CARDIOLOGY GRAND ROUNDS

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1 CARDIOLOGY GRAND ROUNDS Title: Treatment of hyperlipidemia with non-statin therapy and PCSK9 Inhibitors: Ready for Prime Time? Speaker: Thomas G. Knickelbine, MD Minneapolis Heart Institute at Abbott Northwestern Hospital Date: Monday, September 19, 2016 Time: 7:00 8:00 AM Location: ANW Education Building, **WATSON ROOM** **GO TO OUR NORMAL MEETING SPACE** OBJECTIVES At the completion of this activity, the participants should be able to: 1. Review ACC /AHA 2013 and 2016 treatment guidelines 2. Identify the criteria for the use of PCSK9 Inhibitors. 3. Explain how to diagnose Familial Hypercholesterolemia. 4. Discuss cost/ benefit issues of using PCSK9 Inhibitors. Physician: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Allina Health and Minneapolis Heart Institute Foundation. Allina Health is accredited by the ACCME to provide continuing medical education for physicians. Allina Health designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit(s) TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse: This activity has been designed to meet the Minnesota Board of Nursing continuing education requirements for 1.2 hours of credit. However, the nurse is responsible for determining whether this activity meets the requirements for acceptable continuing education. DISCLOSURE STATEMENTS Speaker Dr. Knickelbine has declared that he does not have any conflicts of interest to disclose. Planning Committee Planning Committee: Dr. JoEllyn Carol Moore (Abraham), MD, Dr. Alex Campbell, Dr. Kevin Harris, Rebecca Lindberg, Dr. Michael Miedema, Dr. Scott Sharkey, Eva Zewdie and Jolene Bell Makowesky have declared that they do not have any conflicts of interest associated with the planning of this activity. Dr. David Hurrell declares the following relationship honoraria: Boston Scientific. PLEASE SAVE A COPY OF THIS FLIER AS YOUR CERTIFICATE OF ATTENDANCE Signature: My signature verifies that I have attended the above stated number of hours of the CME activity. Allina Health - Learning & Development Chicago Ave - MR Minneapolis MN 55407

2 Update on the Treatment of Hyperlipidemia with Non Statin Therapy including PCSK9 Inhibitors: Are they ready for Prime Time? Thomas Knickelbine, MD Director: Preventive Cardiology Minneapolis Heart Institute Minneapolis MN Disclosures: Clinical Investigator (site PI) ODYSSEY TRIALS (Alirocumab/Sanofi Regeneron): ODYSSEY CHOICE and ODYSSEY OUTCOMES SPIRE TRIALS (Bococizumab/Pfizer) AEGIS (CSL Behring): Apo A1 infusion DAL 301 (Dalcor): Dalcetrapib PI: CASCADE FH registry Scientific Advisory Board Lipoprotein (a) Foundation Amgen: Clinical Lipidology and Preventive Cardiology Advisory Board No paid consultants 1

3 Objectives Review current Cholesterol Treatment Guidelines 2013 ACC/AHA cholesterol lowering guidelines 2016 update non statin therapy Understand criteria to diagnose FH (Familial Hypercholesterolemia = type IIa hyperlipdemia) Examine the efficacy of PCSK9 Inhibitors in LDL lowering Review which patients are currently approved for use Discuss cost/benefit issues and implications Treatment of Hyperlipidemia First define the risk level. Primary Prevention No known CAD Secondary Prevention Known CAD, PVD Familial Hypercholesterolemia (FH) Then decide therapy.. Dietician visit First Line Therapy is Maximally tolerated Statin Non statin therapy for Statin intolerance or Add on therapy LDL Niacin Zetia Welchol Fibrates PCSK9 therapy 2

4 Long Term Risk of Atherosclerotic Cardiovascular Disease in US Adults With the Familial Hypercholesterolemia Phenotype 68,565 pts Pooled 6 studies LDL > 190 mg /dl risk rose 5X over 30 year period c/w LDL < 130 mg/dl Risk accelerated up to 20 years for men and 30 years for women Perak AM et al. Circulation 2016 xxx xx x xx 3

