Niacin Use in Patients with Low HDL-Cholesterol Receiving Intensive Statin Therapy William E. Boden, MD, FACC, FAHA Jeffrey Probstfield, MD, FACC, FAHA.

Niacin Use in Patients Niacin Use in Patients with Low HDL-Cholesterolwith Low HDL-Cholesterol

Receiving Intensive Statin TherapyReceiving Intensive Statin Therapy

William E. Boden, MD, FACC, FAHAWilliam E. Boden, MD, FACC, FAHAJeffrey Probstfield, MD, FACC, FAHAJeffrey Probstfield, MD, FACC, FAHA

Co-Principal InvestigatorsCo-Principal Investigatorson behalf of the AIM-HIGH Investigatorson behalf of the AIM-HIGH Investigators

American Heart AssociationAmerican Heart AssociationAnnual Scientific SessionsAnnual Scientific Sessions

Orlando, FLOrlando, FLNovember 15, 2011November 15, 2011

AIM-HIGH TrialAIM-HIGH TrialAAtherothrombosistherothrombosis

IIntervention in ntervention in

MMetabolic Syndrome with Low etabolic Syndrome with Low

HHDL/High Triglycerides and DL/High Triglycerides and

IImpact onmpact on

GGlobal lobal

HHealth Outcomesealth Outcomes

BackgroundBackground The direct relationship between increased The direct relationship between increased

LDL-C levels and increased CV risk is firmly LDL-C levels and increased CV risk is firmly established, as is the important role of statins established, as is the important role of statins in reducing CV events by 25%-35%in reducing CV events by 25%-35%

Residual risk persists despite achieving Residual risk persists despite achieving recommended levels of LDL-C on statin recommended levels of LDL-C on statin therapytherapy

A significant, inverse relationship exists A significant, inverse relationship exists between low levels of HDL-C and incident between low levels of HDL-C and incident CV eventsCV events

Evidence from Prior Placebo-Controlled Trials Evidence from Prior Placebo-Controlled Trials Supporting Niacin or Fibrate BenefitSupporting Niacin or Fibrate Benefit

Coronary Drug ProjectCoronary Drug Project (1975) (1975) 5-year follow-up 5-year follow-up • Immediate-release niacin (3,000 mg/day)Immediate-release niacin (3,000 mg/day)• Reduced CHD Death/MI by Reduced CHD Death/MI by 14%14%• Reduced non-fatal MI by Reduced non-fatal MI by 26%26%• Reduced stroke/TIA by Reduced stroke/TIA by 21%21%

VA-HITVA-HIT (1999) (1999) 5-year follow-up 5-year follow-up • Gemfibrozil vs. placebo (no statin therapy)Gemfibrozil vs. placebo (no statin therapy)• Reduced CHD Death/MI by Reduced CHD Death/MI by 22%22%

HATSHATS (2001) (2001) 3-year follow-up 3-year follow-up • niacin + simvastatin niacin + simvastatin • regression of angiographic coronary stenoses and regression of angiographic coronary stenoses and

reductions in clinical eventsreductions in clinical events

ObjectiveObjective

To determine whether the residual risk To determine whether the residual risk associated with low levels of HDL-C in associated with low levels of HDL-C in patients with established CHD whose LDL-C patients with established CHD whose LDL-C therapy was optimized with statins ± therapy was optimized with statins ± ezetimibe would be mitigated with extended-ezetimibe would be mitigated with extended-release niacin vs. placebo during long-term release niacin vs. placebo during long-term follow-upfollow-up

HypothesisHypothesis

Combination dyslipidemic therapy with high-Combination dyslipidemic therapy with high-dose extended-release niacin (1,500-2,000 dose extended-release niacin (1,500-2,000 mg/day), when added to intensive LDL-C mg/day), when added to intensive LDL-C lowering therapy, will be superior to intensive lowering therapy, will be superior to intensive LDL-C lowering therapy alone in reducing the LDL-C lowering therapy alone in reducing the risk of CV events in patients with established risk of CV events in patients with established atherosclerotic cardiovascular disease and atherosclerotic cardiovascular disease and low baseline levels of HDL-cholesterollow baseline levels of HDL-cholesterol

Entry CriteriaEntry Criteria Patients Age ≥ 45 Years withPatients Age ≥ 45 Years with

• Coronary Heart Disease (CHD), orCoronary Heart Disease (CHD), or

• Cerebrovascular Disease (CVD), orCerebrovascular Disease (CVD), or

• Peripheral Arterial Disease (PAD)Peripheral Arterial Disease (PAD)

