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Integrating icosapent ethyl in clinical practice: which patients will benefits?

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Integrating icosapent ethyl in clinical practice: which patients will benefits?

Ponencia realizada el 23 de noviembre de 2022 en CardioTV titulado 'Nuevas fronteras en la reducción del riesgo CV residual. Integrando icosapento de etilo en la práctica clínica' por el Dr. Subodh Verma

Ponencia realizada el 23 de noviembre de 2022 en CardioTV titulado 'Nuevas fronteras en la reducción del riesgo CV residual. Integrando icosapento de etilo en la práctica clínica' por el Dr. Subodh Verma

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Integrating icosapent ethyl in clinical practice: which patients will benefits?

  1. 1. Practical Implications of REDUCE-IT Subodh Verma, MD, PhD, FRCSC, FAHA Professor and Cardiac Surgeon CRC Tier 1 Chair in CV Surgery CardioLink Trials Chair University of Toronto
  2. 2. Disclosures AstraZeneca, Abbott, Amgen, Amarin, Bayer, Boehringer-Ingelheim, CMS, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, PhaseBio, Sanofi, TKTWG
  3. 3. Clinical implication 1 REDUCE-IT confirms safety of IPE
  4. 4. Treatment-Emergent Adverse Events (TEAE) IPE vs placebo Icosapent Ethyl (n = 4,089) Placebo (n = 4,090) P-value Subjects with at Least one TEAE, n(%) 3,343 (81.8%) 3,326 (81.3%) 0.63 Serious TEAE 1,252 (30.6%) 1,254 (30.7%) 0.98 TEAE Leading to Withdrawal of Study Drug 321 (7.9%) 335 (8.2%) 0.60 Serious TEAE Leading to Withdrawal of Study Drug 88 (2.2%) 88 (2.2%) 1.00 Serious TEAE Leading to Death 94 (2.3%) 102 (2.5%) 0.61 TEAE = treatment – emergent adverse event Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.
  5. 5. Adverse Events of interest: Bleeding: IPE vs placebo Icosapent Ethyl (n = 4,089) Placebo (n = 4,090) P-value Bleeding related disorders, n (%) 111 (2.7%) 85 (2.1%) 0.06 Gastrointestinal bleeding 62 (1.5%) 47 (1.1%) 0.15 Fatal Bleeding 0 (0.0%) 0 (0.0%) 1.00 Central nervous system bleeding 14 (0.3%) 10 (0.2%) 0.42 Hemorrhagic Stroke 13 (0.3%) 10 (0.2%) 0.55 Other bleeding 41 (1.0%) 30 (0.7%) 0.19 Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.
  6. 6. Adjudicated Events: Hospitalization for Atrial Fibrillation or Atrial Flutter Primary System Organ Class Preferred Term Icosapent Ethyl (n = 4,089) Placebo (n = 4,090) P-value Positively Adjudicated Atrial Fibrillation / Atrial Flutter 127 (3.1%) 84 (2.1%) 0.004 Note: Percentages are based on the number of subjects randomized to each treatment group in the Safety population (N). All adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA Version 20.1). [1] Includes positively adjudicated Atrial Fibrillation/Flutter clinical events by the Clinical Endpoint Committee (CEC). P value was based on stratified log - rank test. Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.
  7. 7. Clinical implication 2 Efficacy: on top of “placebo”
  8. 8. Key Baseline Characteristics Icosapent Ethyl (n = 4,089) Placebo (n = 4,090) Age (years) , Median (Q1-Q3) 64.0 (57.0 – 69.0) 64.0 (57.0 - 69.0) Female, n (%) 1,162 (28.4%) 1,195 (29.2%) Non-White, n (%) 398 (9.7%) 401 (9.8%) Westernized Region, n (%) 2906 (71.1%) 2905 (71.0%) CV Risk Category, n (%) Secondary Prevention Cohort 2892 (70.7%) 2893 (70.7%) Primary Prevention Cohort 1197 (29.3%) 1197 (29.3%) Ezetimibe Use, n (%) 262 (6.4%) 262 (6.4%) Statin Intensity, n (%) Low 254 (6.2%) 267 (6.5%) Moderate 2533 (61.9%) 2575 (63.0%) High 1290 (31.5%) 1226 (30.0%) Type 2 Diabetes, n (%) 2367 (57.9%) 2363 (57.8%) Triglycerides (mmol/L), Median (Q1-Q3) 2.45 (2.0 – 3.07) 2.44 (1.98 – 3.10) HDL-C (mmol/L), Median (Q1-Q3) 1.03 (0.89 – 1.19) 1.03 (0.91 – 1.19) LDL-C (mmol/L), Median (Q1-Q3) 1.91 (1.59 – 2.28) 1.97 (1.63 – 2.30) Triglycerides Category < 1.69 mmol/L 412 (10.1%) 429 (10.5%) 1.69 to <2.26 mmol/L 1193 (29.2%) 1191 (29.1%) > 2.26 mmol/L 2481 (60.7%) 2469 (60.4%) Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.
