Prospective Natural-History Study of Coronary Atherosclerosis

Transcription

1 Introduction Review of literature from April 2010 to present Concentrated on clinical studies Categories: Atherosclerosis, Lipids, Diabetes and CVD Risk Medical Therapy Statins really could there be anything left to say? Fibrates where do they fit? Fish Oil supplement saga continues? Pipeline? Should any of these new findings help guide changes to our guidelines?

2 N Engl J Med 2011;364: Prospective Natural-History Study of Coronary Atherosclerosis Methods: 697 patients with ACS Baseline coronary angiography and intravascular ultrasound Followed for up to 3.4 years for subsequent major adverse CV events Events were then considered to be due to original culprit lesion (CL) or due to untreated/nonculprit lesions (NCL) Baseline lesions were also classified according to fibroatheroma cap, plaque burden, and luminal area N Engl J Med 2011;364: Time-to-Event Curves for Major Adverse CV Events CL Culprit Lesion NCL Non-Culprit Lesion N Engl J Med 2011;364:

3 Event Rates for Lesions: Thin-Cap Fibroatheromas (TCFA) and Plaque Burden (PB) N Engl J Med 2011;364: Summary and Implications In patients who presented with ACS, major adverse CV events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions. While nonculprit lesions were frequently angiographically mild, most were thin-cap fibroatheromas or characterized by a large plaque burden, a small luminal area, or some combination of these. In other words, MEDICAL THERAPY is still key!!! N Engl J Med 2011;364: Comparative Determinants of 4-Year Cardiovascular Event Rates in Stable Outpatients at Risk of or With Atherothrombosis Deepak L. Bhatt, MD, MPH, Kim A. Eagle, MD, E. Magnus Ohman, MD, Alan T. Hirsch, MD, Shinya Goto, MD, PhD, Elizabeth M. Mahoney, ScD, Peter W. F. Wilson, MD, Mark J. Alberts, MD, Ralph D Agostino, PhD, Chiau-Suong Liau, MD, PhD, Jean-Louis Mas, MD, Joachim Röther, MD, Sidney C. Smith Jr, MD, Geneviève Salette, PharmD, MSc, Charles F. Contant, PhD, Joseph M. Massaro, PhD, Ph. Gabriel Steg, MD, for the REACH Registry Investigators 45,227 patients with CVD or multiple risk factors for atherothrombosis were followed for 4 years Main outcomes: rates of CVD death, MI, and stroke During the follow-up period: a total of 5481 patients experienced at least 1 event, including 2315 with CVD death, 1228 with MI, 1898 with stroke, and 40 with both JAMA 2010;304:

4 Cumulative Incidence for the Composite End Point of CVD Death, MI, or Stroke JAMA 2010;304: Risk of Ischemic Events in the Subsequent 4 Years of Follow-up in Patients According to Baseline Risk Category JAMA 2010;304: Impact of Diabetes on CVD Risk and All-Cause Mortality in Older Men 60 Rate (No. of events) Late Onset DM Early Onset DM Pior MI no DM 0 CHD CVD All Cause Mortality Wannamethee, et al. Arch Intern Med 2011;171:

5 CVD Risk: Summary and Implications Despite more aggressive medical therapy over the last decade or two the CVD event rate for those with prior ischemic events still approaches 20% over 4-5 yrs. In other words, we still have a lot of work to do. Diabetes in the setting of no previous CV event does not necessarily equate to a risk equivalent especially when diabetes is of later onset or shorter duration (<7 y). Should we alter our risk assessment for those with diabetes and no known CVD? Could there be anything new with LDL and LDL lowering? Lancet 2011; 377:

6 Trends in age-standardized mean total cholesterol by region between 1980 and 2008 for men (A) and women (B) Lancet 2011; 377: Summary and Implications Findings: Globally, mean TC is ~180 mg/dl TC changed little b/w (fell <4 mg/dl per decade) TC fell (~8 mg/dl per decade ) in the high-income regions, including Australasia, North America, and Europe yet was still highest in these higher income regions TC increased (3-3.5 mg/dl per decade) in east and southeast Asia and Pacific. Implications: Hypercholesterolemia is still a global problem. Policies and interventions should be used to accelerate improvements in cholesterol in regions with decline and to curb or prevent the rise in Asian populations and elsewhere. Lancet 2011; 377: Meta-analyses of individual participant data from randomized trials involving: at least 1000 participants & 2 years treatment duration more versus less intensive statin regimens 5 trials; 39,612 individuals; median follow-up 5.1 years statin versus control 21 trials; 129,526 individuals; median follow-up 4.8 years Outcomes: average risk reduction average risk reduction per 1 mmol/l LDL-C reduction at 1 year Lancet 2010;376:

7 Effects on any major vascular event in each study More vs less statin 15% RR 28% RR Statin vs control 22% RR 21% RR Overall 22% RR Lancet 2010;376: Effects on major vascular events per 1.0 mmol/l reduction in LDL cholesterol, by baseline prognostic factors Lancet 2010;376: Effects on major CVevents per 1 mmol/l reduction in LDL, by baseline LDL-C on the less intensive or control regimen Lancet 2010;376:

