CCC Dyslipidemia Lipid lowering/atherosclerosis clinical trials update November 17 th, 2018
Faculty/Presenter Disclosure Faculty: Rick Ward Relationships with commercial interests: Grants/Research Support: Pfizer, Lilly, Cortria Corp Speakers Bureau/Honoraria: Astra Zeneca, Bayer, Boehringer Ingelheim, BMS, Eli Lilly, Forest, Janssen, Leo Pharmaceuticals, Novartis, Merck, Pfizer, Sanofi Aventis, Schering-Plough, Shire Consulting Fees: Astra Zeneca, BI, Shire, Pfizer, BMS Other: Nil
Faculty/Presenter Disclosure Faculty: Jean Grégoire Relationships with commercial interests: Grants/Research Support: Amarin Speakers Bureau/Honoraria and Consulting Fees: Amgen, AstraZeneca, Bayer, Boehringer-ingelheim, Bristol-Myers- Squibb, HTS Therapeutics, Jannsen, Merck, Novartis, Novonordisk, Pfizer, Sanofi, Servier, Sunovion, Valeant Former Co-chair Canadian Lipid Guideline 2012-2016
Disclosure of Commercial Support This program has NOT received financial support from any commercial sources. The Canadian Cardiovascular Society is supporting travel and expenses for the speakers.
Mitigating Potential Bias The information presented is based on recent information that is explicitly evidence-based and is solely based on Canadian Cardiovascular Society Guidelines.
Following this program, participants will: 1. Utilize the CCS Dyslipidemia Guidelines and recent evidence to guide the identification and management of patients with lipid disorders with a focus on the elderly and patients with hereditary lipid disorders 2. Incorporate a strategy for patients who are statin intolerant 3. Describe the evidence and indications for the use of new therapies to treat high risk patients with lipid disorders 4. Identify the target of therapy for patients where medical therapy is indicated
Case 1 statin use in the elderly A healthy, active 77 year old man presents for annual health review. He has a history of hypertension and asks about his cholesterol. His LDL is 4.1 mmol/l. His calculated Framingham Risk Score puts him into the High Risk category.
Case 1 - DP Would you have screened him in the first place?
Who to Screen
How to Screen RECOMMENDATIONS We recommend non-fasting lipid and lipoprotein testing which can be performed in adults in whom screening is indicated as part of a comprehensive risk assessment to reduce CVD events (Strong Recommendation, High Quality Evidence). We suggest that for individuals with a history of triglyceride levels >4.5 mmol/l that lipid and lipoprotein levels be measured fasting (Conditional Recommendation, Low Quality Evidence). Practical tip: Compared to fasting lipid values, there will be minimal change with non-hdl-c, a slight decrease in LDL-C and small increase in triglyceride concentrations when individuals do not fast.
Benefits of Non-fasting Lipids Patient convenience no need to go to lab early in the morning and fasting; no need for retesting if not fasting Reduced wait times and reduced early morning patient burden in clinical laboratories Safety prevention of hypoglycemic episodes in diabetics Enhances compliance and avoids delay in lipid screening and follow up tests Enhanced predictive value for CVD and mortality of nonfasting lipids Identification of high remnants/insulin resistance Removal of need to perform fasting blood work generally HbA1c is accepted as a diagnostic test and follow up test by CDA and ADA that does NOT have to be accompanied by a fasting glucose High fasting glucose usually results in HbA1c test
2016 Recommendations We recommend that a cardiovascular risk assessment be completed every 3 to 5 years for men and women age 40 to 75. A risk assessment may also be completed whenever a patient s expected risk status changes. Options include using the 10 Year Risk (Framingham Model) or Cardiovascular Age (Cardiovascular Life Expectancy Model). The results should be shared with the patient to support shared decision making and improve the likelihood that they will reach lipid targets. (Strong Recommendation, High Quality Evidence)
What would you recommend? 1. Ignore and continue a healthy lifestyle 2. Start on a low dose statin 3. Treat to a target of LDL of < 2.0 Mmol/L 4. Order a stress test or other investigations 5. Omega 3 fatty acid supplementation
