1 / 24

HDL: The Bad of the Good

HDL: The Bad of the Good. i.e. What Do We Really Know Jonathan Martin PGY1 June 1 st , 2011. Cardiac Risk Markers. Age LDL - high HDL – low Diabetes Family History Prior Events Etc . . . Table 1. Baseline Characteristics Analyzed for Development of TIMI Risk Score for UA/NSTEMI*.

berke
Download Presentation

HDL: The Bad of the Good

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. HDL: The Bad of the Good i.e. What Do We Really Know Jonathan Martin PGY1 June 1st, 2011

  2. Cardiac Risk Markers • Age • LDL - high • HDL – low • Diabetes • Family History • Prior Events • Etc . . .

  3. Table 1. Baseline Characteristics Analyzed for Development of TIMI Risk Score for UA/NSTEMI*. Antman, E. M. et al. JAMA 2000;284:835-842

  4. Table 1. Baseline Characteristics Analyzed for Development of TIMI Risk Score for UA/NSTEMI*. Risk factors included family history of CAD, hypertension, hypercholesterolemia, diabetes, or being a current smoker Antman, E. M. et al. JAMA 2000;284:835-842

  5. Niacin (B3) • Coenzyme in lipid metabolism, tissue respiration, and glycogenolysis • Inhibits VLDL and LDL synthesis, altering lipid balance and therefore: • Effective at increasing HDL levels

  6. Niacin (B3) • Starting dose ~250mg, titrated up to 1-3G/day • Maximum dose 6G per day (or 4.5G/day) • Major Side Effect: Flushing / Pruritus • Also noted to cause severe hepatotoxicity • Have caution with Statins • Rare but severe rhabdomyolysis

  7. AIM HIGH TRIAL • Niacin Plus Statin to Prevent Vascular Events • 9/2005 – 9/2012 • National Heart, Lung, and Blood Institute (NIH) • With support of Abbott and Merck

  8. AIM HIGH: Primary Endpoints • Randomized, Double Blinded throughout • Composite of CHD Death, Nonfatal MI, Ischemic Stroke, Hospitalization for NSTEMI, or symptom-driven coronary or cerebral revascularization

  9. AIM HIGH: Secondary Endpoints • Composite of CHD Death, non-fatal MI, high-risk ACS, or ischemic stroke • Cardiovascular mortality

  10. AIM HIGH: Inclusion • Age > 45 • Vascular Disease • Documented CAD • Documented cerebrovascular or carotid disease • Documented PAD • Dyslipidemia • LDL less than 160 • Male HDL less than 40, Female HDL less than 50 • 150 < Total < 400

  11. AIM HIGH: Exclusion • CABG within 1 year • PCI within 4 weeks • Hospitalized with ACS within 4 weeks • Fasting Glucose > 180 or A1C > 9% • Non-compliant Diabetes monitoring • Use of certain P450 3A4 metabolizers

  12. AIM HIGH: Enrollment • 3,414 patients enrolled, followed over 32 months • Average age 64 years old • 92% with CAD • 81% with Metabolic Syndrome • 71% with HTN • 34% with Diabetes Mellitus • > 50% with prior MI

  13. AIM HIGH: Lead-In • During lead-in, patients were started on Simvastatin to achieve 40 < LDL < 80 • Simvastatin was dose-adjusted to max dose as needed to achieve LDL • If goal not reached, Ezetimibe 10mg qDay • Not declared what happened to patients who still did not reach goal levels

  14. AIM HIGH: Randomized • 1718 patients then received Niacin ER (Niaspan) 2000mg/day • (if Niacin not tolerated, reduced to 1500mg/day) • If still not tolerated, discontinued • 1696 patient received a placebo

  15. AIM HIGH: 32 month look in • No difference in primary end-point • “Significant increase in HDL” • These numbers have not yet been released • Niacin patients with small increase in strokes • 28 (1.6%) vs 12 (0.7%) • Of these, 9 stopped Niacin up to 4 yrs earlier

  16. AIM HIGH: Predecessors • The ACCORD Trial • Fenofibrate increased HDL and decreased Triglycerides, but no effect on cardiovascular events • The ILLUMINATE Trial • Pfizer drug Torcetrapib

  17. ILLUMINATE: Set up • 15,067 pts with CHD or DM 2 • Avg age 61 • Primary endpoint: composite of CHD death, non-fatal MI, stroke, hospitalization for ACS

  18. ILLUMINATE: Lead In • Lead-in: 10 weeks to achieve LDL < 100 • 10 weeks of lifestyle modification • Adjunct dose-adjusted Atorvastatin • Those that achieved target were randomized to Torcetrapib 60mg vs Placebo

  19. ILLUMINATE: 12 month look in • THE GOOD • 72.1% increase in HDL (p<0.001) • 24.9% decrease in LDL (p<0.001) • 9% decrease in Triglycerides (p<0.001)

  20. ILLUMINATE: 12 month look in • THE BAD • Increased All-Cause Mortality (p=0.006) • Increased Primary Endpoint Events • 464 events in Torcetrapib group • 373 events in statin only group • P = 0.001

  21. ILLUMINATE: Unintended Effects • Systolic Blood Pressure was significantly higher in the treatment group • 5.4mmHg v 0.9mmHg; p<0.001 • Deaths secondary to infection were significantly higher in the treatment group • 9 vs 0

  22. What have we learned? • Cardiac markers determined by studies of correlation, not necessarily causality • No signaling pathways are fully understood • Likely that the majority of signaling molecules are yet to be characterized • Medications often go to phase III with limited harm data • Medications should be used when needed, but limit their use beyond proven benefit

  23. Resources • http://jama.ama-assn.org/content/284/7/835.full • Clinical Trials Registry NCT00120289 • NIH.gov: AIM HIGH Stopped Early • The Failure of Torcetrapib: The Search for the Reason Why: ILLUMINATE: Study Results

More Related