Fixed Targets Don t Add Incremental Benefit to ASCVD Risk Reduction

Transcription

1 Northwestern University Feinberg School of Medicine Fixed Targets Don t Add Incremental Benefit to ASCVD Risk Reduction Neil J. Stone MD, MACP, FACC, FAHA Bonow Professor of Medicine Feinberg School of Medicine

2 Dr. Stone has no disclosures Dr. Stone doesn t accept honoraria from industry

3 Paradigm Shift Prior cholesterol guidelines focused on LDL-C levels as targets for intervention. The new 2013 ACC-AHA guidelines endorse: 1) Increased focus on defining atrisk clinical groups who benefit from statin therapy 2) Prioritizing interventions supported by strong evidence 3) Endorsing clinicianpatient risk discussions for primary prevention before statins are prescribed 3 & for those where RCT evidence is lacking

4 ACC-AHA GUIDELINES ASK THESE QUESTIONS: a) Who merits consideration for statin treatment? b) Does patient belong to a group that benefits? c) Does therapy need to be adjusted based on 1) adequacy of effect 2) adherence This requires follow-up lipids as indicated by the guidelines d) Non-statins: considered if a high risk group?

5 Why Choose RCTs for Guidelines? 1) Durability Class I Cardiology Guideline Recommendations 91% retained if Level of Evidence A: Multiple RCTs or meta-analyses JAMA 2014:311 (20); ) Quantitative weighing of absolute risk reduction vs. adverse effects in defined populations a) Statins first choice as studied in RCTs b) Included many subgroups

6 2013 ACC-AHA Guidelines Statins: Strong evidence first line drugs to reduce ASCVD risk In groups that benefit: Three high risk groups that benefit: 1) Clinical ASCVD 2) Diabetes years with LDL-C 70 mg/dl 3) Severely elevated LDL-C 190 mg/dl Two high risk groups with statin RCTs that do not benefit: Hemodialysis Higher grades of heart failure

7 2013 ACC-AHA Guidelines Fourth Group: A lower risk primary prevention group No diabetes, LDL-C year hard ASCVD risk 7.5% This selects 92% of those 50 with CKD for statin treatment (Colantonio LD et al J Am Soc Nephrol. 2015;26(5): But ASCVD risk doesn t mean that statin assignment is automatic! Need clinician-patient risk discussion

8 Constant Relative Risk Reduction in Multiple Subgroups Per-person RCT meta-analysis Lancet 2010; 376: In all subgroups, about a 22% reduction in relative risk; so the higher the absolute risk, the greater the absolute risk reduction. You multiple absolute risk times fixed relative risk for approximate absolute risk reduction

9 Major difficulties with fixed targets 1) Accuracy of LDL-C a) Fasting LDL-C (calc), non fasting LDL-C (calc) and direct LDL-C accuracy don t agree precisely: b) What if you are at goal with one, but not the other? 2) Targets can result in additional therapy added but 1) Net benefit lacking a) NNT is large: (NNT = number needed to treat) b) Ezetemibe showed low NNT in very high risk patients; if lower risk, then the LDL-C would have to be much higher for comparable NNT 3) Net benefit lacking when additional drugs create safety issues including drug-drug interactions 4) Net benefit may be lacking if cost issues make other needed therapy unaffordable

10 Major difficulties with fixed targets 5. Unknown rate of additional adverse effects to if multidrug therapy used to achieve a specific fixed target 6. Lower was not better in these RCTs. 1) Illuminate: Torcetrapib-atorvastatin (LDL-C: -27%) 2) HPS2-THRIVE: Niacin-lapropriprant (LDL-C -16%) 3) ACCELERATE: No benefit with evacetrapib despite increase in HDL & decrease in LDL (84 to 55 mg/dl) Lower is better, but it matters how you get there and in whom. Stone N.J. and Lloyd-Jones D.M. N Engl J Med 2015; 372: (April 16)

11 Fixed Targets Can Fail Consider: 60 yo man with Type 2 DM for 7 years who was not treated with a statin as LDL-C 95 mg/dl (<100 mg/dl) He developed an acute coronary syndrome: Rx atorvastatin 10 mg/day and LDL-C fell to 69 mg/dl Comments: 1) Should have considered Rx based on risk; not withholding statin just because LDL-C <100 mg/dl. 2) Diabetes and CHD conveys highest risk; he needed high intensity statin or moderate intensity statin + ezetemibe; attaining LDL-C of 69 mg/dl is inadequate to address his risk

12 At any LDL-C, overall ASCVD Risk determines benefit Treatment implication of lower is better The net benefit depends on level of risk! (Robinson J, Stone N Am J Card 2006) CTT 2010: Meta-analysis of 26 RCTs (170,000 Participants Northwestern University Feinberg School of Medicine

13 Relationship of changes in atheroma volume to final LDL-C in IVUS studies (post-hoc) Change in atheroma volume R 2 = 0.47 R² = Final LDL-C in mmol/l Wierzbicki AS Modified After Nissen SE ; Int J Cin Pract 2008; 62 : 981 Puri R et al. Am J Cardiol 2014; 114 : 1465; used with permission by N.Stone