5 Causes: Ongoing risk factors, non adherence Failure to achieve adequate statin therapy intensity, statin intolerance Non statin Therapy Targeting HDL and LDL: Does it work? 4

6 X X Primary Endpoint CHD Death Non-fatal MI Ischemic Stroke Hospitalization for ACS Symptom-Driven Coronary Original Primary Endpoint Composite of CHD Death, All Cardiovascular Death AIM HIGH Trial : Endpoints or Cerebral Revascularization (CHD death, non-fatal MI, ischemic stroke, hospitalization for high-risk ACS) non-fatal MI or ischemic stroke 3414 pts moderate dose simvastatin plus niacin 0.5 Niacin Niacin worse better 5

7 HPS2 THRIVE 25,673 pts Statin plus Niacin/Laropipriant No benefit Niacin at 3.9 yrs Primary endpoint 15% control vs 14.5 % treatment 10% less revascularization in treatment arm More complications in Niacin/Lar arm More myalgias, bleeding, GI symptoms, rashes 1.8% excess new diabetes Raises HDL up to 35% Lowers LDL 20%, TC, TGs Lowers Lp(a) Niacin Coronary Drug Project (CDP): Pre statin era, monotherapy: reduced CHD risk by 19% Non HDL cholesterol in AIM HIGH and HPS 2 Thrive very low 102 mg/dl and 86 mg/dl non HDL Cholesterol Average TG in AIM HIGH 160 mg/dl, and 125 mg in HPS 2 6

8 Fibrates: lower TG, raise HDL ACCORD study: No benefit Tricor added to Simvastatin NEJM April Pts with Type 2 DM on simvastatin. Fenofibrate (Tricor) + statin vs statin + placebo NO reduction in CV events Fibrates (PPAR agonists) Gemfibrozil Fenofibrate (Tricor) Lower TG s by 30 40% Increased risk of rhabdomyolysis when combined with a statin Gemfibrozil >>>>> Fenofibrate Summary: Fibrate (TG > 500) prevent pancreatitis 7

9 Bile Acid Sequestrants (BAS) Non absorbed, lipid lowering polymer Cholestyramine, Colestipol, Colesevelam (Welchol) Binds bile acids impeding their resporption Lowers LDL cholesterol 15%, may increase TG s LRC CPPT Trial 1984 monotherapy: 20% reduction in MI/CHD death ISSUES: No outcome trials to guide use in combination with statins GI side effects common Zetia/Ezetimibe: IMPROVE IT Trial Zetia inhibits Niemann Pick like 1 (NPL1) protein Reduces LDL cholesterol modestly LDL 69 mg/dl Simva alone group, 53 mg/dl in Simva +Zetia group 2% absolute risk reduction, 6% relative risk reduction in composite endpoint of CV death, MI, unstable angina, PCI or stroke at 7 years ISSUE: COST for small overall clinical benefit but has given new life to the concept of treating to LDL target rather than intensity based 8

10 Lowering LDL further: PCSK What?? Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans PCSK9 Inhibitors: Approval July

11 Approval PCSK9 Inhibitors Two groups were approved by FDA : 1. Familial Hypercholesterolemia (FH) 2. ASCVD Not achieving adequate LDL control»alirocumab (PRALUENT)»Evolocumab (REPATHA) Administration Sub Q injection Eliminated via saturable binding to target No dose adjustment with renal or hepatic failure PRALUENT (Alirocumab): 75 mg SC 2 weeks, Titration to 150 mg if LDL suboptimal at 8 weeks REPATHA (Evolocumab) 140 mg SC 2 wks or 420 SC q month Ho FH: 420 mg SC q month over 9 min with on body infuser 10

12 Over expression of PCSK9 function associated with severe hyperlipidemia In 2003, French researchers identified GOF (gain of function) mutations in Familial Hypercholesterolemia families protein to become known as PCSK9 Similar GOF identified in Portugal, Norway, New Zealand These GOF mutations were associated with low LDL receptor density and very high cholesterol levels ARIC: Cohen JC et al. N Engl J Med 2006;354:

