Old vs new targets april 2015

Lipids: Old vs. New Targets

Henry Tran, MD, MSc

April 24th, 2015

Disclosures

• None

Goals

• ATP III and CHD Risk Assessment

• Major Trials after ATP III

• Review the 2013 Guidelines for Cholesterol treatment

• 4 Groups that Benefit from Statin

• ASCVD Risk Assessment

• Future Directions

ATP III Guidelines

NCEP. NIH 2002

• Extended ATP II guidelines to lower LDL goals in patients without CHD

• Risk model included risk factors or global risk for CHD

• Diabetes as CHD risk equivalent• LDL-C < 100 mg/dL is “optimal”

Clinical Case #1

• Mr. Simon is a 60 yo man with no significant PMHx. He presents for his annual physical feeling well. He doesn’t smoke. Jogs 4x/wk.

• BP 122/84 HR 68 BMI 24.3 kg/m2

• Total Chol 180, HDL-C 40, LDL-C 108.

• A1c 5.4%

• He asks if his cholesterol should be treated?

Clinical Case #1

No, 10 yr CHD risk < 10%. LDL-C is already lower than goal

Major Trials after ATP III

• 2005 Treating to New Targets (TNT)

• 2008 JUPITER

• 2010 ACCORD-LIPID

• 2011 AIM-HIGH

Treating to new Targets (TNT)

• 10,000+ patients with CVD randomized to Atorvastatin 10 mg vs Atorvastatin 80mg for 5 years

LaRosa et al. NEJM 2005

LDL-C Total Chol Trig HDL-C

10mg 101 178 156 47

80mg 77 150 132 47

Mean Lipid Levels (mg/dL) During the Study

Outcomes of TNT

• 1o: Reduced Major CV events driven by reduced non-fatal MI (HR 0.78, p<.0002)

• No change in CV Death (HR 0.80, p=0.09)

• No difference in overall mortality (insufficient power)

• Atorvastatin 80mg:

– More adverse events (p<0.001)

– Signal for increased non-CV death

LaRosa et al. NEJM 2005

JUPITER Trial

• 17,802 patients without CVD randomized to rosuvastatin 20mg vs placebo

• Mean age: 66 yo• Metabolic Syndrome: 41 %• All patients hs-CRP ≥ 2• Stopped early after 1.9 years (5 years planned)

Ridker PM et al. NEJM 2008

LDL-C Trig HDL-C

Rosuvastatin 20mg 55 99 50

Placebo 109 108 50

Mean Lipid Levels (mg/dL) During the Study

Ridker PM et al. NEJM 2008

ACCORD Lipid

ACCORD Study Group. NEJM 2010; 362:1563-74.

• 5518 pts T2DM treated with simvastatin randomized to fenofibrate or placebo

• The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes.

• Possible benefit in men but harm in women (P=0.01 for interaction)

ACCORD LipidPrimary Outcome: First occurrence of nonfatal MI, nonfatal stroke, or CV death

ACCORD Study Group. NEJM 2010; 362:1563-74.

AIM-HIGH Trial• 3414 patients with CVD randomized to simvastatin

vs simvastatin + niacin

• Goal LDL 40-80 mg/dL, pts could receive ezetimibe10mg

• 1o: First event of CV death, nonfatal MI, CVA, hospitalization for ACS, or revascularization Stopped early due to futility

AIM-HIGH Investigators. NEJM 2011

LDL-C Total Chol Trig HDL-C

Simvastatin 68 141 152 39

Simvastatin + niacin 65 137 120 44

Mean Lipid Levels (mg/dL) at 3 years of the Study

AIM-HIGH Primary Outcome

AIM-HIGH Investigators. NEJM 2011

Results

Fenofibrates

Statins for Secondary Prevention

Niacin (HDL Hypothesis)

Statins for Primary Prevention

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic

Risk in Adults

• 2008 Task Force convened by NHLBI

– Used data from 1995 – 2009, additional data until July 2013 added

• 2013 writing was transferred to ACC/AHA

• Two clinical questions:– What is the evidence for LDL–C and non-HDL–C goals for

the secondary prevention of ASCVD?