8 Effects on mortality per 1 mmol/l reduction in LDL-C Lancet 2010;376: Summary and Implications Further reductions in LDL-C safely produce further reductions in the incidence CVD: Each 1 mmol/l reduction reduces the annual rate of major CV events by just over 20% The size of the proportional reduction in major CV events is proportional to the absolute LDL-C reduction achieved. No evidence of any threshold within the cholesterol range studied. All subgroups obtained similar benefits, including those with higher baseline HDL-C concentrations. Lancet 2011; 377: Post-hoc analysis of JUPITER trial: adults without diabetes or previous CVD and baseline LDL-C < 130 mg/dl and hscrp 2 mg/l Randomized to rosuvastatin 20 mg or placebo Outcomes: Association between quartiles of HDL-C or apo A1 and the JUPITER primary endpoint of first non-fatal MI or stroke, hospitalization for unstable angina, arterial revascularization, or CV death Lancet 2010;376:

9 Incidence rates (per 100 person years of exposure) for the JUPITER primary endpoint according to baseline concentrations of HDL-C Q1 Q2 Q3 Q4 HDL-C men >55 women >66 Placebo Rosuvastatin Lancet 2010;376: Incidence rates (per 100 person years of exposure) for the JUPITER primary endpoint according to on-treatment concentrations of HDL-C Q1 Q2 Q3 Q4 HDL-C men >55 women >66 Placebo Rosuvastatin Lancet 2010;376: Summary and Implications Low HDL-C concentrations at baseline is clearly associated with increased incidence of CV events. Treatment of this population with rosuvastatin resulted in reduced risk for CV events regardless of baseline or ontreatment HDL-C. Authors Conclusions: Although measurement of HDL-C is useful as part of initial CV risk assessment, HDL-C is not predictive of residual CV risk among patients treated with potent statin therapy who attain very low LDL-C. LDL lowering as a primary goal continues to have the most support Lancet 2010;376:

10 Methods: 1600 patients with CHD aged <75 years, LDL-C >100 mg/dl and TG <400 mg/dl Randomized to receive statin or usual care (could include statins) Post-hoc Analysis: RR for recurrent CV event in patients with moderately abnormal LFTs (ALT/AST < 3X ULN) treated with a statin compared with those who did not receive a statin. RR compared with patients with normal LFTs treated (or not) with statin. Lancet 2010;376: LFTs during 3-yr f/ u in patients on statins (A) and those not on statins (B) 7 of 880 participants (<1%) who received a statin discontinued statin treatment because of liver-related adverse effects (LFTs > 3X ULN). Lancet 2010;376: CV Events by LFT and Statin Status 12 Rate (events per 100 patient-years) % 39% Statin No Statin 0 Abnormal LFTs Normal LFTs Lancet 2010;376:

11 Summary and Implications Statin use in those with mild abnormalities in LFTs is safe and may be beneficial in reducing LFT levels. Significant CV event risk reduction is achieved with statin therapy in those with abnormal LFTs and may be greater than in those with normal LFTs. Lancet 2010;376: What about residual risk? Should we be targeting triglycerides, HDL, and/or non-hdl-cholesterol? Where do fibrates fit in?

12 N Engl J Med 2010;362: The ACCORD Study Methods: 5518 patients with type 2 diabetes who were being treated with open-label simvastatin were randomly assigned to receive either fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years N Engl J Med 2010;362: The ACCORD Study: Baseline Characteristics Characteristic N = 5518 Age 62 ± 7 years Women 31% White 68% Previous CVD 36% BMI 32 ± 5 kg/m 2 Diabetes duration 9 years A1c 8.3 ± 1.0 % Total Cholesterol 175 ± 37 mg/dl LDL-Cholesterol 101 ± 31 mg/dl HDL-Cholesterol 38 ± 8 mg/dl Triglyceride 162 mg/dl N Engl J Med 2010;362:

13 The ACCORD Study: Lipid Values N Engl J Med 2010;362: The ACCORD Study: Primary Outcome nonfatal MI, nonfatal stroke, or death from CV causes N Engl J Med 2010;362: The ACCORD Study: Sub-Groups N Engl J Med 2010;362:

14 The ACCORD Study: Sub-Groups N Engl J Med 2010;362: ACCORD: Summary and Implications The addition of fenofibrate to simvastatin therapy in of itself does not appear to add significant CVD benefit in most patients with T2DM who are at high risk for CVD. But then again who s doing this any ways? We would generally add fibrate therapy in the setting of more significant hypertriglyceridemia, and the CVD benefit in this scenario has not been truly tested yet N Engl J Med 2010;362: Meta-analyses of randomized controlled trials assessing the effects of fibrates on CVD outcomes 18 trials were identified providing data for 45,058 participants, including 2870 major CV events, 4552 coronary events, and 3880 deaths. Outcomes: major CV events coronary events, stroke, heart failure, coronary revascularization all-cause mortality, cardiovascular death, non-vascular death, sudden death new onset albuminuria drug-related adverse events Lancet 2010;375:

15 10% RR 10% RR Effect of fibrates on all outcomes Lancet 2010;375: Summary and Implications Fibrates modestly (10%) improve risk for major CV events primarily by lowering coronary events (13%). Fibrates, however, do not appear to improve mortality Effects were greater with higher baseline TG and with greater TG lowering Interesting improvements in microvascular outcomes. My take? Use fibrates primarily to reduce significant hypertriglyceridemia. Lancet 2010;375: Despite the less than positive data with fibrate trials.

