Statins and PCSK9 inhibitors for stroke prevention

Statins and PCSK9 inhibitors for stroke prevention Haralampos Milionis Professor of Internal Medicine School of Medicine, University of Ioannina Ioannina, Greece

Reduction in CV events (%) Every 1 mmol/l reduction in LDL-C reduces annual CV risk by up to 28%, regardless of mechanism 50 More LDL lowering and risk reduction 40 30 20 Ezetimibe Fibrate Bile acid resin Niacin Diet/unsaturated fatty acid Ileal bypass 10 IMPROVE-IT CTTC trials (statin) 0 10 20 30 40 50 60 70 80 Reduction in LDL-C (mg/dl) There is no evidence of any lower LDL-C threshold Data from studies of non-statin lipid-lowering medications superimposed upon data from the Cholesterol Treatment Trialists Collaboration (CTTC) 2005 meta-analysis. The IMPROVE-IT trial was adequately powered to show the efficacy on incremental LDL-C lowering on CV outcomes. [To convert, 100 mg/dl=2.59 mmol/l]. CV, cardiovascular; IMPROVE-IT, IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL-C, low-density lipoprotein cholesterol. CTT Collaboration. Lancet 2005:366;1267 78; CTT Collaboration. Lancet 2010;376:1670 81; Cannon CP, et al. N Engl J Med 2015;372:2387 97.

Major Statin trials in Primary Prevention and Risk of Stroke Barkas F & Milionis H. Semin Neurol 2017;37:286-93

Statins & Neuroprotection?

Potential mechanisms whereby statins may reduce the risk of stroke P. Amarenco, et al. Arch Med Sci 2007;3:S109-S114

Stroke reduction and neuroprotection by statins Vaughan C J, Delanty N Stroke 1999;30:1969-1973

Statins & Acute phase of stroke

Acute Statin Therapy, Survival, and Improved Functional Outcome After Ischemic Stroke: The North Dublin Population Stroke Study Association Between Acute Statin Ni Croinin D. et al. Stroke 2011;42:1021-9

Kaplan-Meier curves indicating 90-day survival according to statin therapy (prestroke statin treatment, new acute poststroke statin treatment, and statin-untreated). N=448 Ní Chróinín D et al. Stroke 2011;42:1021-1029

Treatment with statins and ischemic stroke severity: Does the dose matter? Pretreatment with statins is associated with lower stroke severity, at high as well as at low to moderate doses. A higher probability of mild stroke severity in the in the propensity score matched analysis (OR, 2.023, 95%CI 1.248 3.281 for the low to moderate doses and OR, 3.502, 95% CI 1.477 8.300 for the high doses of statins) Martinez-Sanchez P et al. Neurology 2013;80:1800 1805

Statin treatment withdrawal in ischemic stroke: A controlled randomized study Neurology 2007;69:904 910

Study Design Consecutive pts admitted with acute hemispheric stroke <24 hrs duration Randomly assigned to: Continuing statin therapy (atorva 20mg/d) OR Stopping for 3 days Outcome: death, dependency or END Bianco M et al. Neurology 2007;69:904 910

Results 4.66 8.67 Bianco M et al. Neurology 2007;69:904 910

Statins & Secondary Prevention

Major statin trials in subjects at high CVD risk or with a Hx of CAD and risk of stroke Barkas F & Milionis H. Semin Neurol 2017;37:286-93

Statin plus Ezetimibe after MI prevents strokes IMPROVE-IT (N=18,144 ACS patients) 30% 20% 10% Simvastatin 40 mg Simvastatin 40mg & Ezetimibe 10mg HR = 0.94* (CI 0.89-0.99) NNT= 50/6y Ischemic stroke: HR = 0.79* 1 2 3 4 5 6 7 yrs IMPROVE-IT/ Cannon NEJM 2015

SPARCL: Study design Stroke or TIA in 6 months, no known CHD, LDL-C 100 190 mg/dl N = 4731 Atorvastatin 80 mg daily n = 2365 Randomized Double blind Placebo n = 2366 Primary end point: Fatal/nonfatal stroke Secondary end points: Major coronary or CV events Follow-up: ~5 years (until >540 primary end points) SPARCL Investigators. N Engl J Med. 2006;355:549-59.

SPARCL: High-dose statin treatment reduces fatal/nonfatal stroke Primary outcome Fatal/ nonfat al stroke (%) 16 12 8 4 16% RRR* HR 0.84 (0.71 0.99) P = 0.03 Placebo Atorvastatin NNT = 46 patients for 5 years 0 0 1 2 3 4 5 6 Time since randomization (years) *Adjusted SPARCL Investigators. N Engl J Med. 2006;355:549-59.