– What is the evidence for LDL–C and non-HDL–C goals for the primary prevention of ASCVD?

Stone et al. JACC 2013.

New Areas in the Guidelines

• 4 Groups with statin benefits

• A new perspective on lipid goals– No RCT evidence to support continued use of targets

– Non-statin therapies

• Global risk assessment for ASCVD– Pooled Cohort Equation

– Abandoned Framingham 10 years CHD Risk

• Safety Recommendations

• Monitoring therapy

Clinical Question

• Mr. Jones is a 73 yo man with ischemic cardiomyopathy. He had an MI 6 years ago s/p stent to LAD . At that time LVEF 35%. He complains of mild ankle edema and dyspnea after 1/4 mile walking.

• LDL-C 137 HDL-C 48

• He has been taking aspirin 81 mg.

• Would you add a statin to his regiment?

Statin Benefit Groups

Excluding patients with heart failure symptoms or hemodialysis-dependent

LDL > 190 mg/dL

10-year ASCVDRisk > 7.5%

Diabetic Patients(40-75 yo)

Established Atherosclerosis


CORONA Trial

• 5011 pts NYHA II-IV randomized to rosuvastatin 10mg vsplacebo for ~3 years

• 60% hx of MI• LVEF 31%• Baseline

– LDL-C 138 mg/dl– HDL-C 48 mg/dl

Kjekshus et al. NEJM 2007

CORONA Trial

• Rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic heart failure, although the drug did reduce the number of cardiovascular hospitalizations.

Kjekshus et al. NEJM 2007

Established ASCVD

<75 yo > 75 yo

First Choice High-intensity- Atorvastatin 80mg or- Rosuvastatin 20mg

Moderate-intensity

Second Choice Moderate-Intensity Individualize therapy


Statin Therapy Intensity

High-Intensity Moderate-Intensity Low-Intensity

LDL-C reduction >50% LDL-C 30%-<50% LDL-C Reduction <30%

Atorvastatin (40)-80 mgRosuvastatin 20 (40) mg

Atorvastatin 10 (20) mgRosuvastatin (5) 10mgSimvastatin 20-40 mgPravastatin 40 (80) mgLovastatin 40 mgFluvastatin XL 80mgFluvastatin 40mg BIDPitavastatin 2-4mg

Simvastatin 10mgPravastatin 10-20 mgLovastatin 20mgFluvastatin 20-40 mgPitavastatin 1 mg


Hyperlipidemia (LDL-C > 190)Secondary Cause Elevated LDL-C Elevated Triglycerides

Diet Saturated or trans fats, weight gain, anorexia

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

Drugs Diuretics, cyclosporine, glucocorticoids, amiodarone

Oral estrogens, glucocorticoids, bile acid sequestrants, protease inhibitors, retinoic acid, anabolic steroids, sirolimus, raloxifene, tamoxifen, beta blockers (not carvedilol), thiazides

Disease Biliary obstruction, nephrotic syndrome

Nephrotic syndrome, chronic renal failure, lipodystrophies

Disorders andaltered states of metabolism

Hypothyroidism, obesity, pregnancy*

Diabetes (poorly controlled), hypothyroidism, obesity; pregnancy*

*Cholesterol and triglycerides rise progressively throughout pregnancy ; treatment with statins, niacin, and ezetimibe are

contraindicated during pregnancy and lactation.


