Investigator Meeting. Monday, September 12, 2016

Transcription

1 Investigator Meeting Monday, September 12, 2016

2 Principal Investigators Milan Gupta, MD, FRCPC, FACC Associate Clinical Professor of Medicine, McMaster University Brampton, ON Steering Committee David Bewick, MD, FRCP, FACP, FACC Associate Professor, Dalhousie University Saint John, NB Daniel Gaudet, MD, PhD Lipid Unit Director, Community Genomic Medicine Center Associate Professor, Université de Montréal Montréal, QC Jacques Genest, MD, CM, FRCPC, FACC, FAHA Professor, Faculty of Medicine, McGill University Montréal, QC Narendra Singh, MD, FRCPC, FACC, FAHA Clinical Assistant Professor, Medical College of Georgia at Augusta University Atlanta, GA Rob Hegele, MD, FRCPC, FACP, FAHA, FCAHS Department of Medicine, Schulich School of Medicine and Dentistry, Western University London, ON Eva Lonn, MD, MSc (HRM, McMaster), FRCPC, FACC Professor, Division of Cardiology, Department of Medicine McMaster University Hamilton, ON Daniel Ngui, MD, BSc (P.T), MD, CFPC, FCFP Vancouver, BC

3 Agenda 12:00 Introduction Dr. Milan Gupta 12:05 Practical Management, PCSK9i/Ezetimibe Dr. Milan Gupta 12:15 Lipid Guidelines Update Dr. Jacques Genest 12:25 Question and Answer Dr. Narendra Singh 12:35 REACT Protocol Review Michelle Tsigoulis 12:42 Case Report Form Review Mahesh Kajil 12:49 Good Clinical Practice Guidelines Stephanie Effendi 12:54 Question and Answer Michelle and Dr. Gupta 1:00 Closing remarks Dr. Milan Gupta

4 Scandinavian Simvastatin Survival Study (1994) Primary End Point: Total Mortality Secondary End Point: Major Coronary Events Proportion alive Placebo Simvastatin 30% Total mortality P=.0003 Proportion without major coronary event Placebo Simvastatin 34% Major coronary events P= Years since randomization 4S=Scandinavian Simvastatin Survival Study Group. Primary end point of trial was total mortality. Secondary end point was first major coronary event defined as coronary death, nonfatal definite or probable myocardial infarction (MI), silent MI, or resuscitated cardiac arrest. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344: Years since randomization

5 Lessons from the CTTC meta-analysis Statins lower risk to the same relative degree independent of baseline risk and baseline LDL-C The absolute risk benefit with statins is greatest in the highest risk patients High intensity vs. lower intensity statin therapy further lowers risk No RCT has tested a specific strategy of dosing statin to achieve a pre-specified LDL-C target However, evidence suggests that treatment at lower and lower levels, leading to lower and lower achieved LDL-C levels, supports a "lower is better" philosophy 1. Cholesterol Treatment Trialists (CTT) Collaboration. Lancet. 2010;376: Cholesterol Treatment Trialists (CTT) Collaborators. Lancet. 2005;366:

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7 26,846 High-Risk Patients Worldwide Mean LDL = 2.6 mmol/l

8 Barriers to LDL-C Management Over reliance on diet Use of insufficient starting doses Inability to reach more aggressive targets even with high dose statin Lack of followup for uptitration Complacency with sub-optimal cholesterol values achieved Confusion around recommended lipid targets Fear of sideeffects of statins Inertia Patient Non- Adherence Media / Dr. Google 8

9 Why REACT? The benefits of LDL-C lowering in high risk patients are irrefutable. We have new evidence demonstrating that risk can be lowered with non-statin drugs (ezetimibe / IMPROVE-IT). New non-statin drugs, PCSK9 inhibitors, have been introduced into the Canadian marketplace. Updated recommendations for the diagnosis and management of statin intolerance have recently been published. We have new, evidence-based lipid guidelines in Canada. Incorporating new guidelines and drugs into clinical practice should result in better outcomes for high risk patients.

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11 Lipid Guidelines Update Jacques Genest MD, CM, FRCPC, FACC, FAHA

12 DYSLIPIDEMIA GUIDELINES DYSLIPIDEMIA Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult DYSLIPIDEMIA GUIDELINES

13 Canadian Journal of Cardiology DOI: ( /j.cjca ) Copyright 2016 Terms and Conditions

14 Canadian Journal of Cardiology DOI: ( /j.cjca ) Copyright 2016 Terms and Conditions

15 Framingham Risk Score Estimation of 10-year CVD Risk

16 Primary and Secondary Lipoprotein Determinants Recommendations We recommend that non-hdl-c and apo B should continue to be considered alternate targets to LDL-C to evaluate risk in adults Strong Recommendation, High Quality Evidence Values and preferences As clinicians are most familiar with LDL-C we continue to recommend its use as the primary target, but anticipate a shift to preferential use of non-hdl-c or apo B in the future.