When to Consider Pharmacological Treatment in Risk Management RECOMMENDATIONS Statin indicated conditions: We recommend management that includes statin therapy in high risk conditions including clinical atherosclerosis, abdominal aortic aneurysm, most diabetes mellitus, chronic kidney disease (age >50 years) and those with LDL-C 5.0 mmol/l to lower the risk of CVD events and mortality (Strong Recommendation, High Quality Evidence). Primary prevention: a) We recommend management that does not include statin therapy for individuals at low risk (modified FRS < 10 %) to lower the risk of CVD events (Strong Recommendation, High Quality Evidence). b) We recommend management that includes statin therapy for individuals at high risk (modified FRS 20%) to lower the risk of CVD events (Strong Recommendation, High Quality Evidence). c) We recommend management that includes statin therapy for individuals at intermediate risk (IR; modified FRS 10-19%) with LDL-C 3.5 mmol/l to lower the risk of CVD events. Statin therapy should also be considered for IR persons with LDL-C <3.5 mmol/l but with apo B 1.2 g/l or non-hdl-c 4.3 mmol/l or in men 50 and women 60 years of age with 1 CV risk factor (Strong Recommendation, High Quality Evidence). Values and preferences - This recommendation applies to individuals with an LDL-C 1.8 mmol/l. Any decision regarding pharmacological therapy for CV risk reduction in IR persons needs to include a thorough discussion of risks, benefits, and cost of treatment, alternative nonpharmacological methods for CV risk reduction and each individual s preference. The proportional risk reduction associated with statin therapy in RCTs in (IR) persons is of similar magnitude to that attained in highrisk persons. Moreover, irreversible severe side effects are very rare and availability of generic statins results in low cost of therapy. However, the absolute risk reduction is lower. Statin therapy may be considered in persons with FRS of 5%-9% with LDL-C 3.5 mmol/l or other CV risk factors as the proportional benefit from statin therapy will be similar in this group as well.
10 yrs Risk vs Lifetime Risk 70 Men (n = 3564) 69 70 Women (n = 4362) 60 60 Adjusted cumulative incidence of CVD (%) 50 40 30 20 50 46 36 50 40 30 20 50 39 27 10 0 50 60 70 80 90 5 10 Attained age (years) 0 50 60 70 80 90 8 2 Major RFs 1 Major RF 1 Elevated RF 1 Not optimal RF All optimal RFs Lloyd-Jones DM et al. Circulation 2006; 113:791-798. Anderson TJ, et al. Canadian Cardiovascular Society Guidelines for the management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult, Canadian Journal of Cardiology (2016), doi: 10.1016/ j.cjca.2016.07.510.
RRs of MI and Stroke NNT 83 NNT 142
RRs of All-Cause Death and CV Death
Recommendations for Primary Prevention With Statins in Apparently Healthy People Mortensen MB, Falk E. et al. Jam Coll Cardiolo 2017;71:85-94.
What if.. 1. The patient also had well controlled T2DM? 2. The patient was already on a statin for a uncomplicated MI he suffered when he was 67? 3. The patient had been on a statin for primary prevention for the past 5 years?
Case 2 Statin intolerance A 62 year old overweight and inactive lawyer with hypertension and T2DM is a patient in your practice who presented to the ED with moderate sized STEMI. He comes to your office shortly after discharge complaining of side effects from pills. Since he has been home, he has noted generalized muscle pain. He googled this and is certain it is the high dose statin on which he was discharged. You review blood work done 9 months prior to his MI.* * He cancelled numerous appoints with you and your dietician to review
Case 2 Statin Intolerance T chol 5.59 TG 7.19 HDL.81 LDL Unable to calculate Non-HDL 4.78 HbA1c 7.5
Do you think the statin is causing his pain?
What would you recommend? 1. Stop Statin, monitor myalgia and rechallenge. 2. Reduce to lowest tolerated dose. 3. Since major issue is TG s and HDL start on fibrate. 4. Change to niacin, bile acid sequestrant, Ezetimibe or PCSK9 Inhibitor. 5. Tell him to ride it out that the pain will improve over time.
Principles of Management of Statin Intolerance Is there an indication for statin therapy? Does the patient have features limiting or precluding use of statins? Is the patient fully aware of the indication for statin treatment, intended benefits and safety of statins, and properly counselled to avoid nocebo effects*? Have dietary, weight and exercise goals been included in the therapeutic plan? Have supplements used to avoid myalgia while taking statins been discouraged? Has systematic challenge/de-challenge/re-challenge occurred and failed to result in achievement of therapeutic goal? If needed, which non-statin agent is likely to help achieve therapeutic goal with or without dual therapy to avoid polypharmacy? *Nocebo effects; perceived adverse reactions experienced by a patient who receives a placebo. Mancini GB et al. Can J Cardiol 2016 Jul;32(7 Suppl):S35-65.
What if our patient truly was statin intolerant and very high risk? 1. Ezetimibe? 2. Bile Acid Sequestrant? 3. PCSK9 Inhibitor?