Hyperlipidemia

• Evaluate family for familial hypercholesterolemia (FH)

• Reasonable to start high-intensity statin (goal < 50% reduction of LDL-C)

• Non-statin medications are often needed to lower to “acceptable levels”


Patients with Diabetes

• Since 2012, ADA Standard of Care recommend statin therapy to all diabetics regardless of baseline LDL-C

• High-intensity statin to diabetics with 10 year ASCVD risk > 7.5%

ADA. VI. Prevention, Management of Complications. Diabetes Care 2013

10 yr ASCVD Risk > 7.5%

• Unclear where cutoff was derived

• >7.5%: moderate to high-intensity statin (~45% RR)

• 5-7.5%: moderate-intensity statin (~30 RR)

• Engage in discussion:– ASCVD risk reduction benefits

– Adverse events ( Diabetes)

– Drug-Drug Interactions

– Patient Preferences


New Risk Calculator

• Pooled Cohort Equations for 10yr risk of CVD (risk of hard CV events: first MI, CV death, CVA) age 40-80

– Sex specific

– Race specific

• Other covariates similar to prior – age, BP, HTN, lipids, smoking, DM

• Reassess every 4-6 years


Other Risk Factors (if calculator insufficient)

• Class IIb recommendations

– Family history

– CRP

– Calcium score

– ABI

• Class III recommendation – Routine carotid intima media thickness

• Unknown – ApoB, CKD

Clinical Case #1

• Mr. Simon is a 60 yo man with no significant PMHx. He presents for his annual physical feeling well. He doesn’t smoke. Jogs 4x/wk.

• BP 122/84 HR 68 BMI 24.3 kg/m2

• Total Chol 180, HDL-C 40, LDL-C 108

• A1c 5.4%

• He asks if his cholesterol should be treated?

10 Year ASCVD Risk

10 year risk of ASCVD: 8.2%10 year with optimal risk factors 5.7%

Cholesterol Goals

• Panel removed treat-to-goal paradigm

– Unclear what target should be

– RCT evidence shows maximum tolerated statin dose is most effective

• No routine role for non-statin therapies to get to a goal

• Check lipids only to assess effect (high dose statin 50% reduction, mod dose 30-50%)


Follow-up

• Repeat lipid testing 4-12 weeks after to monitor adherence and biologic response.

• Repeat lipids every 3-12 months thereafter

• CK and ALT monitoring are NOT recommended

• Reinforce adherence of lifestyle changes

Statin Benefit Groups

Excluding patients with heart failure symptoms or hemodialysis-dependent

LDL > 190 mg/dL

10-year ASCVDRisk > 7.5%

Diabetic Patients(40-75 yo)

Established Atherosclerosis


Fibrates

• Gemfibrozil should not be initiated in statin users (Class III: Harm)

• Fenofibrate should not be used in patients with GFR < 30 mL/min (Class III: Harm)

• Fenofibrate may be considered for use in low-or moderate-intensity statin users if Trig >500 or ASCVD reduction deemed beneficial (Class IIB).


Future Directions

• Evidence gaps:

– RCT data for patients > 75 yo on statins

– Outcomes of treat to lipid or apolipoproteintargets

– Clinical outcomes of new-onset DM associated with statin therapy

– RCT of new lipid-modifying treatments


Potential Future Therapies

• PCSK9 inhibitors reduce the degradation of hepatic LDL receptors

Zhang et al. Int j Biol Sci 2012

OSLER• OSLER-1 and -2 4,465

patients randomized open-label treatment with evolocumab (140 mg sq every 2 weeks or 420 mg monthly) vsstandard therapy

• CV events nearly reduced by 50%

Sabitine MS, et al. NEJM 2015

ODYSSEY Long-Term• 2,300 patients

raondomized to 150 mg of alirocumab or placebo as a 1-mL subcutaneous injection every 2 weeks for 78 weeks.

• MACE reduced to 1.7% in the alirocumabgroup vs 3.3% in the placebo group (p=0.02)

Thank You

SEARCH Trial

• Lower is Better Hypothesis:

– Examined high vs low dose simvastatin

• Homocysteine

IDEAL Trial

• Atorvastatin 80mg vs Simvastatin 20mg

• No significant difference in vascular events

• No difference in mortality or CV death

Old vs new targets april 2015

Health & Medicine

Transcript of Old vs new targets april 2015