13 PCSK9 is the Liver LDL receptor density modulator 12

14 Inhibition of PCSK9 increases LDL liver receptor density and lowers LDL Clinical Trials PCSK9 Degree of LDL lowering? Safety? Optimal dosing? Does it work in differing populations? Familial Hypercholestrolemia (FH)? Add on therapy on statins Statin intolerant patients as monotherapy Effect vs adding zetia...does it lower CV events? 13

15 Alirocumab (PRALUENT) On high intensity statin Monotherapy (no statin due to intolerance) vs zetia On moderate Statin RX FH PTS Vs Zetia Alirocumab (PRALUENT) : ODYSSEY TRIALS FH : LDL reduced 49% c/w placebo over maximally tolerated statin, maintained over 78 weeks > 70% pts achieving goal LDL vs < 11% OPTIONS I, II: ASCVD or high risk not at goal on statin: LDL reduced 44 54% COMBO I, II: High risk on max statin: LDL reduced 46% vs 21 % for zetia 77% achieved goal vs 45% for zetia Statin intolerant pts ALTERNATIVE: LDL reduced 45% vs 15% for zetia LONG TERM on max statin: FH, high risk, Diabetics : LDL 48%, similar for DM and No DM Sible et al. Cardio in Rev. 24, 3, June

16 Evolocumab (REPATHA): PROFICIO Trials (Program to Reduce LDL c and CV Outcome following inhibition of PCSK9 in Different Populations ) 20 Trials, 30,000 pts GAUSS 2 statin intolerant pts: LDL 56% 140 mg q 2wk, LDL 53% 420 q mo MENDEL 2: Monotherapy vs Zetia Hyperlipidemia pts LDL 57% 150 mg dose vs 39% zetia DESCARTES: REPATHA vs diet, atorvastatin 10 80, 80 + zetia LDL 49 to 61% RUTHERFORD 2: HeFH pts on max statin. LDL 57% 150 mg LDL 61% q monthly TESLA: Ho FH patients on max statin and zetia REPATHA 420 q month, LDL 31% Sible et al. Cardio in Rev. 24, 3, June 2016 Odyssey Trials: Adverse Reactions Odyssey FH: 2 3 x more injection site reactions Nasopharyngitis more common in PCSK9 group in two trials (11.5% vs 3.9% in Odyssey MONO) Neurocognitive Overall events TEA rates more similar common in two trials: ALTERNATIVE (2.4% vs 1.6%) and LONG TERM (1.2 % vs.5%) No differences in elevations in CK, AST/ALT Overall TEAE rates similar Sible et al. Cardio in Rev. 24, 3, June

17 Evolocumab (REPATHA): PROFICIO Adverse events GAUSS 2: Statin intolerant pts vs zetia Myalgias 8 % Repatha vs 18% placebo No difference in TEAE MENDEL 2: No differences in TEAE including neurocognitive events, CPK, LFTs, Upper respiratory Sx Overall TEA rates similar DESCARTES: Slight increase in TEAE: nasopharyngitis, influenza, and back pain TESLA: More nasopharyngitis, influenza, gastroenteritis in evolocumab group. Sible et al. Cardio in Rev. 24, 3, June 2016 Odyssey Long Term: LDL Over Time with PCSK9 Inhibitor Robinson JG et al. N Engl J Med 2015;372:

18 DESCARTES (Repatha): % Change in UC LDL C from Baseline Mean Percent Change in UC LDL C Overall Diet Alone Atorvastatin 10 mg Atorvastatin 80 mg Atorvastatin 80 mg + Ezetimibe 10 mg 57% 56% 61% 57% 49% Placebo Evolocumab Treatment Difference Odyssey FH subgroups No significant Difference in LDL lowering in Any Demographic or existing Statin treatment LDL 50% 17

