2013 ACC/AHA Blood Cholesterol

Treatment Guidelines“Intensity Of Statin Therapy”

Aim to Reduce RISK … not at Target levels

DR.PRAVEEN NAGULA

Scope of guideline• to reduce atherosclerotic cardiovascular disease(ASCVD)risk

{RCTs,systematic analysis and metaanalysis of RCTs}.

• ASCVD – coronary heart disease(CHD),stroke,and peripheral arterial disease,all of presumed atherosclerotic origin.

• to provide strong evidence-based foundation.• only evidence from statin RCTs were used to develop

guidelines.****

• Comprehensive approach to lipid management for purposes with relation to ASCVD reduction only,not for complex lipid disorders.

What do present guidelines say.....

Patient centered approach rather than

one treatment fits all

What’s new in the guideline…?

Benefits of Statins• High intensity therapy – lowering LDL cholesterol by >50%.• Moderate intensity therapy - lowering LDL cholesterol by 30-50%.• Reduces ASCVD events across the spectrum of baseline LDL-C

levels > 70 mg/dl.• Relative reduction in ASCVD risk is consistent for primary and

secondary prevention.

Absolute reduction in ASCVD events is proportional to baseline absolute ASCVD risk.

Statin therapy only for individuals at increased ASCVD risk .

Who are to be benefited by Statins ?????

Primary prevention of ASCVD

• Based on the estimated absolute 10 yr risk of ASCVD (non fatal MI,CHD death,nonfatal and fatal stroke)…

• The omnibus CV risk calculator for

Pts without clinical ASCVD and LDL 70-189mg/dl Estimates 10 yr risk of ASCVD In diabetics ,for primary prevention

Not in pts with clinical ASCVD

Statin treatment:Recommendations

Primary prevention in patients with LDL>190mg/dl

Management

Evaluate for cause

Age>21 years LDL-C>190mg/dl

primary

High dose statin

I B

Maximum tolerated

dose

I B

LDL-C reduction of atleast 50%

IIaB

secondary

Evaluate and treat

accordingly

Primary prevention in patients with diabetes

Statins

Age

DiabetesLDLcholesterol70-189 mg/dl

40-75 yrs

Moderate intensity statins

I A

High intensity statins

with risk >7.5%

IIa B

<40 yrs,>75yrs

Balance between ASCVDbenefits and

adverse effects

IIa C

Age of the patient

10 yr ASCVD risk estimate

Patients without diabetes,primary preventionLDLcholesterol

70-189 mg/dl

>7.5%

40-75 yrs

Moderate to high intensity

therapy

I A

>75yrs

Assess risk,

benefits

5-7.5%

40-75 yrs

Moderate intensity therapy

IIa B

>75 yrs

Assess risks

benefits

Statins in Heart Failure,Hemodialysis patients

LDLcholesterol

>190 mg/dl

Pt had CAD, HTN,smoker,not on statins

Age 45 yrs

Start Statins to the

maximum tolerated

dose

Age 75 yrs

Assess risk,benefits

Pt diabetic,no

CAD,ASCVDrisk

>7.5%

High intensity statins

Pt not diabetic,noCAD

Evaluate secondary

causes

High dose statin

therapy

70-189 mg/dl

Pt CAD

Statins

Pt diabetic

Moderat dose

statins

Pt no h/o

CAD,DM2,

risk <7.5%

Assess risk,

benefits

Pt having CKD

No EBT for

statins

High- Moderate – and Low –Intensity Statin Therapy

Clinical application by Statin dose

STATINSHIGH INTENSITY THERAPY

MODERATE INTENSITY THERAPY

LOW INTENSITY THERAPY

Daily dose lowers LDL-C on average,by approximately ≥50%

Daily dose lowers LDL –C on average,by approximately 30-50%

Daily dose lowers LDL –C <30%

Atorvastatin (40) 80 mg

Atorvastatin 10 (20) mg

Simvastatin 10 mg

Rosuvastatin 20 (40) mg

Rosuvastatin (5) 10 mg

Pravastatin 10-20 mg

Simvastatin 20-40 mg

Lovastatin 20 mg

Pravastatin 40 (80) mg

Fluvastatin 20-40 mg

Lovastatin 40 mg Pitavastatin 1 mgFluvastatin XL 80 mgFluvastatin 40 mg bidPitavastatin 2-4 mg

Safety recommendations of statinsNHLBI ACC/AHA

CORLOE

1.Creatine Kinase,routinely not needed A III no benefiit A

2.Baseline CK in pts at risk of events E IIa C3.Baseline ALT before initiating statins B I B4.Decreasing the statin dose,if 2 consecutive values of LDL-C <40 mg/dl.