And DyslipidemiaAnd Dyslipidemia

• Low Levels of Baseline HDL-C Low Levels of Baseline HDL-C

<40 mg/dL for men; < 50 mg/dL for women; <40 mg/dL for men; < 50 mg/dL for women;

• Triglycerides 150-400 mg/dL; Triglycerides 150-400 mg/dL;

• LDL-C < 180 mg/dLLDL-C < 180 mg/dL

Adjust simva to LDL 40 – 80 mg/dL

Adjust simva to LDL 40 – 80 mg/dL

Study DesignStudy Design

Months Relative to RandomizationMonths Relative to Randomization

-2-2 -1-1 00 11 22 33 66 1212

Open-Label Run-In: Up-Titrate Niacin

from 500mg to 2,000mg/day

4-8 weeks

Open-Label Run-In: Up-Titrate Niacin

from 500mg to 2,000mg/day

4-8 weeks

Follow to end

of study

Follow to end

of study

ER Niacin ER Niacin + 40-80 mg/day + 40-80 mg/day simvastatinsimvastatin

PlaceboPlacebo + 40-80 mg/day + 40-80 mg/day simvastatinsimvastatin

R

Study PopulationStudy PopulationScreenedScreenedN=8,162N=8,162

Began Open Label Run-inBegan Open Label Run-inN=4,275N=4,275

RandomizedRandomizedN=3,414N=3,414

Niaspan + Niaspan + Simvastatin 40-80mgSimvastatin 40-80mg

N=1,718N=1,718

Placebo + Placebo + Simvastatin 40-80mgSimvastatin 40-80mg

N=1,696N=1,696

EndpointsEndpoints Primary Outcome Composite (Time to First Primary Outcome Composite (Time to First

Occurrence):Occurrence):• Coronary Heart Disease DeathCoronary Heart Disease Death• Non-Fatal MINon-Fatal MI• Ischemic (Non-Hemorrhagic) StrokeIschemic (Non-Hemorrhagic) Stroke• Hospitalization for ACSHospitalization for ACS• Symptom-Driven RevascularizationSymptom-Driven Revascularization

Secondary Composite Endpoints:Secondary Composite Endpoints:• CHD Death, Non-Fatal MI, Ischemic Stroke, or CHD Death, Non-Fatal MI, Ischemic Stroke, or

Hospitalization for High-Risk ACS Hospitalization for High-Risk ACS • CHD Death, Non-Fatal MI or Ischemic StrokeCHD Death, Non-Fatal MI or Ischemic Stroke• Cardiovascular Mortality Cardiovascular Mortality

Statistical AnalysesStatistical Analyses Event-driven trial with projected 800 primary outcomes; Event-driven trial with projected 800 primary outcomes;

2.5-7 year follow-up (mean 4.6 years)2.5-7 year follow-up (mean 4.6 years)

85% power to detect a 25% reduction in the 5-85% power to detect a 25% reduction in the 5-component primary endpoint (one-sided test of component primary endpoint (one-sided test of significance; alpha level=0.025significance; alpha level=0.025

Pre-specified, conservative asymmetric boundaries for Pre-specified, conservative asymmetric boundaries for potential early stopping based on efficacy/lack of efficacypotential early stopping based on efficacy/lack of efficacy

Trial stopped on 5/25/11: lack of efficacy and concern of Trial stopped on 5/25/11: lack of efficacy and concern of ischemic stroke imbalance with niacin after a ischemic stroke imbalance with niacin after a 36-month 36-month average follow-upaverage follow-up

Selected Baseline CharacteristicsSelected Baseline Characteristics

Number randomizedNumber randomized 3,4143,414

Mean (SD) ageMean (SD) age 64±9 64±9

MaleMale 85%85%

CaucasianCaucasian 92%92%

Current smokersCurrent smokers 20%20%

History of HypertensionHistory of Hypertension 71%71%

History of DiabetesHistory of Diabetes 34%34%

Metabolic SyndromeMetabolic Syndrome 81%81%

History of MIHistory of MI 56%56%

History of Cerebrovascular History of Cerebrovascular DiseaseDisease

21%21%

All baseline characteristics balanced between treatment groupsAll baseline characteristics balanced between treatment groups

Concomitant Medications at EntryConcomitant Medications at Entry

On a StatinOn a Statin 94%94%

Duration of Statin Therapy*Duration of Statin Therapy*

≥ ≥ 1 year1 year 76%76%

≥ ≥ 5 years5 years 40%40%

Prior Niacin UsePrior Niacin Use 20%20%

ASA/Antiplatelet TherapyASA/Antiplatelet Therapy 98%98%

ΒΒeta-Blockereta-Blocker 80%80%

ACEI / ARBACEI / ARB 74%74%

Use of all secondary prevention therapies wasUse of all secondary prevention therapies was

well-balanced between treatment groupswell-balanced between treatment groups*Duration of statin therapy not ascertained in 6%*Duration of statin therapy not ascertained in 6%