19 PCSK9 Reduces more than just LDL DESCARTES (REPATHA): Week 52 ApoB Percent Change from Baseline, Mean (%) % 42% HDL C Percent Change from Baseline, Mean (%) % Lp(a) Triglycerides Percent Change from Baseline, Median (%) Percent Change from Baseline, Median (%) % ( 21 to 1) 3% ( 17 to 25) 28% ( 49 to 6) 9% ( 26 to 13) ApoA1 Percent Change from Baseline, Mean (%) Placebo QM 1% Evolocumab 420 mg QM Error bars represent standard error Data in parentheses represent Q1 to Q3 2% Summary: LDL lowering by pt type Statin Intolerance Odyssey ALTERNATIVE (PRALUENT): LDL 45% GAUSS 1 and 2 (REPATHA): LDL 41 51% SPIRE SI: ongoing (BOCOCIZUMAB) Monotherapy MENDEL 1 and 2 (REPATHA) LDL 57% Odyssey MONO (PRALUENT) LDL 54% Adjunct to max statin therapy Odyssey COMBO 1 and 2 (PRALUENT) LDL 48 52% Odyssey OPTIONS 1 and 2 (PRALUENT) LDL 44 52% DESCARTES (REPATHA) LDL 51 61% SPIRE 1 and 2 ongoing (BOCOCIZUMAB) FH Patients Odyssey FH 1 and 2 (PRALUENT) LDL 49% RUTHERFORD 2 (REPATHA) LDL 57% TESLA B (REPATHA): HoFH LDL 31% SPIRE FH (BOCOCIZUMAB) 18

20 Neurocognitive Concerns Self reported Memory, confusion, or amnesia OSLER 1 and 2 (REPATHA):.9% rate evolocumab vs 0.3 % standard care ODYSSEY LONG TERM (PRALUENT) and ALTERNATIVE 1.2 % alirocumab vs 0.5% in control arm Evaluating PCSK9 Binding antibody Influence on cognitive HeAlth in High cardiovascular Risk Subjects (EBBINGHAUS). Evolocumab + background statin therapy versus statin therapy alone. The primary outcome will be the Spatial Working Memory test Do PCSK9 inhibitors reduce long term CV events and mortality? 19

21 Odyssey Long Term (Praluent) Post Hoc CV Events 2341 pts at high risk LDL > 70 mg/dl on Max tolerated statin Alirocumab 150 mg q 2 weeks for 78 weeks LDL 62% c/w placebo llllxlllllll 1.7% events in PCSK9 ARM vs 3.3% events placebo P.02 Hazard ratio:.52 Evolocumab OSLER Trials: Exploratory Analysis 4465 pts completed a parent trials 2:1 ratio evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone with a 61% reduction in LDL c/w placebo F/U 11.1 months. Sabatine MS et al. N Engl J Med 2015;372:

22 OSLER Trial Events 2.18% in the standard therapy vs 0.95% in the evolocumab group (HR 0.47 P = 0.003) Sabatine NEJM 2015 Cardiovascular events were death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and hospitalization for heart failure PCSK9 Meta Analysis BMC RCTs Reduced death RR.43 Increased injection rxs RR 1.48 Reduced abnormal LFTs.RR.43 No difference TEAEs including myalgias Annals April RCTs Reduced all cause mortality OR.45 Reduced CV mortality OR.5 Reduced MI OR.49 No diff serious adverse events European Heart Journal Nov RCTs Reduce all cause mort OR.43 Increased neurocog events OR

23 Outcomes 24 RCTs 10,000 pts LDL 48 to 69% Reduced total mortality OR.45 Navarese et al ann internal med 2015;163: 40 PCSK9 Outcome Trials Variable ODYSSEY Outcomes FOURIER SPIRE 1/2 Sample size 18,600 27,500 17,000/11,000 Patients post ACS past year MI, Stroke, PAD High Risk CVD Statin Evidence based Atorvastatin > 20 mg conventional RX LDL c > 70 mg/dl > 70 mg/dl or > 100 PCSK9 Alirocumab 2 wks Evolocumab 2/4 wks Bococizumab 2 wks End point CHD death, MI, stroke, TIA, UA req hospitalization CV death, MI, Stroke, UA, PCI CV death, MI, Stroke, UA req PCI Completion February 2018 November 2016 June 2018/July

24 2016 Guidelines: Non Statin Therapy Guidance intentionally left broad to allow for MD discretion Emphasis on shared decision making Re introduced the concept of LDL goals Statin Intolerance ACC: Statin Intolerance needs to be rigorously evaluated and documented Symptoms documented to recur with 2 or 3 separate statin re challenges with statins of different lipophilicity, metabolic pathways 23