SPARCL: Reductions in major coronary events 10 Major coronary events* (%) 8 6 4 2 35% RRR HR 0.65 (0.49 0.87) P = 0.003 Placebo Atorvastatin 0 0 1 2 3 4 5 6 Time since randomization (years) *Cardiac death, MI, resuscitated cardiac arrest SPARCL Investigators. N Engl J Med. 2006;355:549-59.

Benefit with Statin Treatment in Stroke pts SPARCL trial Men and Women 1 Young and Elderly (to 85 yrs) 2 All stroke subtypes 3 Patients with Carotid Artery Disease (symptomatic asymptomatic), Diabetes or Chronic Renal Disease 4 1: Stroke 2008; 39:2444-8 2: Neurology 2009; 72:688-94 3: Stroke 2009 ; 40:1405-9 4: Stroke 2008: 39:3297-302

Post-discharge Statin Therapy and Outcome After 1 st ever Ischemic Stroke: The Athenian Stroke Registry Milionis H et al. Neurology 2009;72:1816-22

Post-discharge statin therapy reduces 10-yr recurrence after a first-ever acute ischemic stroke Milionis et al. Neurology 2009;72:1816 1822 HR=0.65 (95%CI 0.39 to 0.97, p<0.01) 35%

Post-discharge statin therapy improves 10-yr survival after a first-ever acute ischemic stroke Milionis et al. Neurology 2009;72:1816 1822 HR=0.43 (95%CI 0.29 to 0.61, p<0.01) 57%

Forest plots of 90-day outcomes (good functional outcome and death) with statin treatment at stroke onset, in observational studies Good functional outcome N= 113,148 Death Ní Chróinín D et al. Stroke 2013;44:448-456

Lipid lowering prevents strokes Setting RR for any stroke type Statins 1 prevention 0.81* Statins 2 prevention 0.88* + Ezetimibe 2 prevention 0.79* Treatment better 0.5 1.0 2 Placebo better Amarenco Lancet Neurol 2009 IMPROVE-IT/ Cannon NEJM 2015

LDL-C Treatment Targets Very high: - CVD (including Stroke) - DM w/ target-organ lesion or w/ 1 major RF - CRD(GFR<30) - SCORE 10% Risk Category High: - 1 aggravating RG (TChol>310 mg/dl, BP>180/110 mmhg) - DM - CRD (GFR 30-59) - SCORE 5-10%, Moderate-Low: SCORE <5% LDL-C <70 or LDL-C >50% (if 70-135) LDL-C <100 or LDL-C >50% (if 100-200) LDL-C <115 Adapted from 2016 European Guidelines on CVD prevention in clinical practice

Despite benefits of current LLTs, many secondary prevention patients do not achieve LDL-C goals EUROASPIRE IV n=7998, all patients with established CHD 87% on LLTs, almost exclusively statins Almost 80% of patients on LLTs failed to reach an LDL-C goal of <1.8 mmol/l (<70 mg/dl) 42% Only 21% of patients on LLTs were at goal 79% of patients on LLTs did NOT achieve 79% NOT an at LDL-C goal goal of <1.8 mmol/l (<70 mg/dl) Data collected from patients <80 years old with established CHD, 25% women, mean age 64 years, one-third <60 years CHD, coronary heart disease; EUROASPIRE, European Action on Secondary and Primary Prevention through Intervention to Reduce Events; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy. http://www.escardio.org/about/press/press-releases/esc13-amsterdam/pages/euroaspire-iv-success-challengessecondary-prevention-cvd-europe.aspx. [Accessed 11 May 2015].

Despite benefits of current LLTs, many secondary prevention patients do not achieve LDL-C goals EUROASPIRE IV n=7998, all patients with established CHD 87% on LLTs, almost exclusively statins Almost 80% of patients on LLTs failed to reach an LDL-C goal of <1.8 mmol/l (<70 mg/dl) 42% Only 21% of patients on LLTs were at goal 79% of patients on LLTs did NOT achieve 79% NOT an at LDL-C goal goal of <1.8 mmol/l (<70 mg/dl) Data collected from patients <80 years old with established CHD, 25% women, mean age 64 years, one-third <60 years CHD, coronary heart disease; EUROASPIRE, European Action on Secondary and Primary Prevention through Intervention to Reduce Events; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy. http://www.escardio.org/about/press/press-releases/esc13-amsterdam/pages/euroaspire-iv-success-challengessecondary-prevention-cvd-europe.aspx. [Accessed 11 May 2015].