Baseline Lipids (mg/dL)Baseline Lipids (mg/dL)

On StatinOn Statin Off Statin Off Statin

LDL-C LDL-C (mean)(mean)

(n=3,196)(n=3,196)

7171

(n=218)(n=218)

12591259

HDL-C HDL-C (mean)(mean) 3535 3333

Triglycerides Triglycerides (median)(median)

161161 215215

Non-HDL Non-HDL (mean)(mean) 107107 165165

Apo-BApo-B (mean) (mean) 8181 111111

Simvastatin Dose and Ezetimibe UseSimvastatin Dose and Ezetimibe Use

Mono-Mono-therapytherapy

Combination Combination TherapyTherapy

P-valueP-value

Simva Dose:Simva Dose:

< 40 mg/day< 40 mg/day 11%11% 19%19%

40 mg/day40 mg/day 50%50% 50%50% 0.0180.018

> 40 mg/day> 40 mg/day 25%25% 18%18%

On EzetimibeOn Ezetimibe 22%22% 10%10% < 0.001< 0.001

}

HDL-C at Baseline & Follow-upHDL-C at Baseline & Follow-up

*

Triglycerides at Baseline and Follow-upTriglycerides at Baseline and Follow-up

LDL-C at Baseline & Follow-upLDL-C at Baseline & Follow-up

P < 0.001

*

Primary & Secondary EndpointsPrimary & Secondary Endpoints

Hazard Ratio

95% CI

Primary Endpoint 1.02 0.87, 1.21

Secondary Endpoints

CHD Death, MI, Ischemic Stroke, High-Risk ACS

1.08 0.87, 1.34

CHD Death, MI, Ischemic Stroke

1.13 0.90, 1.42

Cardiovascular Death

1.17 0.76, 1.80

Time (years)Time (years)

Cu

mu

lati

ve %

wit

h P

rim

ary

Ou

tco

me

Cu

mu

lati

ve %

wit

h P

rim

ary

Ou

tco

me

00

1010

2020

3030

4040

5050

00 11 22 33 44

MonotherapyMonotherapyCombination TherapyCombination Therapy

HR 1.02, 95% CI 0.87, 1,21HR 1.02, 95% CI 0.87, 1,21Log-rank P value= 0.79Log-rank P value= 0.79

N at riskN at risk

MonotherapyMonotherapy

Combination TherapyCombination Therapy

16961696

17181718

15811581

16061606

13811381

13661366

910910

903903

436436

428428

Primary OutcomePrimary Outcome

16.2%

16.4%

Primary and Secondary EndpointsPrimary and Secondary Endpoints

All Cardiovascular DeathAll Cardiovascular Death

non-fatal MInon-fatal MI or ischemic strokeor ischemic stroke

Composite of CHD Death, Composite of CHD Death,

hospitalization for high-risk ACS)hospitalization for high-risk ACS)

(CHD death, non-fatal MI, ischemic stroke,(CHD death, non-fatal MI, ischemic stroke,

Original Primary EndpointOriginal Primary Endpoint

or Cerebral Revascularizationor Cerebral Revascularization

Symptom-Driven CoronarySymptom-Driven Coronary

Hospitalization for ACSHospitalization for ACS

Ischemic StrokeIschemic Stroke

Non-fatal MINon-fatal MI

CHD DeathCHD Death

Primary EndpointPrimary Endpoint

0.50.5 11 1.51.5 22 2.52.5 33 3.53.5Niacin worse Niacin worse Niacin Niacin

betterbetter

P=0.11

Pre-Specified SubgroupsPre-Specified Subgroups

OFF Statin at EntryOFF Statin at EntryON Statin at EntryON Statin at Entry

No Prior MINo Prior MIPrior MIPrior MI

No Metabolic SyndromeNo Metabolic SyndromeMetabolic SyndromeMetabolic Syndrome

No DiabetesNo DiabetesDiabetesDiabetes

WomenWomenMenMen

Age < 65 yearsAge < 65 yearsAge ≥ 65 yearsAge ≥ 65 years

OverallOverall

0.50.5 11 1.51.5 22Niacin worse Niacin worse Niacin betterNiacin better

Interpretation of Study Findings Interpretation of Study Findings and Therapeutic Implicationsand Therapeutic Implications