25 Secondary Prevention: Non statin therapy ASCVD without comorbidities on maximally tolerated statin ASCVD with comorbidities on statin * < 50% LDL reduction and LDL > 100 mg /dl < 50% LDL reduction and LDL > 70 mg /dl or Non HDL cholesterol > 100 mg/dl if DM Zetia (or BAS if TG <300 ) Consider adding PSCK9 Inhibitor *DM, MI while on statin, CKD, elevated Lp(a) 2016 ACC Expert Consensu Decision Pathway on the Role of Non Statin Therapies for LDL cholesterol lowering. JACC 68, (1) 2016 Primary Prevention: Non statin therapy Baseline LDL > 190 mg/dl on statin Baseline LDL < 190 mg/dl on statin, +/ DM < 50% LDL reduction and LDL > 100 mg /dl Zetia or BAS PCSK9 inhibitor Zetia or BAS X NO PCSK9 inhibitor Persistent LDL elevation > 190 mg/dl Referral to Lipid clinic: Mipomersen, Lomitapide, LDL apheresis 2016 ACC Expert Consensu Decision Pathway on the Role of Non Statin Therapies for LDL cholesterol lowering. JACC 68, (1)

26 ASCVD and baseline LDL > 190 mg/dl (FH patients) on statin therapy < 50% LDL reduction LDL > 70 mg /dl Consider adding with PSCK9 Inhibitor Evolocumab if HoFH Zetia (or BAS if TG <300 ) Persistent LDL elevation > 190 mg/dl Referral to Lipid clinic: Mipomersen, Lomitapide, LDL apheresis 2016 ACC Expert Consensu Decision Pathway on the Role of Non Statin Therapies for LDL cholesterol lowering. JACC 68, (1)

27 Costs Annual charges Alirocumab (PRALUENT) $14,600 Evolocumab (REPATHA) $14,100 Statin: $100 1,000 per year All US elegible residents Heterozygous FH ASCVD and LDL > 70 mg /dl FH: Zetia 214,00 fewer events $152,000 per QUALY PCSK9 316,000 fewer CV events $503,000 per QUALY ASCVD: Zetia 2.7 million fewer CV events $154,000 per QUALY PCSK9 4.3 million fewer events $ 414,000 per QUALY < $4,536 Full implementation would add 120 billion annually in costs JAMA. 2016;316(7): doi: /jama

28 LDL How Low? OSLER 1 and 2: Rates of overall adverse events, serious adverse events, and elevations in aminotransferase or creatine kinase levels were similar among patients in the evolocumab group who had LDL cholesterol levels of less than 40 mg per deciliter or less than 25 mg per deciliter Odyssey long term: no difference in adverse events in 575 pts achieving LDL < 25 mg/dl on two occasions Compound Heterzygotes for PCSK9 Mutations ( Zhao 2006) 21 yo female with LDL 15 mg/dl, normal cognition Outcome studies will evaluate as they have a significant number of patients with LDL < 50 mg /dl. What s Coming with PCSK9? PCSK9 vaccine Pfizer is developing an oral PCSK9 inhibitor, currently in phase II trials. RNA interference (RNAi) therapeutics that inhibit PCSK9 synthesis Alnylam Pharmaceuticals 27

29 MHI Experience: Cholesterol (LDL) Apheresis PSCK9 Inhibitors and Plasma Apheresis Odyssey ESCAPE Trial 62 pt undergoing apheresis Alirocumab 150 q 2 wks Duration of follow up: 18 weeks LDL 42% c/w placebo There was a 75% reduction in the need for apheresis among alirocumab versus placebo treated patients (p < ). Apheresis was discontinued in 63% of patients. Moriarty PM, Parhofer KG, Babirak SP, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J 2016;Aug 29 28

30 Use of the EHR to identify FH FH underdiagnosed: 4.3 % cases correctly identified as FH Supports EHR screening for FH, cascade screening and identification pts suitable for PCSK9 therapy MHI 2016: Begin to identify and treat CASCADE screening and documentation of potentially affected relatives. 29

31 Criteria for FH Diagnosis FH now has its own ICD 10 Code The two new ICD 10 codes approved for familial hypercholesterolemia E78.01: Familial hypercholesterolemia Z83.42: Family history of familial hypercholesterolemia Teffective on October 1,