Aggressive Reduction of LDL-cholesterol PCSK9 inhibitors

Pro-protein convertase subtilisin-like kexin type 9 (PCSK9) is a secreted protease of 692 amino acids primarily expressed in the liver, intestine and kidney

MECHANISMS OF ACTION OF STATINS AND MAb AGAINST PCSK9 Statins + PCSK9 inhibitors : may prove synergistic PCSK9: From discovery to therapeutic Applications Michel Farnier - Archives of Cardiovascular Disease (2014) 107, 58 66 36

Mean Percentage Changes in Lipid Parameters with PCSK9 Inhibitors Robinson JG et al. NEJM 2015;372:1489-99 Sabatine MS et al. NEJM 2015;372:1500-9

PCSK9 Inhibition & Regression of Atherosclerosis

PCSK9 Inhibition & Cardiovascular Outcomes

PCSK9 Loss of Function and Risk of CHD or Stroke Blacks Whites Blacks CHD Stroke RR 0.51 0.82 0.84 Whites 1.06 Lower Odds 0.5 1.0 2 Higher Odds Kent St et al. Circ Cardiovasc Genet. 2017;10:e001632

Outcome Studies Evolocumab Fourier (NCT01764633) Bococizumab Spire-1 (NCT01975376) Enrolling MI, CVA, or PAD + RF; Rx with atorva 20 mg or equivalent; LDL > 70 or nonhdl > 100; Endpoint time to 1 st ASCVD event; Rx w/ 140 Q2W or 420 mg QM vs placebo; n=27,500 Enrolling high risk CVD event; LDL 70-100 or nonhdl 100-130; on LLRx; Randomized to Boco 150 mg SC Q2W vs placebo; n=12,000 Spire-2 (NCT01975389) Alirocumab ODYSSEY Outcomes (NCT01663402) Same as above except LDL > 100 or nonhdl > 130; n=6300 Enrolling post-acute MI or hospital UA w/in 12 mon; Rx w/ atorva 40/80 mg/d, rosuva 20/40 mg/d or max tolerated; LDL > 70, nonhdl > 100, or apo B > 80; Endpoint time to ASCVD event; n=18,000 www.clinicaltrials.gov

ODYSSEY Outcomes: Study Design Patient population: Recent ACS (4-52 wks before randomization*) At least one of the following: LDL-C 70 mg/dl (1.81 mmol/l), or non-hdl-c 100 mg/dl (2.59 mmol/l), or apo B 80 mg/dl despite optimal statin treatment Primary endpoint: Composite of CHD death Non-fatal MI Ischemic stroke Unstable angina requiring hospitalization Run-In Period (up to 16w) Double-Blind Treatment Period (~ 2 to 5 years) Until Month 2: 75 mg every 2w At Month 2 and beyond: 75 mg or 150 mg every 2w (adjusted at Month 2 in blinded fashion to achieve LDL-C<50 mg/dl) R Randomization M2 Alirocumab (n=9000) Placebo (n=9000) Atorvastatin 40/80mg, rosuvastatin 20/40 mg, or maximal tolerated dose of one of these statins, with non- Background Lipid Treatment: statin lipid treatments allowed Diet: NCEP-ATPIII Therapeutic Lifestyle Changes or equivalent throughout study Upon amendment 6 approval only (4-16 weeks prior to amendment 6 approval) ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS. 43 Schwartz G.G., et al., American Heart Journal 2014 168:5 (682-689.e1)

FOURIER: Study population FOURIER: Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk 27,564 patients aged 40 85 years of age Clinically evident cardiovascular disease History of myocardial infarction Non-haemorrhagic stroke Symptomatic peripheral artery disease 5330 (19.3 %) Plus 1 additional CV risk factors Fasting LDL-C 70 mg/dl or non-hdl-c 100 mg/dl Sabatine MS, et al. Am Heart J 2016;173:94 101.