Contemporary optimal medical therapy and aggressive Contemporary optimal medical therapy and aggressive secondary prevention (particularly with intensive LDL-secondary prevention (particularly with intensive LDL-C lowering therapy) may make it increasingly difficult C lowering therapy) may make it increasingly difficult to demonstrate incremental treatment superiority to demonstrate incremental treatment superiority

Previous therapy in patients receiving statins (94%) Previous therapy in patients receiving statins (94%) and niacin (20%) may have limited our ability to and niacin (20%) may have limited our ability to demonstrate a favorable treatment effect with niacindemonstrate a favorable treatment effect with niacin

The unexpected 9.8% increase in HDL-C in placebo-The unexpected 9.8% increase in HDL-C in placebo-treated patients could have minimized between-group treated patients could have minimized between-group event rate differencesevent rate differences

Interpretation of Study Findings Interpretation of Study Findings and Therapeutic Implicationsand Therapeutic Implications

? Intensive use of statin therapy for ≥1 year in ~ ? Intensive use of statin therapy for ≥1 year in ~ 75% of patients may have caused 75% of patients may have caused ““delipidationdelipidation”” of of lipid-rich necrotic cores, converting high-risk lipid-rich necrotic cores, converting high-risk vulnerable plaques → stable, quiescent plaquesvulnerable plaques → stable, quiescent plaques

Residual risk in AIM-HIGH patients during follow-Residual risk in AIM-HIGH patients during follow-up up waswas appreciable (5.4% event rate/year), but appreciable (5.4% event rate/year), but was not mitigated by niacinwas not mitigated by niacin

Whether niacin benefit might have been discerned Whether niacin benefit might have been discerned during a longer follow-up remains uncertainduring a longer follow-up remains uncertain

ConclusionsConclusions Among patients with stable, non-acute, Among patients with stable, non-acute,

cardiovascular disease and LDL-C levels of <70 cardiovascular disease and LDL-C levels of <70 mg/dL, there was no incremental clinical benefit mg/dL, there was no incremental clinical benefit from the addition of niacin to statin therapy during from the addition of niacin to statin therapy during a 36-month follow-up, despite significant a 36-month follow-up, despite significant improvements in HDL-C and triglycerides improvements in HDL-C and triglycerides

AIM-HIGH reaffirms current NCEP ATP-III AIM-HIGH reaffirms current NCEP ATP-III treatment guidelines for LDL-C lowering as the treatment guidelines for LDL-C lowering as the principal target of lipid treatment principal target of lipid treatment

Additional analyses will be required to determine Additional analyses will be required to determine if certain subsets of patients with low HDL-C in if certain subsets of patients with low HDL-C in AIM-HIGH may benefit from niacin treatment AIM-HIGH may benefit from niacin treatment

Study OrganiizationStudy OrganiizationExecutive CommitteeExecutive Committee: : Clinical Events Committee: Clinical Events Committee: DCC:DCC:

W.E. Boden (Co-Chair)W.E. Boden (Co-Chair) B.R. Chaitman (Chair)B.R. Chaitman (Chair) J. L. Probstfield (Co-Dir.) J. L. Probstfield (Co-Dir.)

J.L. Probstfield (Co-Chair)J.L. Probstfield (Co-Chair) D. Anderson R. McBride (C-Dir.)D. Anderson R. McBride (C-Dir.)

T. AndersonT. Anderson R. BachR. Bach J. Kaiser J. Kaiser

B.R. ChaitmanB.R. Chaitman S. Cruz-FloresS. Cruz-Flores K. Seymour K. Seymour

P. Desvigne-NickensP. Desvigne-Nickens G. GosselinG. Gosselin S. Claire S. Claire

J. FlegJ. Fleg S. NashS. Nash B. Ricker B. Ricker

M. KashyapM. Kashyap C. SilaC. Sila C. Wallum C. Wallum

S. MarcovinaS. Marcovina DSMB:DSMB: ECG Core LabECG Core Lab::

R. McBride, PhDR. McBride, PhD J. Wittes (Chair)J. Wittes (Chair) B. R. Chaitman B. R. Chaitman

M. McGovernM. McGovern D. ArnettD. Arnett Northwest Lipid MetabolismNorthwest Lipid Metabolism

K.K. TeoK.K. Teo J. LaRosaJ. LaRosa & Diabetes Research Lab: & Diabetes Research Lab:

W.S. WeintraubW.S. Weintraub E. MeslinE. Meslin S. Marcovina S. Marcovina

T. OrchardT. Orchard

K. WatsonK. Watson

Participating CentersParticipating Centers

Published NEJM 11/15/2011 (online)Published NEJM 11/15/2011 (online)