17 Canadian Journal of Cardiology DOI: ( /j.cjca ) Copyright 2016 Terms and Conditions

18 Figure 2 Strong Recommendation, Moderate-Quality Evidence

19 Figure 3 Conditional Recommendation, Moderate-Quality Evidence Strong Recommendation, Moderate-Quality Evidence

20 Figure 4 Strong Recommendation, High-Quality Evidence

21 Approach to Risk Management

22 Figure 5 Risk Level Initiate therapy if Primary Target LDL-C High FRS 20% Intermediate FRS 10-19% Consider treatment in all (Strong, High) LDL-C 3.5 mmol/l (Strong, Moderate) For LDL-C < 3.5 consider if: Apo B 1.2 g/l or Non-HDL-C 4.3 mmol/l TARGETS 2 mmol/l or 50% decrease in LDL-C (Strong, High) 2 mmol/l or 50% decrease in LDL-C (Strong, Moderate) Alternate Target Apo B 0.8 g/l Non HDL-C 2.6 mmol/l (Strong, High) Apo B 0.8 mg/l Non HDL-C 2.6 mmol/l Low FRS <10% LDL-C 5.0 mmol/l Familial hypercholesterolemia (Strong, Moderate) 50% reduction in LDL- C (Strong, Moderate)

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24 Practical Management, PCSK9i/Ezetimibe Milan Gupta MD, FRCPC, FACC

25 Practical Management Issues High potency statins (atorvastatin mg, rosuvastatin mg) should be used to achieve LDL-C targets. Statin intolerance Ezetimibe PCSK9 inhibitors

26 The Elephant in the Room: Goal-inhibiting Statin Intolerance (GISI) Mancini GBJ et al. Can J Cardiol 2016; 10:1016

27 Trials of Atorvastatin mg daily/intermittently Trials of Rosuvastatin 5-40 mg daily/intermittently Partial or complete intolerance Partial or complete intolerance Trials of Rosuvastatin 5-40 mg daily/intermittently Trials of Atorvastatin mg daily/intermittently Partial or complete intolerance to Atorvastatin and/or Rosuvastatin* *Other statins (Simva 40 mg, Lova 80 mg, Prava 40 mg, Fluva 80 mg) may be the only tolerated statins but due to lower potency and ineffectiveness of intermittent dosing schedules, failure to achieve goals solely through trials of these statins would not normally be considered adequate for establishing GISI. Mancini et al, DOI:

28 Practical Management Issues High potency statins (atorvastatin mg, rosuvastatin mg) should be used to achieve LDL-C targets. Statin intolerance Ezetimibe PCSK9 inhibitors

29 IMPROVE-IT Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization ( 30 days), or stroke Hazard Ratio, (95% CI, ) p=0.016 Simvastatin: 34.7% events Mean LDL-C = 1.8 mmol/l NNT*= 50 Event Rate (%) Simvastatin/Ezetimibe: 32.7% events Mean LDL-C = 1.4 mmol/l Time since randomization (years) * NNT = Number Needed to Treat Cannon CP et al. N Engl J Med 2015;372:

30 IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit IMPROVE-IT CTT Collaboration. Lancet 2005; 366: ; Lancet 2010;376:

31 Non-Statin Therapy 31 Recommendations 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 31

32 Practical Management Issues High potency statins (atorvastatin mg, rosuvastatin mg) should be used to achieve LDL-C targets. Statin intolerance Ezetimibe PCSK9 inhibitors

33 In the Presence of PCSK9, the LDL-R Is Degraded and Does Not Cycle Back to Cell Surface LDL Plasma PCSK9 LDL LDL-R LDL-R Endocytosis Hepatocyte Endocytosis Endosom e PCSK9 Self-procession LDL-R Recycling Endosome LDL Degradation LDL, LDL-R and PCSK9 Degradation Nucleu s Golgi Apparatus Endoplasmic Reticulum (ER) 2013 Amgen Canada Inc. All rights reserved. Qian YW, et al. J Lipid Res. 2007;48: ; Horton JD, et al. J Lipid Res. 2009;50(suppl):S172-S177.