C IIb C

5.Simvastatin at 80 mg daily harmful B III harm A6.New onset diabetes on statin therapy,continue statins

B I B

7.If muscle symtpoms develop,discontinue,use again

E II a C

8.Confusional state,see secondary causes

E II b C

Monitoring statin treatment

What do guidelines say..

Lifestyle is the foundation for ASCVD risk reduction

Adhering to a healthy heart diet,Regular exercise habitsAvoidance of tobacco productsMaintenance of healthy weight

• Remains critical component both prior to and in concert with the use of cholesterol lowering drug therapies

What is the fate of nonstatins in guidelines

are they Ignored??

Niacin

Baseline hepatic transaminases,FBS,HBA1c

Hepatic transaminases elevations are higher

>2-3ULN

Persistent severe cutaneous symptoms,hyperglycemia,

acute gout

New onset AF,weight loss

Niacin

Start at low dose

Take niacin with food or aspirin

500 mg ER to 2000mgER

Bile acid sequestrants

Baseline TG

>300 mg/dl

250-299 mg/dl

Cholesterol absorption inhibitors

Baseline hepatic transaminases

Discontinue if ALT>3 times

occur

Fibrates

Gemfibrozil in patients on statin therapy

If TG>500mg/dl and benefit>risks

GFR<30 ml/min

Omega 3 fatty acids

Severe hypertriglyceridemia

Evaluate GI disturbances

I AIIa/IIbBIII

Secondary causes of hyperlipidemiaSecondary cause Elevated LDL - C ELEVATED TRIGLYCERIDES

DIET Saturated or trans fats,wt gain,anorexia

Wt gain,very low fat diets, high intake of refined carbohydrates,excessive alcohol intake

DISEASES Biliary obstruction ,nephrotic syndrome

Nephrotic syndrome, CKD,lipodystrophies

DRUGS Duiretics,cyclosporine,glucocorticoids,amiodarone

Oral estrogens,glucocorticoids,bile acid sequestrantsprotease inhibitors,retinoic acid,sirolimus,beta blockers,thiazides

ALTERED METABOLISM

Hypothyroidism,Obesity,pregnancy

Diabetes, hypothyroidism,obesity, pregnancy

Statins,niacin,ezetimbe C/I in pregnancy,lactation

Evolution of guidelines

NCEPATP I1988

NCEPATP II1993

NCEPATPIII2001

NCEPATP III

REVISED 2004

NCEPATP IV2013??

ACC/AHA2013

Basis for the New Guidelines

RCTs reviewed showed a consistent reduction in ASCVD events from Statins therapy in secondary and primary prevention, no ASCVD event reduction in those with NYHA class II-IV HF or receiving maintenance hemodialysis.

Only fixed doses of statins with placebo or untreated controls,comparison of high dose with moderate intensity statins.

No evaluation of the effect of titrated (dose adjusted) statin treatment to achieve prespecified LDL- C or non HDL-C goals.

Use of niacin to additionally lower non HDL –C,once an LDL target was achieved,did not further reduce ASCVD outcomes.(AIM HIGH trial)

The intensity of statin therapy is appropriate on those most likely to benefit.

• Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207 • AFCAPS-TEXCAPS, JAMA 1998;279:1615–1622• MEGA trial, Lancet 2006;368:1155–1163.

3 CQs –CQ1 - secondary,(19RCT)CQ2 – primary prevention (6RCT)CQ3 – comprehensive management,safety of each drug

Why other approaches ignored???