16 Use of Fibrates in the United States and Canada Monthly Fibrate Prescriptions in the US (per 100,000) IMS Health data from the US & Canada between Jan 2002 and Dec 2009 JAMA 2011;305: What about HDL? Still waiting on niacin+statin outcome trials What else? N Engl J Med 2010;363:

17 The DEFINE Study Anacetrapib is a cholesteryl ester transfer protein inhibitor that raises HDL-C and reduces LDL-C Methods: 1623 patients with or at high risk for CHD who were at LDL goal on statin therapy were randomized to 100 mg of anacetrapib or placebo daily for 18 months Primary end points: Change in LDL-C at 24 weeks Safety and side-effect profile of anacetrapib through 76 weeks. Secondary end points: Change in HDL-C CV events and deaths were prospectively adjudicated N Engl J Med 2010;363: % Change in LDL and HDL Cholesterol 138% N Engl J Med 2010;363: Change in LDL and HDL Cholesterol 40% As compared to placebo, treatment with anacetrapib was associated with: Apo-B 21% Apo-A-I 45% Non-HDL cholesterol 32% Lp(a) 36% Triglycerides 7% 138% N Engl J Med 2010;363:

18 The DEFINE Study: Safety No changes were noted in BP, electrolytes or aldosterone levels with anacetrapib as compared with placebo No difference in prespecified composite CV end point (death from CV causes, MI, hospitalization for unstable angina, or stroke): 16 patients in the anacetrapib group (2.0%) as compared with 21 in the placebo group (2.6%) (p=0.40; hazard ratio, 0.76; 95% confidence interval, ) N Engl J Med 2010;363: Summary and Implications CETP inhibition clearly improves lipid parameters beyond statin therapy. Anacetrapib appears to be safe at least on a short-term basis. Longer-term event trials are needed and appear to be warranted. Too soon to throw out this class? N Engl J Med 2010;363: What s the latest stink on fish oil?

19 2010;363: Circulation 2010;122: Alpha Omega Trial: Cumulative Incidence of Major CV Events and Fatal CHD N Engl J Med 2010;363: OMEGA Study: Cumulative Incidence of Major CV Events and Fatal CHD Circulation 2010;122:

20 Fish Oils: Summary and Implications A diet enriched in fish oils appears to be beneficial for reducing CVD risk as have some previous studies of supplementation. From these 2 large RCTs, however, fish oil supplementation does not appear to be of significant benefit. Is this because of improvements in other cardioprotective treatments? Or is everyone consuming more fish oil in their diet? Or does this relate to the concept of replacing good fat for bad fat vs. simply adding good fats (potentially on top of bad fat)? What else is in the pipeline? Thyroid Hormone Analogue Eprotirome Paul W. Ladenson,, E. Chester Ridgway, et al. N Engl J Med 2010;362: Methods: Hypercholesterolemic on statin, mean LDL-C 141 mg/dl Randomized to receive eprotirome (25, 50, or 100 µg per day) or placebo for 12 weeks Results: Eprotirome resulted in a reduction in LDL-C of 15-25% over placebo Similar reductions were seen in apo B, TG, and Lp(a) Eprotirome was not associated with adverse effects on the heart or bone No change in levels of serum TSH or T3 but a decrease in T4 Conclusions: Eprotirome may be a viable treatment option for the future

21 Mipomersen Mipomersen - 2 nd generation antisense oligonucleotide that inhibits apo B-100 protein synthesis in the liver Akdim et al. J Am Coll Cardiol 2010;55: Phase 2 dose escalation study in patients with hypercholesterolemia on statin therapy (mean LDL-C 135 mg/dl) Placebo vs Mipomersen (30, 100, 200, 300, 400 mg) sc weekly Change in LDL-C compared to placebo: +6, -18, -24, -48, and -34 % respectively Similar reductions were seen in apo B, VLDL, and TG Raal et al. Lancet 2010; 375: Phase 3 randomized trial in patients with homozygous FH 21% further reduction with 200 mg Mipomersen sc weekly Conclusions: Mipomersen may hold promise for treatment of patients not reaching target LDL-C levels So, where does that leave us? NCEP ATP III: Updated LDL-C Goals Risk Category LDL-C Goal (mg/dl) 1 RF <160 2 RFs <130 (CAD risk 20%) optional: <100 CAD or <100 CAD risk equivalent optional: <70 * (CAD risk >20%) *consider in very high-risk patients Grundy et al. Circulation. 110:227, 2004

22 Optimizing Statin Treatment for Primary Prevention of CAD Ann Intern Med 2010;152:69-77.