34 Blocking PCSK9 Activity Inhibits Intracellular Degradation of LDL-R PCSK9 MAb Plasma LDL LDL-R Recycling LDL-R Endocytosis Hepatocyte Endosom e PCSK9 Self-procession LDL Degradation Lyosome Nucleu s Golgi Apparatus Endoplasmic Reticulum (ER) 2013 Amgen Canada Inc. All rights reserved. Qian YW, et al. J Lipid Res. 2007;48: ; Horton JD, et al. J Lipid Res. 2009;50(suppl):S172-S177.

35 PCSK9 Inhibitors Alirocumab Administration 1 injection SC q2wk, Doses: 75 mg or 150 mg Auto-injector ALIROCUMAB ALIROCUMAB Evolocumab Administration 1 injection SC q2wk, Dose: 140 mg 3 injections SC q4wk Total Dose: 420 mg Auto-injector 35

36 Evolocumab: Phase III LDL-C Lowering Summary % Change from Baseline In Reflexive LDL-C % 56.9% MENDEL-2* (Monotherapy) Q2W 0.4% 1.4% 1.3% 17.5% Q2W 57% QM GAUSS-2* (Statin Intolerance) 19.2% 56.1% 56.1% 17.8% 18.1% 19.1% 58.8% 56.1% QM 16.6% 55.3% 52.6% % % LAPLACE-2 (Combo with Statin) Q2W QM +6.8% +8.1% +3.2%+4.6% 62% 63% 64% 58% 1% 1% RUTHERFORD-2 (FH, Combo with Statin) Q2W QM 61% 61% +2% +5% 64% 56% Placebo wk10&12 Placebo wk12 EvoMab wk10&12 EvoMab wk12 Ezetimibe wk10&12 Ezetimibe wk12 *Ezetimibe comparator Koren MJ, et al. J Am Coll Cardiol. 2014;63(23): (MENDEL-2); Stroes E, et al. JACC 2014: /j.jacc (GAUSS-2); Robinson JG, et al. JAMA. 2014;311(18): doi: /jama (LAPLACE-2); Raal F, et al. Lancet Published Online October 2,

37 Alirocumab: Phase III LDL-C Lowering Summary % change from baseline in calculated LDL-C Monotherapy Q2W n=52 EZE n=51-16% -47% (26.9% had dose increase at W12) FH I 20.7% Alirocumab 75 mg with potential to 150 mg Q2W SC at week 12 LDL-C >1.8mmol/L Unable to tolerate at least 2 different statins, including one at lowest dose, due to muscle-related symptoms. Alternative Kastelein JJP, et al. Presented at ESC Sept 2014 (FH I & FH II); Roth EM, et al. Int J Cardiol Sep;176(1):55-61 (MONOTHERAPY); Cannon CP, et al. Presented at ESC Sept 2014 (COMBO II): Moriarity PM, et al. Presented at AHA Nov 2014 (Alternative). FH II COMBO II (HeFH, Combo with Statin) (Combo with Statin) (Statin intolerant ) Q2W EZE 9.1% Q2W EZE Q2W EZE 2.8% N=163 N=322 N=81 N= % 48.7% (43.4% had dose increase at W12) (38.6% had dose increase at W12) N= % (18.4% had dose increase at W12) N=240 N= % N=122 (49.5% had dose increase at W12) 14.6% Placebo Alirocumab Ezetimibe

38 Evolocumab: Adverse Event Profile at Week 52 (OSLER 1 and 2) Evolocumab + stnd of care (N=2976) Standard of care alone (N=1489) Adverse Events (%) Any 69.2% 64.8% Serious 7.5% 7.5% Leading to discontinuation of evolocumab 2.4% n/a Injection-site reactions 4.3% n/a Muscle-related 6.4% 6.0% Neurocognitive 0.9% 0.3% Laboratory results (%) ALT or AST >3 ULN 1.0% 1.2% Creatine kinase >5 ULN 0.6% 1.1% Pooled analysis from extension studies (OSLER 1 and 2) Sabatine MS, et al. N Engl J Med. 2015;372(16):