Key Subgroups Subgroup Patients Overall 27564 Type of disease MI alone 19113 Stroke alone 3366 PAD alone 1505 Polyvascular disease 3563 Baseline LDL-C Q1 (<80 mg/dl) 6961 Q2 (80-<92 mg/dl) 6886 Q3 (92-109 mg/dl) 6887 Q4 (>109 mg/dl) 6829 Baseline statin intensity High 19103 Not high 8461 Ezetimibe Yes 1440 No 26124 Initial Dosing Regimen Every 2 weeks 24774 Monthly 2790 PEP HR (95% CI) Key SEP HR (95% CI) All P interactions NS An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School 0.4 1.0 2.5 0.4 1.0 2.5 EvoMab better Pbo better EvoMab better Pbo better

Amarenco Lancet Neurol 2009; IMPROVE-IT/ Cannon NEJM 2015 FOURIER / Sabatine NEJM 2017 Lipid lowering prevents strokes Setting RR Statins 1 prevention 0.81* Statins 2 prevention 0.88* + Ezetimibe 2 prevention 0.79* + Evolocumab 2 prevention 0.79* Treatment better 0.5 1.0 2 Placebo better

Aggressive Reduction of LDL-cholesterol & Safety issues?

No apparent detrimental effects associated with very low LDL-C Study treatment PROVE-IT TIMI 22 1 IMPROVE-IT 3 JUPITER 2 Atorvastatin 80 mg vs pravastatin 40 mg Rosuvastatin 20 mg vs placebo Simvastatin 40 mg ± ezetimibe 10 mg History of CVD? Yes No Yes LDL-C groups 40 mg/dl >40 60 mg/dl >60 80 mg/dl >80 100 mg/dl <50 mg/dl >50 mg/dl <30 mg/dl 30 50 mg/dl 50 70 mg/dl 70 mg/dl Safety endpoints assessed Hemorrhagic stroke, liverrelated events, musclerelated events, retinal AEs, trauma/suicide, study drug discontinuation due to AEs All treatment-emergent AEs Study drug discontinuation due to AEs, myalgias with CK, hemorrhagic stroke, AST/ALT >3x, neurocognitive AEs, gall bladder AEs, cancer, CHF causing hospitalization, non-cv death No difference in the frequency of adverse events was reported between patient groups with differing LDL-C levels [To convert, 100 mg/dl=2.59 mmol/l]. AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CHF, congestive heart failure; CK, creatine kinase; CV, cardiovascular; CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol. 1. Wiviott SD, et al. J Am Coll Cardiol 2005;46:1411 6; 2. Hsia J, et al. J Am Coll Cardiol 2011;57:1666 75; 3. Giugliano RP, et al. Presented at European Society of Cardiology, London, 2015.

Safety Evolocumab (N=13,769) Placebo (N=13,756) Adverse events (%) Any 77.4 77.4 Serious 24.8 24.7 Allergic reaction 3.1 2.9 Injection-site reaction 2.1 1.6 Treatment-related and led to d/c of study drug 1.6 1.5 Muscle-related 5.0 4.8 Cataract 1.7 1.8 Diabetes (new-onset) 8.1 7.7 Neurocognitive 1.6 1.5 Laboratory results (%) Binding Ab 0.3 n/a Neutralizing Ab none n/a New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC

Lancet 2017;Aug28

Amarenco Lancet Neurol 2009; IMPROVE-IT/ Cannon NEJM 2015 FOURIER / Sabatine NEJM 2017 Lipid lowering may increase hemorrhagic strokes Setting RR Statins 1 prevention 0.81 Statins 2 prevention 1.73* + Ezetimibe 2 prevention 1.38 + Evolocumab 2 prevention 1.16 Treatment better 0.5 1.0 2 Placebo better

Statins and cognition Current knowledge Regulatory authorities UK: MHRA warning in 2009 USA: FDA warning in 2012 PROSPER and HPS: no cognitive effects 4 RCT of statins for Alzheimer s: no effects Given the weight of evidence against adverse effects of statin therapy on memory or other aspects of cognition,... it would now be appropriate... to consider their removal from lists of potential adverse effects on the drug labels. (Collins Lancet 2016) Courtesy of P. Michel PROSPER: Trompet J Neurol 2010; HPS: Lancet 2002 Alzheimers: McGuinness / Cochrane 2014

Lipid lowering and stroke Summary of scientific data Statins: significant reduction of stroke (1 and 2 prev.) 1 mmol/l LDL reduction = 21-26% stroke Risk of hemorrhagic stroke in 2 prev.??? Adding ezetimibe: 21% stroke Adding evolocumab : 21% stroke No risk of hemorrhagic stroke; no cogn. problems Amarenco Lancet Neurol 2009; IMPROVE-IT/ Cannon NEJM 2015 *CTTC Lancet 2010; FOURIER / Sabatine NEJM 2017 Courtesy of P. Michel

Ischemic Stroke: Multi-modal Intervention Lipid-lowering therapy Lifestyle Changes CVD Risk Reduction Glycemic BP control control Antiplatelet / Anticoagulant Tx