Statin based Options for LDL-Cholesterol Lowering in Statin Intolerant Patient Lower statin dose Switch to alternative statin Altered dosing regimens Rosuvastatin 2.5-10 mg 3 x weekly or alternate days Rosuvastatin 5-20 mg once weekly Low dose / alternative statin /alternating day rosuvastatin + Ezetimibe and/or Bile acid binding resin PCSK9 inhibitor
RECOMMENDATIONS Non-Statin Therapy We recommend ezetimibe as second-line therapy to lower LDL-C in patients with clinical cardiovascular disease if targets are not reached on maximally tolerated statin therapy (Strong Recommendation, High Quality Evidence). We recommend that niacin not be added to statin therapy for CVD prevention in patients who have achieved LDL-C targets (Strong Recommendation, High Quality Evidence). Values and preferences - It remains unclear whether niacin offers CV benefits in other patient groups, such as those with LDL-C above target or those with low HDL-C or high TG. We recommend that fibrates not be added to statin therapy for CVD event prevention in patients who have achieved LDL-C targets (Strong Recommendation, High Quality Evidence). Values and preferences - In sub-group analysis, patients with elevated triglycerides and low HDL-C may benefit from fibrate therapy. Anderson TJ, Gregoire J, Pearson GJ et al., Can J Cardiol 2016 (In-Press). DOI: 10.1016/j.cjca.2016.07.510
Non-Statin Therapy RECOMMENDATIONS We suggest that bile acid sequestrants be considered for LDL-C lowering in high risk patients who remain above target despite statin +/- ezetimibe therapy (Conditional Recommendation, Low Quality Evidence). We suggest the use of PCSK9 inhibitors (evolocumab, alirocumab) to lower LDL-C for patients with heterozygous familial hypercholesterolemia whose LDL-C remains above target despite maximally tolerated statin therapy (Conditional Recommendation, Moderate Quality Evidence). We suggest that Evolocumab be added to background therapy in patients with homozygous familial hypercholesterolemia and continued if LDL-C lowering is documented (Conditional Recommendation, Moderate Quality Evidence). We suggest that PCSK9 inhibitors be considered to lower LDL-C for patients with atherosclerotic cardiovascular disease in those not at LDL-C goal despite maximally tolerated statin +/- ezetimibe therapy (Conditional Recommendation, Moderate Quality Evidence). Values and preferences - Definitive outcome trials with PCSK9 inhibitors are underway but have not yet been completed. However, phase 3 efficacy trials show consistent reduction in LDL-C and reassuring trends towards reduced CV events, even though not powered for such. Given the very high lifetime risk faced by patients with FH or ASCVD, clinicians should balance the anticipated benefits of robust LDL C lowering with PCSK9 inhibitors against the lack of definitive outcomes data. We suggest lomitapide and mipomersen* may be considered exclusively in patients with homozygous familial hypercholesterolemia (Conditional Recommendation, Moderate Quality Evidence). *not approved in Canada Anderson TJ, Gregoire J, Pearson GJ et al., Can J Cardiol 2016 (In-Press). DOI: 10.1016/j.cjca.2016.07.510
Case 3 Familial Hypercholesterolemia A 40 year old patient comes in for a periodic health review. His father recently died from complications of MS but you are reminded he had an MI in his 50 s with long standing hypertension and dyslipidemia. Our patient is asymptomatic, normotensive, somewhat active with a BMI of 27 The only abnormalities of his blood work are his lipid profile.
Cholesterol Panel - CT : 11.35 mmol/l - TG : 2.20 mmol/l - LDL: 8.72 mmol/l - HDL: 1.58 mmol/l - Non-HDL: 9.77 mmol/l Other Lab Values - LFT: Normal - Creatinine: 82 umol/l - TSH: 2.4 mui/l - Glycemia: 5.3 mmol/l - HBA1C: 0.052% - No proteinuria.
Does he have FH?
HeFH Diagnostic Information Canadian criteria for HeFH Definite clinical familial hypercholesterolemia Imputed baseline / untreated LDL-C 8.5 mmol/l Tendinous xanthomata Premature ASCVD Family history of premature CVD (1 male relative <55 yo) Simon Broome Register criteria for HeFH Definite diagnosis for clinical familial hypercholesterolemia Imputed baseline / untreated LDL-C >4.9 mmol/l Tendinous xanthomata Family history of premature CVD (1 male relative <55 yo) Dutch Lipid Clinic Network criteria for HeFH Definite clinical familial hypercholesterolemia Imputed baseline / untreated LDL-C 8.5 mmol/l Premature coronary artery disease Tendinous xanthomata Family history of premature CVD (1 male relative <55 yo)
Canadian definition for the clinical diagnosis of familial hypercholesterolemia
Case 3 1. Would you treat? 2. How would you treat? 3. What is your target?