39 Alirocumab: Adverse Event Profile at Week 70 (ODYSSEY Long Term study) Alirocumab (n=1550) Placebo (N=788) Adverse Events (%) Any 81% 82.5% Serious 18.7% 19.5% Leading to discontinuation of alirocumab 7.2% 5.8% Injection-site reactions 5.9% 4.2% Muscle-related 5.4% 2.9% Neurocognitive 4.2% 4.4% Laboratory results (%) ALT & AST >3 ULN 1.8% & 1.4% 2.1% & 2.3% Creatine kinase >3 ULN 3.7% 4.9% Adverse events were defined as those that developed, worsened, or became serious after the first injection and up to 10 weeks after the last injection Adapted from Robinson J, et al. N Engl J Med. 2015;372(16):

40 Outcome Trials with PCSK9 Inhibitors Study FOURIER ODYSSEY OUTCOMES SPIRE-1/ SPIRE-2 Treatment Evolocumab: 420 mg QM or 140 mg Q2W Background: optimal lipid lowering therapy Alirocumab: 75 mg Q2W (up titrated to 150 mg Q2W if LDL >1.3 mmol/l; down titrated if LDL <0.65 mmol/l) Background: optimized lipid lowering therapy Bococizumab: 150 mg Q2W Background: lipid lowering therapy Population MI or stroke ( last 4 weeks) OR PAD (plus Risk factors for CVD) Patients hospitalized for ACS (<12 months before randomization) Patients at high risk of a CV event # patients 27,500 18,000 SPIRE-1: 17,000 SPIRE-2: 9,000 LDL-C for eligibility LDL-C 1.8 mmol/l (or non- HDL-C 2.6 mmol/l) after 4 week stabilization with optimal lipid lowering therapy 1.8 mol/l or non-hdl-c 2.6 mmol/l SPIRE-1: LDL-C 1.8 and <2.6 mmol/l SPIRE-2: LDL-C 2.6 mmol/l or non-hdl-c 3.4 mmol/l Estimated study completion 2017 December 2017 SPIRE-1:June 2018 SPIRE-2: March 2018 ACS: acute coronary syndrome; CAD: coronary artery disease; CHD: coronary heart disease; CVD: coronary vascular disease; EZE: ezetimibe; FH:Familial Hypercholesterolemia; HeFH: Heterozygous Familial Hypercholesterolemia; PAD: peripheral-artery disease; T2DM: type 2 diabetes mellitus. clinicaltrials.gov accessed August 25, 2015.

41 Non-Statin Therapy 41 Recommendations 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. 41

42 Questions and Answers Narendra Singh MD, FRCPC, FACC, FAHA

43 REACT Protocol Review Michelle Tsigoulis CCRN Executive Director

44 Protocol Review: REACT Title: Relating Evidence to Achieve Cholesterol Targets Description: An observational practice assessment. Design: A prospective, non-interventional, multicentre, practice assessment of Canadian adults with ASCVD and FH.

45 Protocol Review: REACT Primary Objective To facilitate the identification and management of patients with high residual CV risk attributable to LDL-C

46 Secondary Objectives To characterize the clinical profile, lipid levels, and treatment strategies of patients at high risk for CV events (those with ASCVD and those with FH) To provide a contemporary assessment of patients with LDL-C above target, and the potential reasons for this To enable clinicians to use evidence-based guidelines and treatments to close care gaps, resulting in more patients achieving LDL-C target levels

47 Patient Eligibility Inclusion Criteria: Consecutive subjects over 18 years of age with documented atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH) LDL-C level within past 3 months >3.0 mmol/l despite maximally tolerated statin treatment Willingness to give informed consent

48 Patient Eligibility Exclusion Criteria: Current use of a PCSK9 inhibitor Active participation in a randomized clinical trial involving a lipid-modifying agent Co-morbidities with anticipated life expectancy < 12 months Pregnancy or nursing mothers

49 Visit Outline Baseline - Week 0 Site follow-up Week 12 (± 4 weeks) Site follow-up Week 24 (± 4 weeks)

50 Visit 1 Patient consent Demographics Medical history and CV risk factors Vital signs and anthropometric measurements Laboratory collection (-12 to +1 wk) Concomitant therapies Investigator assessment of patient LDL-C target and goal Investigator decision regarding LDL-C/Lipidlowering therapy

51 Protocol Review: REACT Visit 2 - wk 12 and Visit 3 - wk 24 (+/- 4wks) Vital signs and anthropometric measurements Laboratory collection (+/-2wks) Concomitant therapies Investigator assessment of patient LDL-C target and goal Investigator decision regarding LDL-C/Lipidlowering therapy Assessment for adverse events/suspected adverse drug reactions since last visit Assessment for ASCVD events and/or death since last visit

52 Collection of ASCVD Events/Death Death any cause Myocardial Infarction or Acute Coronary Syndrome PCI or CABG Angiogram confirming at least 70% stenosis of a major epicardial coronary artery or at least 50% stenosis of the left main coronary artery Ischemic stroke not-attributable to atrial fibrillation Carotid revascularization by endarterectomy or stenting Peripheral arterial disease with either symptomatic with ABI < 0.9 or requiring revascularization or amputation Atherosclerosis felt to be clinically relevant by physician

53 Collection of Events The coordinating centre office will collect source documents for reported medical events occurring after the baseline visit. The site will complete the event report and fax supporting documentation to CCRN on a shuttle form.