1.Treat to Target – widely used for past 15 yrs What is the target ? What is the additional risk reduction beyond one target lower

than other? adverse effects from multidrug therapy that occur in achieving

goal undertreatment with statins, overtreatment with nonstatins 2.lowest is best adverse effects? 3.lifetime risk long term follow up >15 yrs? statins>10yrs?

Why Target level therapy ignored..how came the picture of statin benefit groups?

Hypothesis or Evidence based..Myth or reality

A.Secondary Prevention Evidence – high intenisty therapy to maximally lower LDL –C than using a

target.

Ex – LDL –C 78mg/dl on a dose of atorvas 80 mg/dl –receiving EBT.

No data to show that adding a nonstatin drug to high intenisty statin therapy will provide incremental ASCVD risk reduction benefit with acceptable margin of safety.(AIM HIGH,ACCORD).

This patient may be exposed to adverse effects if started of a drug with no evidence of benefit,just because his LDLis more than arbitrarily level.

This is treated as a case of failure..for a lag of 8 mg/dl..Is it justifiable ???

AIM HIGH trial NewEngl J Med 2011;365:2255-67

ACCORD, N Engl J Med 2010;362:1563–74.

B.FH with LDL –C >190 mg/dl many does not achieve <100mg/dl. maximum may be 120 mg/dl on 3 drugs. These pts may have fallen short of target ,but their LDL –C

>50% ,more ASCVD risk reduction. Not treatment failures.C.Type2Diabetes : have lower LDL-C than with without diabetes. goal directed therapy encourages low statin doses,use of drugs

for addressing HDL-C/high TG. maximally tolerated therapy to be given primary importance.D.Estimated ASCVD >7.5%

Cholesterol Treatment Trialists Collaboration, Lancet 2012;380:581–90. Taylor F, Ward K, Moore TH et al. 2011:CD004816

Limitations• Clinical judgement required in pts,for whom RCT evidence is

insufficient• Younger adults< 40 yrs with <7.5% ASCVD risk for 10

yrs,high lifetime risk.• HIV pts,rheumatological pts,IBD pts.• RCTS,Systematic reviews,meta analysis of RCTs were taken

into consideration.

New Drugs

• Cholesterol ester transfer protein (CETP) inhibitors - Anacetrapib(DEFINE,REVEAL), dalcetrapib

• Ab to pro-protein convertase subtilisin/kexin 9 (PCSK9).

• Apolipoprotein B synthesis inhibitors - Mipomersen

• Microsomal triglyceride transfer protein (MTP) inhibitors,

• Thyroid hormone analogue Eprotirome

Future.. Primary prevention in >75 yrs age Alternate treatment strategies. Effectiveness of submaximal doses of statins vs nonstatins in

intolerant pts Evaluation of the incidence of new onset diabetes associated

with statin therapy. Outcomes of RCTs of new lipid modifying agents to determine

the incremental ASCVD reduction when added to statin therapy.

Future updates required for..

1.The treatment of Hypertriglyceridemia. 2.Use of NonHDL-C in decision making. 3.Whether on-treatment markers such as

apoB,Lp(a),LDLparticles are useful in guiding decisions. 4.Best approaches to use noninvasive imaging for refining

risk estimates to guide treatment. 5.Optimal age for starting treatment for reducing lifetime risk

of ASCVD. 6.What to do in pts with HF,hemodialysis. 7.Long term effects of statin associated new onset diabetes and

management.

Conclusions Patient centered approach is to be given importance rather than one treatment fits all concept. Statins to be given at high intenisty,moderate intensity doses but not

with target levels of attainment. Nonstatins give no ASCVD benefit in pts with high intensity statin

therapy. Use of lipoprotein a ,non HDLcholesterol levels assessment is not

recommended. Pts without ASCVD should be started of the statins after assessing 10 yr

risk by omnibus calculators. New onset diabetes due to statins needs further assessment in future. New drugs in pipeline,RCT s required for their incremental benefit in

ASCVD risk reduction when added to statins Lifestyle modification remains the key concept of the management of

blood cholesterol.

THANK YOU