  9. 9. NNT4.9 years
  10. 10. Clinical implication 3 Reduction in CV Death
  11. 11. 20% reduction in CV Death in REDUCE-IT RRR 25% 26% 25% 31% 35% 20% 32% 28% 23% Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.
  12. 12. Clinical implication 4 Benefit at all levels of LDL-C and TG
  13. 13. Benefit agnostic of baseline TG or LDL-C (≥1.70 mmol/L) (≥ 2.26 mmol/L) (≤0.90 mmol/L) (≤1.73 mmol/L) (>2.17 mmol/L) (>1.73 to ≤ 2.17 ) Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.
  14. 14. Clinical implication 5 Consistent efficacy in high risk primary and secondary prevention
  15. 15. Consistent benefits in both cohorts Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.
  16. 16. Clinical implication 6 Efficacy across all eGFR
  17. 17. Consistent Efficacy Benefit across all eGFR categories Prespecified and Post-hoc Analysis Overall Population 0.75 (0.68 – 0.83) 901/4090 (22.0%) 705/4089 (17.2%) Prespecified Baseline eGFR Group <60 mL/min/1.73 m² 60 to <90 mL/min/1.73 m² ≥90 mL/min/1.73 m² 0.41 Post hoc Baseline eGFR Group ≥15 to <30 mL/min/1.73 m² ≥30 to <45 mL/min/1.73 m² ≥45 to <60 mL/min/1.73 m² ≥60 mL/min/1.73 m² 0.52 Interaction P-value Endpoint/Subgroup Hazard Ratio (95% CI) Icosapent Ethyl n/N (%) Placebo n/N (%) Icosapent Ethyl vs Placebo HR (95% CI) 0.5 Icosapent Ethyl Better Placebo Better 1.0 1.5 2.5 Primary Composite Endpoint 0.71 (0.59 – 0.85) 0.80 (0.70 – 0.92) 0.70 (0.56 – 0.89) 263/911 (28.9%) 468/2238 (20.9%) 170/939 (18.1%) 197/905 (21.8%) 380/2217 (17.1%) 128/963 (13.3%) 0.59 (0.21 – 1.68) 0.83 (0.59 – 1.16) 0.66 (0.53 – 0.84) 0.77 (0.69 – 0.87) 10/37 (27.0%) 77/232 (33.2%) 176/642 (27.4%) 638/3177 (20.1%) 7/29 (24.1%) 63/219 (28.8%) 127/657 (19.3%) 508/3180 (16.0%) Primary Endpoint by Baseline eGFR Majithia A et al. Circulation. 2021;144:1750–1759; Majithia A, Bhatt DL, Friedman AN, et al. ASN 2020, Virtual
  18. 18. Clinical implication 7 Marked reduction in stroke
  19. 19. Icosapent Ethyl Reduced First Ischemic Strokes (RRR 36%) Cumulative Events per Patient 0 1 5 2 3 4 Years Since Randomization 0.0 0.01 0.02 0.03 0.04 0.08 0.06 0.07 0.05 Placebo: First Events Icosapent Ethyl: First Events Bhatt DL. ISC 2021, virtual.
  20. 20. Clinical implication 8 Broad generalizability
  21. 21. Québec Heart CABG Population Kosmopoulos A, Verma S, Meglis G, Bhatt DL, Verma R, Mazer CD, Voisine P. Curr Opin Cardiol 2020.
  22. 22. 1 in 4 would patients with ASCVD would meet REDUCE-IT Criteria
  23. 23. Clinical implication 9 Translational data: atherosclerosis regression
  24. 24. Univariable analysis and multiple linear regression were used to examine the change in plaque levels between the cohorts. Multivariable models were adjusted by baseline plaque, age, sex, diabetes status, hypertension, and baseline triglyceride levels. Budoff M et al. Eur Heart J. 2020 Aug 29:ehaa652. 25 EVAPORATE Trial: Change in Plaque Low Attenuation P = .0061 Fibro-Fatty P = .0002 Fibrous P = .0028 Calcification P = .0531 Total Non- calcified P = .0005 Total Plaque P = .0005 -0,33 -0,91 -0,85 -0,03 -0,84 -0,45 0,86 0,48 0,02 0,44 0,33 0,45 -1,0 -0,5 0,0 0,5 1,0 Mean Log-Adjusted Change in Plaque Volume From Scan 1 to Scan 3 Icosapent… Primary Endpoint Secondary Endpoints Change in Log-Adjusted Plaque Volume From Baseline to Final Scan, Randomized by Treatment Group
  25. 25. Clinical implication 10 Widespread guideline endorsement
