Niacin Use in Patients Niacin Use in Patients with Low HDL-Cholesterol with Low HDL-Cholesterol Receiving Intensive Statin Receiving Intensive Statin Therapy Therapy William E. Boden, MD, FACC, FAHA William E. Boden, MD, FACC, FAHA Jeffrey Probstfield, MD, FACC, FAHA Jeffrey Probstfield, MD, FACC, FAHA Co-Principal Investigators Co-Principal Investigators on behalf of the AIM-HIGH Investigators on behalf of the AIM-HIGH Investigators American Heart Association American Heart Association Annual Scientific Sessions Annual Scientific Sessions Orlando, FL Orlando, FL November 15, 2011 November 15, 2011
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Niacin Use in Patients Niacin Use in Patients with Low HDL-Cholesterolwith Low HDL-Cholesterol
AIM-HIGH TrialAIM-HIGH TrialAAtherothrombosistherothrombosisIIntervention in ntervention in MMetabolic Syndrome with Low etabolic Syndrome with Low
HHDL/High Triglycerides and DL/High Triglycerides and IImpact onmpact onGGlobal 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 CV between low levels of HDL-C and incident CV eventsevents
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
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-component 85% power to detect a 25% reduction in the 5-component primary endpoint (one-sided test of significance; alpha primary endpoint (one-sided test of significance; alpha level=0.025level=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 CharacteristicsNumber randomizedNumber randomized 3,4143,414Mean (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 EntryOn a StatinOn a Statin 94%94%Duration of Statin Therapy*Duration of Statin Therapy*
Use of all secondary prevention therapies wasUse of all secondary prevention therapies waswell-balanced between treatment groupswell-balanced between treatment groups
*Duration of statin therapy not ascertained in 6%*Duration of statin therapy not ascertained in 6%
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. AndersonR. BachR. Bach J. Kaiser J. KaiserB.R. ChaitmanB.R. Chaitman S. Cruz-FloresS. Cruz-Flores K. Seymour K. SeymourP. Desvigne-NickensP. Desvigne-Nickens G. GosselinG. Gosselin S. Claire S. ClaireJ. FlegJ. Fleg S. NashS. Nash B. Ricker B. RickerM. KashyapM. Kashyap C. SilaC. Sila C. Wallum C. WallumS. 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. ChaitmanM. McGovernM. McGovern D. ArnettD. Arnett Northwest Lipid MetabolismNorthwest Lipid MetabolismK.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. OrchardK. WatsonK. Watson
Participating CentersParticipating Centers
Published NEJM 11/15/2011 (online)Published NEJM 11/15/2011 (online)