32 Prior Authorization (PA) criteria general guidelines as eligibility varies with insurers Indicated Populations History of clinical ASCVD or HeFH or HoF Current LDL C At least 70 mg/dl or failure to achieve ACC/AHA goal LDL C reduction on high intensity statin Required lipid lowering therapy High intensity statin (usually a trial on atorvastatin and rosuvastatin) and ezetimibe Minimum duration of lipid lowering therapy 2 3 months Specialist prescribing required Cardiologist, lipidologist or endocrinologist Documentation requirements Chart note must document all of above requirements Definite FH clinical criteria of Simon Broome or Dutch Lipid Network 61 MHI Patient Census PCSK9 Inhibitors MHI 105 patients insurance approved for PCSK9 inhibitors >90% prior authorization insurance approval (national average <46%) practiced insurance submission team Patient costs: Medicare high copay costs ($290 $513/m) All cover FH, most cover ASCVD with LDL > 100 mg/dl Copay card support for commercial insurance Patient Assistance Program (PAP) pharmacy support maximum income to qualify $55,755 household of 2 Minimal side effect profile and LDL lowering 3 patients replaced apheresis with PCSK9 inhibitors Hyper responders and non responders 62 31

33 Prevention Cardiology Team Thomas Knickelbine, MD, FACC, FSCCT Terrence Longe, MD, FACC, FSCCT Michael Miedema, MD, MPH Sandra Oberembt, PA C, ParmD Donna Skoog, RN, CNP Also: Therese Meszaros, RDT Laura Onstodt, RN Susan White, RDN Administrative and Program Lead Gretchen DiTolla, RN Christine Majeski, RN Clinical Research Mgr Stephanie Ebnet, RN Clinical Research Sam/Amanda Pharm D Summary FDA approval was based on LDL as a surrogate marker and not outcome studies Statins have best long term outcome data and should be considered first line agents High cost per QUALY : TARGET HIGH RISK Await outcome data! 32

34 PCSK9: Ready for Prime time? Steve Nissen: As tough a guy as I am, I wouldn t wait.. This is probably the most important class of drugs we ve seen in a decade : Cleveland Clinic Neil Stone: it would be premature to endorse these drugs for widespread use before the ongoing clinical trials are available : Northwestern Thank You! 33

35 PCSK9 antibodies Approximately.1% pts 3 pts in FH I, II Odyssey trials and 5 OPTIONS I, II patients trials developed PCSK9 antibodies This did not alter the LDL reduction seen in the study patients MHI Lipid Clinic Statin intolerance > 20% Increasing recognition of Familial Hypercholesterolemia 1:200 persons Many do not achieve adequate LDL lowering with statins alone Complex cholesterol lowing medications Increasing regulation and costs Opportunity for participation in clinical trials if not an FDA approved candidate 34

36 Serious Adverse events N o no difference in discontinuation rates c/w placebo or zetia Forrest plots comparing the incidence of all-cause mortality, cardiovascular death, cardiovascular events, and neurocognitive adverse events for patients randomized to proprotein convertase subtilisin-kexin type 9 serine protease inhibitors or placebo. Michael J. Lipinski et al. Eur Heart J 2016;37: Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please journals.permissions@oup.com. 35

37 Statins: Risk Reductions/residual risk Primary Prevention: Cholesterol treatment realists: 19 trials, 60,000 pts showed 27% reduction in combined fatal/non fatal CV events Effect equivalent in high and low risk individuals Absolute event reduction highest in high risk individuals Small overall reduction in mortality Secondary Prevention FH Minority of patients achieve plaque regression, benefits seen as early as 6 months: Plaque stabilizatoin, endothelial funciton, decreased thrombogenicity playing a role.. Options for Add on therapy Only ~20% of patients with HeFH treated with LLTs reached a pre-defined LDL-C target level of 2.59 mmol/l (100 mg/dl) Prevalence of statin intolerance (> 10%) Prevalance of failure to achieve adequate LDL in ASCVD patients. Check the cost paper for this 36

38 MHI Experience: Lipid Apheresis 37