NNT in very high risk

patients; if lower risk, then the LDL-C would

have to be much higher for comparable NNT

3) Net benefit lacking when additional drugs create safety issues including drug-drug interactions

4) Net benefit may be lacking if cost issues make

other needed therapy unaffordable

Major difficulties with fixed targets

5. Unknown rate of additional adverse effects to if multidrug therapy used to achieve a specific fixed target 6. Lower was not better in these RCTs. 1) Illuminate: Torcetrapib-atorvastatin (LDL-C: -27%) 2) HPS2-THRIVE: Niacin-lapropriprant (LDL-C -16%) 3) ACCELERATE: No benefit with evacetrapib despite increase in HDL & decrease in LDL (84 to 55 mg/dl) “Lower is better, but it matters how you get there and in whom.” Stone N.J. and Lloyd-Jones D.M. N Engl J Med 2015; 372:1564-1565. (April 16)

Fixed Targets Can Fail Consider:

60 yo man with Type 2 DM for 7 years who was not treated with a statin as LDL-C 95 mg/dl (<100 mg/dl)

He developed an acute coronary syndrome: Rx atorvastatin 10 mg/day and LDL-C fell to 69 mg/dl Comments:

1) Should have considered Rx based on risk; not withholding statin just because LDL-C <100 mg/dl.

2) Diabetes and CHD conveys highest risk; he needed high intensity statin or moderate intensity statin + ezetemibe; attaining LDL-C of 69 mg/dl is inadequate to address his risk

Northwestern University Feinberg School of Medicine

At any LDL-C, overall ASCVD Risk determines benefit

Treatment implication of “lower is better” –

The net benefit depends on level of risk! (Robinson J, Stone N Am J Card 2006)

CTT 2010: Meta-analysis of 26 RCTs (170,000 Participants

Relationship of changes in atheroma volume

to final LDL-C in IVUS studies (post-hoc)

R² = 0.58

-0.5

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0.5

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1.5

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1.5 1.75 2 2.25 2.5 2.75 3

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ath

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%)

Final LDL-C (mmol/L)

R2=0.47

Wierzbicki AS Modified After Nissen SE ; Int J Cin Pract 2008; 62 : 981

Puri R et al. Am J Cardiol 2014; 114 : 1465; used with permission by

N.Stone

Change in atheroma volume

Final LDL-C in mmol/L

Evidence: Risk Based Guideline

Outperforms Fixed Goals of ATP 3

1) More adult potentially eligible for statins compared to ATP3

-43 million (37.5%) 56 million (48.6%)

although no automatic statin assignment Pencina MJ, et al N Engl J Med. 2014 Apr 10;370(15):1422-31.

--Adherence to guidelines could prevent ~ 450, 000 ASCVD

events over 10 years

--Increase mainly in older adults; acknowledges risk discussion

2) Has greater accuracy and efficiency in identifying

increased risk of incident CVD and subclinical CAD,

particularly in intermediate-risk participants.

Pursnani A et al JAMA. 2015; 314(2):134-41

Evidence: Risk Based Guideline

Outperforms Fixed Goals of ATP 3

3) Better match risk level to amount of atherosclerosis

than targets of ATP III Johnson KM and Dowe DA. JACC 2014 Sep 2;64(9):910-9.

–Treats high-risk patients with greater burden

– Avoids treating low-risk with low burden

2013 ACC-AHA Guidelines Cost-Effective Treats more but with a low NNT (DPaixao ARM et al Circ Cardiovasc Qual Outcomes. 2014;7: Dallas Heart Study)

Cost effective down to 10 yr ASCVD risk as low as 5% Pandya A, Sy S, Cho S, Weinstein MC, Gaziano TA.. JAMA. 2015;314(2):142-50

Treats more, but more cost effective Galber PZ PLoS One. 2015 Sep 30;10(9):e0138092

Figure 5.