54 Adverse Events and Suspected Adverse Drug Reactions AE s will be collected at visit 2 and 3 on the Adverse Event form. AE s suspected to be an adverse drug reaction related to any of the patient s current drug therapies will require further reporting on the Suspected Adverse Drug Reaction report form. The SADR form will capture all Events that in the investigator s opinion is believed to be potentially related to a current medical therapy. SADR form to be submitted to CCRN within 24 hours of becoming aware of the suspected adverse drug reaction.

55 Case Report Form Review Mahesh Kajil Project Manager

56 REACT Visit Schedule Visit 1 (Baseline): Week 0 Visit 2: Week 12 (+/- 4 weeks) Visit 3: Week 24 (+/- 4 weeks) All three visits are clinic visits

57 Visit 1 Baseline Inclusion Criteria PAGE #1

58 Pt ID will be prefilled. The first 3 digits corresponds to your site # and the last 2 digits will be the patient number. Visit 1-Baseline, PAGE #1 Electronic Data Capture form EDC training to be provided

59 Visit 1 Baseline PAGE #2

60 Pt ID will be auto filled Visit 1 Baseline PAGE #2 EDC

61 Visit 1 Baseline PAGE #3

62 Visit 1 Baseline PAGE #4 Question A is optional. Required only if the patient is not currently receiving a potent statin therapy Question B is required only if the patient is statin intolerant

63 Visit 1 Baseline PAGE #5

64 Visit 1 Baseline PAGE # 6 **The LDL-C target goal must be indicated by the investigator

65 Visit 1 Baseline PAGE #7 OPTIONAL

66 Visit 2/3

67 Visit 2/3

68 Visit 2/3

69 Visit 2/3 OPTIONAL

70 ASCVD or Death Event Report Form Visit 2/3

71 Adverse Event Report Form Visit 2/3

72 Suspect Adverse Drug Reaction Form Visit 2/3 Paper-based form to be faxed to CCRN within 24hrs of becoming aware of the event.

73 Good Clinical Practice Stephanie Effendi Project Coordinator

74 Definition and Goals What is GCP? GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials What are the goals of GCP? 1. To protect the rights, safety and welfare of humans participating in research 2. To assure the quality, reliability and integrity of the data collected 3. To provide standards and guidelines for the conduct of clinical research

75 3 Key Principles of GCP 1. Research is conducted by a qualified investigator 2. Informed consent 3. Ethics

76 Qualified Investigator Responsibilities Be qualified by education, training and experience Holds the overall responsibility for the conduct of the study as well as the safety and medical care of the participants. Communication with the Research Ethics Board Compliance with the protocol Maintenance of study records and reports Oversight of research staff

77 What is the Research Ethics Board? (REB) An institution that reviews the ethical acceptability of all research involving humans The review committee consists of a body of researchers, community members, and others with specific expertise (e.g. in ethics, in relevant research disciplines)

78 REB Approval Before an investigator can begin a study at his/her site, REB approval must first be obtained. The REB will review the following: Study protocol Informed consent form Any documents being provided to or to be viewed by the study subjects The REB will conduct continuing review of each ongoing trial at least once a year.

79 Informed Consent Informed consent must be obtained from all study participants prior to engaging in any study related activities.

80 How to Obtain Informed Consent Ensure the study subject meets all inclusion and exclusion criteria Provide the subject time to read the consent form and to ask questions Ensure questions are answered to the subjects satisfaction Allow the subject time to discuss participation with others Have the subject sign and date the consent form The PI or delegated study staff obtaining consent must also sign and date the consent form Provide the subject a copy of the signed consent

81 What constitutes GCP in research? Research conducted by a qualified investigator Research ethics board (REB) approval of protocol Valid informed consent Proper documentation and record keeping Accurate reporting Data verification and monitoring plan

82 Questions and Answers Milan Gupta MD, FRCPC, FACC Michelle Tsigoulis CCRN Executive Director

83 Close