  26. 26. Leading Global Medical Societies Recognize IPE as an Important CV Treatment Option 27 28 Global Medical Societies recognize IPE as an important treatment for ASCVD 3 Years of continuous and progressive recognition from multiple societies with supports from endocrinologists, cardiologists, and stroke neurologists. ESC/EAS Aug 20195 Jan 20192 Thrombosis Canada Feb 20207 CCS Dyslipidemia Mar 20219 1. American Diabetes Association. Diabetes Care. 2020;43(Suppl 1): S111-S134; 2. Kimura K, et al. Circ J. 2019;83(5):1085-1196; 3. Orringer CE, et al. J Clin Lipidol. 2019;13(6):860-872; 4. Skulas-Ray AC, et al. Circulation. 2019;140(12):e673-e691; 5. Mach F, et al. Eur Heart J. 2020;41(1):111-188; 6. Garber AJ, et al. Endocr Pract. 2020;26(1):107-139; 7. Thrombosis Canada. 2020; https://thrombosiscanada.ca/wp-content/uploads/2020/02/Stroke-Secondary-Prevention_26Feb2020.pdf; 8. Arnold SV, et al. Circulation. 2020;141:e000–e000. 9. Pearson GJ, et al. Can J Cardiol. 2021;37(8):1129-1150; 10. Kleindorfer DO, et al. Stroke. 2021;52(7):e364-e467; 11. Gladstone DJ, et al. Can J Neurol Sci. 2021:1-69; 12. Virani SS, et al. J Am Coll Cardiol. 2021;78(9):960-993; 13. Visseren FLJ, et al. Eur Heart J. 2021;42(34):3227-3337; 14. Handelsman y, et al. J Diabetes Complications. 2021; https://doi.org/10.1016/j.jdiacomp.2021.108101. 15. Abramson et al, 2022 Canadian Cardiovascular Society Guidelines for Peripheral Artery Disease, Canadian Journal of Cardiology; DOI:https://doi.org/10.1016/j.cjca.2022.02.029 ESC Guidelines on CVD Prevention Aug 202113 CSC Jun 202111 2019 2021 2020 May 20191 Jan 20206 Sep 20193,4 Apr 20208 May 202110 ACC DCRM14 July 202112 Dec 2021 Feb 2022 CCS PAD 15
  27. 27. The 2021 Canadian Lipid Guidelines for Icosapent Ethyl (IPE) Pearson GJ et al. Can J Cardiol. 2021 Mar 26:S0828-282X(21)00165-3. doi: 10.1016/j.cjca.2021.03.016. We recommend the use of IPE to lower the risk of CV events In patients with ASCVD STRONG RECOMMENDATION HIGH QUALITY EVIDENCE In patients with diabetes and  1 risk factor TG 1.5-5.6 mmol/L and maximum tolerated statin
  28. 28. It’s not sequential – but horizontal integration Adapted from Pearson GJ et al. Can J Cardiol. 2021 Mar 26:S0828-282X(21)00165-3. doi: 10.1016/j.cjca.2021.03.016. Intensify LDL-C lowering IPE 2g BID
  29. 29. 2022-11-23 30
  30. 30. Salim S. Virani et al. J Am Coll Cardiol 2021; 78:960-993.
  31. 31. Clinical implication 11 Its not fish oil: Formulation matters
  32. 32. Pearson GJ et al. Can J Cardiol. 2021 Mar 26:S0828- 282X(21)00165-3. doi: 10.1016/j.cjca.2021.03.016. We do not recommend the use of OTC omega-3 PUFA supplements to lower the risk of CV events These are marketed as natural health products in Canada STRONG RECOMMENDATION HIGH QUALITY EVIDENCE The 2021 Canadian Lipid Guidelines
  33. 33. Pearson GJ et al. Can J Cardiol. 2021 Mar 26:S0828- 282X(21)00165-3. doi: 10.1016/j.cjca.2021.03.016. The 2021 Canadian Lipid Guidelines Supplementation with OTC long chain PUFAs marketed as natural health products in Canada that include EPA alone, EPA and DHA mixtures, or fish oils from supplements or dietary sources does not offer any clear advantage for CVD risk reduction
  34. 34. “It should be noted that data are lacking with other omega-3 fatty acids, and results of the REDUCE-IT trial should not be extrapolated to other products.”
  35. 35. -Life saving -Safe+++++ -Guideline changing -Cost saving
  36. 36. Eur Heart J, Volume 42, Issue 1, 1 January 2021, Pages 113–131, https://doi.org/10.1093/eurheartj/ehaa099 Key contemporary residual risk pathways in secondary prevention
  37. 37. • 66-year-old male • MI 3 years ago, DES X 2, restenosis • CABG 1 year ago 38 Meet the Patient: Timothy, Teacher • BMI: 27 kg/m2 • BP: 125/80 mmHg • Atorvastatin 40 mg QD (stable for 5 years) • ASA 81 mg QD • Ticagrelor 60 mg BID • Ramipril 10 mg BID • Fasting TG: 2.0 mmol/L • LDL-C: 1.6 mmol/L • HDL-C: 1.1 mmol/L .
  38. 38. • 53-year-old female • T2DM for 8 years • Hypertension • No clinically evident CV disease 39 Meet the Patient: Maria, Lawyer • BMI: 30 kg/m2 • BP: 135/85 mmHg • HbA1c: 7.1% • Sitagliptin/metformin HCl (100 mg/1000 mg) QD • Atorvastatin 40 mg QD • Ramipril 10 mg QD • Takes omega-3 supplement • Fasting TG: 2.4 mmol/L • LDL-C: 1.9 mmol/L • HDL-C: 1.0 mmol/L

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