Statin Therapy:

Monitoring

Therapeutic

Response and

Adherence

2013 ACC-AHA Guidelines

Non-Statins Not First-Line Guidelines Stated: Use the maximum tolerated intensity of statin

But consider adding nonstatin drug therapy if:

• A less-than-anticipated therapeutic response persists

• ASCVD risk-reduction benefits outweigh the potential for

adverse effects in higher-risk persons:

- Clinical ASCVD <75 years of age

- Baseline LDL–C ≥190 mg/dL

- Diabetes mellitus 40 to 75 years of age

Nonstatin cholesterol-lowering drugs shown to reduce ASCVD

events in RCTs are preferred

Non Statins and IMPROVE-IT

Study RCT; Duration 6-7 yrs

Population: High Risk Secondary Prevention

(Acute Coronary Syndrome with One High Risk Feature)

Intervention/Comparator

• Simvastatin 40 + Ezetemibe 10 mg vs. Simvastatin 40 + Placebo

Results: -LDL-C 69 to about 54 in intervention arm

-No safety signal of harm

CVD Outcomes:

No effect on total mortality (not powered to do so)

But reduced rate of ischemic stroke (RRR -21%)

and reduced rate of MI (RRR -13%)

Cannon CP, Blazing MA, Gugliano RP et al.

IMPROVE-IT Investigators. N Engl J Med. 2015 Jun 18;372(25):2387-97.

Non Statins and IMPROVE-IT

Significance (continued)

1) Diabetic patients seemed to show a greater benefit with

ezetimibe/simvastatin

–Those at highest absolute risk benefit from incremental

LDL-C lowering

2) Trial reaffirms that clinical benefit is proportional to the

extent of LDL-C lowering, but note that it matters how you

get there and in whom (not a trial of low risk patients)

Non Statins and IMPROVE-IT

Significance (continued)

Consider 2 patients with coronary disease both on a moderate

intensity statin :

Which one has enough absolute risk reduction to give a low

number needed to treat?

Patient A is at goal; Patient B is not; Patient A has net benefit

from further LDL-C lowering therapy; not clear net benefit for

patient B especially if you factor in costs.

Acute Coronary Syndrome

Diabetes LDL-cholesterol

Patient A Yes Yes 69 mg/dl

Patient B No No 78 mg/dl

2016 ACC Expert Consensus

Decision Pathway

Acknowledges that there can be significant discrepancies in levels of directly measured versus calculated LDL-C within the same sample, especially at lower LDL-C levels

The uncertainty in LDL-C measurement provides further support for the Committee’s position that the thresholds for consideration of net ASCVD risk-reduction benefit should merely be factors to be considered and not firm triggers for intensification of therapy.

Ref: 2016 016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk JACC 2016

1) Evidence shows that follow-up lipid testing as recommended by the 2013 ACC AHA guidelines (with a focus on adequacy of effect (% lowering), adherence and safety is supported by multiple lines of evidence.

2) A focus on fixed targets especially as performance measures isn’t supported by high quality RCTs

3) Fixed targets can result in confusion when accuracy of various methods for measuring LDL-C is taken into account

4) Fixed targets can lead to unnecessary cost and increased harms

ACC May Meeting- 2016

25

Lancet 2015; 385: 2264–71

A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy

2016 ACC Expert Consensus Decision

Pathway Writing Committee

Judged that it was appropriate to provide levels of LDL-C, or “thresholds”, in terms of both percentage LDL-C reduction from baseline and absolute on-treatment LDL-C measurement, which, if not achieved by adherent patients, would serve as factors to consider in decision making regarding further therapy.

The Writing Committee emphasizes that these are not firm triggers for adding medication but factors that may be considered within the broader context of an individual patient’s clinical situation.

Paradigm Shift The new cholesterol guidelines changed ASCVD

risk reduction through cholesterol lowering with:

1) increased focus on defining atrisk clinical benefit

groups;

2) prioritizing interventions supported by strong

evidence;

3) endorsing clinicianpatient risk discussions

not automatic statin prescription;

4) For those in whom initial evidence based therapy

is judged inadequate,

an ACC Clinical Expert Consensus Panel has

offered further recommendations