14 Evidence: Risk Based Guideline Outperforms Fixed Goals of ATP 3 1) More adult potentially eligible for statins compared to ATP3-43 million (37.5%) 56 million (48.6%) although no automatic statin assignment Pencina MJ, et al N Engl J Med Apr 10;370(15): Adherence to guidelines could prevent ~ 450, 000 ASCVD events over 10 years --Increase mainly in older adults; acknowledges risk discussion 2) Has greater accuracy and efficiency in identifying increased risk of incident CVD and subclinical CAD, particularly in intermediate-risk participants. Pursnani A et al JAMA. 2015; 314(2):134-41

15 Evidence: Risk Based Guideline Outperforms Fixed Goals of ATP 3 3) Better match risk level to amount of atherosclerosis than targets of ATP III Johnson KM and Dowe DA. JACC 2014 Sep 2;64(9): Treats high-risk patients with greater burden Avoids treating low-risk with low burden

16 2013 ACC-AHA Guidelines Cost-Effective Treats more but with a low NNT (DPaixao ARM et al Circ Cardiovasc Qual Outcomes. 2014;7: Dallas Heart Study) Cost effective down to 10 yr ASCVD risk as low as 5% Pandya A, Sy S, Cho S, Weinstein MC, Gaziano TA.. JAMA. 2015;314(2): Treats more, but more cost effective Galber PZ PLoS One Sep 30;10(9):e

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18 2013 ACC-AHA Guidelines Figure 5. Statin Therapy: Monitoring Therapeutic Response and Adherence

19 Non-Statins Not First-Line Guidelines Stated: Use the maximum tolerated intensity of statin But consider adding nonstatin drug therapy if: A less-than-anticipated therapeutic response persists ASCVD risk-reduction benefits outweigh the potential for adverse effects in higher-risk persons: - Clinical ASCVD <75 years of age - Baseline LDL C 190 mg/dl - Diabetes mellitus 40 to 75 years of age Nonstatin cholesterol-lowering drugs shown to reduce ASCVD events in RCTs are preferred

20 Non Statins and IMPROVE-IT Cannon CP, Blazing MA, Gugliano RP et al. IMPROVE-IT Investigators. N Engl J Med Jun 18;372(25): Study RCT; Duration 6-7 yrs Population: High Risk Secondary Prevention (Acute Coronary Syndrome with One High Risk Feature) Intervention/Comparator Simvastatin 40 + Ezetemibe 10 mg vs. Simvastatin 40 + Placebo Results: -LDL-C 69 to about 54 in intervention arm -No safety signal of harm CVD Outcomes: No effect on total mortality (not powered to do so) But reduced rate of ischemic stroke (RRR -21%) and reduced rate of MI (RRR -13%)

21 Non Statins and IMPROVE-IT Significance (continued) 1) Diabetic patients seemed to show a greater benefit with ezetimibe/simvastatin Those at highest absolute risk benefit from incremental LDL-C lowering 2) Trial reaffirms that clinical benefit is proportional to the extent of LDL-C lowering, but note that it matters how you get there and in whom (not a trial of low risk patients)

22 Non Statins and IMPROVE-IT Significance (continued) Consider 2 patients with coronary disease both on a moderate intensity statin : Acute Coronary Syndrome Diabetes LDLcholesterol Patient A Yes Yes 69 mg/dl Patient B No No 78 mg/dl Which one has enough absolute risk reduction to give a low number needed to treat? Patient A is at goal; Patient B is not; Patient A has net benefit from further LDL-C lowering therapy; not clear net benefit for patient B especially if you factor in costs.

23 2016 ACC Expert Consensus Decision Pathway Acknowledges that there can be significant discrepancies in levels of directly measured versus calculated LDL-C within the same sample, especially at lower LDL-C levels The uncertainty in LDL-C measurement provides further support for the Committee s position that the thresholds for consideration of net ASCVD risk-reduction benefit should merely be factors to be considered and not firm triggers for intensification of therapy. Ref: ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk JACC 2016

24 ACC May Meeting ) Evidence shows that follow-up lipid testing as recommended by the 2013 ACC AHA guidelines (with a focus on adequacy of effect (% lowering), adherence and safety is supported by multiple lines of evidence. ) A focus on fixed targets especially as performance measures isn t supported by high quality RCTs ) Fixed targets can result in confusion when accuracy of various methods for measuring LDL-C is taken into account ) Fixed targets can lead to unnecessary cost and increased harms

25 Lancet 2015; 385: A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy 25

26 2016 ACC Expert Consensus Decision Pathway Writing Committee Judged that it was appropriate to provide levels of LDL-C, or thresholds, in terms of both percentage LDL-C reduction from baseline and absolute ontreatment LDL-C measurement, which, if not achieved by adherent patients, would serve as factors to consider in decision making regarding further therapy. The Writing Committee emphasizes that these are not firm triggers for adding medication but factors that may be considered within the broader context of an individual patient s clinical situation.

27 Paradigm Shift The new cholesterol guidelines changed ASCVD risk reduction through cholesterol lowering with: 1) increased focus on defining atrisk clinical benefit groups; 2) prioritizing interventions supported by strong evidence; 3) endorsing clinicianpatient risk discussions not automatic statin prescription; 4) For those in whom initial evidence based therapy is judged inadequate, an ACC Clinical Expert Consensus Panel has offered further recommendations