Cumulative event-free survival (%) CHD Free Survival Among Individuals with FH according to Statin Treatment Kaplan Meier curve estimates of cumulative CHD-free survival among individuals with familial hypercholesterolemia according to statin treatment (P < 0.001 for difference) Statin treatment No statin treatment Follow-up (years) Nordestgaard B G et al. Eur Heart J 2013;34(45):3478-90a.
You confirmed the diagnosis of FH. What would be your initial lipid lowering therapy? 1) Lifestyle modifications for 3 months. 2) Atorvastatin 20 mg daily. 3) Atorvastatin 80 mg daily. 4) Lifestyle modifications and Atorvastatin 80 mg daily
Pharmacological Treatment Indications & Targets Category Consider Initiating pharmacotherapy if: Target NNT Primary Prevention High (FRS 20%) Intermediate (FRS 10-19%) LDL-C <2.0 mmol/l or >50% 35 40 LDL-C 3.5 mmol/l or Non-HDL-C 4.3 mmol/l or Apo B 1.2 g/l or Men 50 & women 60 yrs and 1 CV risk factor Or Apo B <0.8 g/l Statin Indicated Conditions** Clinical atherosclerosis* (CAD, CVD, PAD) Or 20 Abdominal aortic aneurysm Diabetes mellitus: 40 yrs, or >15 yrs duration & age 30 yrs (DM 1), or microvascular disease non-hdl-c <2.6 mmol/l CKD (age 50 yrs): egfr < 60 ml/min/1.73 m 2, or ACR >3 mg/mmol LDL-C 5.0 mmol/l >50% in LDL-C * consider LDL-C < 1.8 mmol/l for subjects with ACS within last 3 months;** statins indicated as initial therapy
After 3 months on Atorvastatin 80 mg daily, LDL-C is 4.54 mmol/l. What will be your next step? 1) No change 2) Switch to Rosuvastatin 40 mg/day 3) Add Ezetimibe 10 mg to Atorvastatin 80 mg/day 4) Add a PCSK9 inhibitor
After 3 months on Atorvastatin 80 mg daily and Ezetimibe 10 mg daily, LDL-C is 3.2 mmol/l. Are you satisfied with the result? 1) Yes 2) No
What if our patient had a history of ASCVD and the LDL-C on treatment with Atorvastatin 80 and Ezetimibe is 3.2 mmol/l? 1) No change 2) Add Colesevelam to Atorvastatin 80 mg/day and Ezetimibe 10 mg/day 3) Add a PCSK9 inhibitor
Evolocumab: RUTHERFORD-2 Add-on to Statins: Significant LDL-C Lowering with Monthly or Bi-weekly Placebo wk10&12 EvoMab wk10&12 % Change from Baseline in LDL-C 10 0-10 -20-30 -40-50 -60 1% 1% Q2W 61% 61% +2% +5% QM 64% 56% Placebo wk12 EvoMab wk12 HeFH Study (N = 331) HeFH patients unable to achieve an LDL-C < 2.6 mmol/l despite statin therapy with or without ezetimibe ~ 60%LDL lowering in this difficult patient group Reflexive LDL-C measurements; Co-primary Endpoints: Mean % change from baseline in LDL at week 10/12 and at Week 12 Adapted from Robinson JG, et al. JAMA. 2014;311(18):1870-1882 (LAPLACE-2); Raal F, et al. Lancet. 2015;385(9965):331-40.
LS mean (SE) % change from baseline to Week 24 Alirocumab: ODYSSEY FH I and FH II Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Placebo 20 10 0 Primary Endpoint: Percent Change from Baseline to Week 24 in LDL-C All patients on background max-tolerated statin ±other lipid-lowering therapy FH I 9.1% FH II 2.8% Alirocumab Placebo -10 N=322 N=163 N=166 N=81-20 -30-40 43.4% had dose increase at W12 38.6% had dose increase at W12-50 -60 LS mean difference (SE) vs. placebo: -48.8% -48.7% 57.9% (2.7) P<0.0001 51.4% (3.4) P<0.0001 KasteleinJ.P John et al. European Heart Journal. 2015;36(43):2996-3003 ODYSSEY FH I & II)
The LDL-C on Atorvastatin 80 plus Ezetimibe 10 and Evolocumab 140 is now at 1.12 mmol/l What else do you need to do now? Cascade screening
QUESTIONS?