Outpatient Medicine Updates 2020

Leonard Mankin, MD, FACP Associate Program Director OHSULegacy Health, Portland, OR Associate Professor of Medicine Oregon Health & Science University Assistant Professor of Medicine Western COMP-NW [email protected] Disclosures

• In the 3rd grade, I did not like Stephen Belcher. On the day when the class planted seeds in pots, I placed a rock over his seed so it wouldn’t grow… Stephen, if you are in the audience today, OHSUI am truly sorry I have no financial relationships to disclose OHSU A.M. Clinic Schedule

Time Age/Sex Reason for visit

7:55 am 44 F are getting worse!

8:25 am 32 F New patient - headaches

9:10 am 58 F Constipation and bloating

9:45 am 64 M Chest pain

OHSU10:15 am 54 M Follow up of CAD, HTN and lipids

10:45 am 64 M ED follow up for kidney stones Patient 1

• 44 yr old woman with migraines - Headaches 16-20 days/month - Using maximum amounts of covered by her insurance - Affecting her life as a working mother of OHSUtwo young children Indication for migraine prophylaxis

• ≥ 4 headaches/month • ≥8 headache days/month • Debilitating attacks despite acute therapy OHSU• Difficulty tolerating meds for acute attack

Am Fam Physician 2019;99:17-24 Which drugs are first-line for OHSUprevention of migraines? Migraine prophylactic agents

Class Drugs Comorbid Indications Antihypertensives -Beta blockers metoprolol*, atenolol HTN, tachycardia, anxiety, tremor, *, * CAD, angina

-Calcium blockers , diltiazem HTN, tachycardia, Raynaud’s OHSUACE/ARB lisinopril/candesartan HTN, DM, CHF

Am Fam Physician 2019;99:17-24 * First line treatment Migraine prophylactic agents

Class Drugs Comorbid Indications Antihypertensives -Beta blockers metoprolol*, atenolol HTN, tachycardia, anxiety, tremor, propranolol*, timolol* CAD, angina

-Calcium blockers verapamil, diltiazem HTN, tachycardia, Raynaud’s

ACE/ARB lisinopril/candesartan HTN, DM, CHF Anti-epileptics * Seizures, Obesity OHSUdivalproic acid* Seizures, Bipolar disorder

Am Fam Physician 2019;99:17-24 * First line treatment Migraine prophylactic agents

Class Drugs Comorbid Indications Antihypertensives -Beta blockers metoprolol*, atenolol HTN, tachycardia, anxiety, tremor, propranolol*, timolol* CAD, angina

-Calcium blockers verapamil, diltiazem HTN, tachycardia, Raynaud’s

ACE/ARB lisinopril/candesartan HTN, DM, CHF Anti-epileptics topiramate* Seizures, Obesity

divalproic acid* Seizures, Bipolar disorder OHSUAntidepressants Depression, Insomnia venlafaxine Depression, Hot flashes

Am Fam Physician 2019;99:17-24 * First line treatment Migraine prophylactic agents

Class Drugs Comorbid Indications Antihypertensives -Beta blockers metoprolol*, atenolol HTN, tachycardia, anxiety, tremor, propranolol*, timolol* CAD, angina

-Calcium blockers verapamil, diltiazem HTN, tachycardia, Raynaud’s

ACE/ARB lisinopril/candesartan HTN, DM, CHF Anti-epileptics topiramate* Seizures, Obesity

divalproic acid* Seizures, Bipolar disorder OHSUAntidepressants amitriptyline Depression, Insomnia venlafaxine Depression, Hot flashes Neurotoxins onabotulinum toxin A ---

Am Fam Physician 2019;99:17-24 * First line treatment Other Migraine prophylaxis

• Herbals - Butterbur, feverfew, riboflavin, magnesium, coenzyme Q10

• Non-pharmacologic methods - Aerobic exercise, CBT, biofeedback, OHSUacupuncture, transcranial magnetic stimulation, TENS of supraorbital nerve

Am Fam Physician 2019;99:17-24 Are there any new therapies for OHSUmigraine prevention? CGRP

• Calcitonin Gene-Related (CGRP) modulates pain as well as vasodilation in neurogenic inflammation and appears to play a central role in migraine OHSUpathogenesis

N Engl J Med 2017;377:2190-2191 New meds for migraine prevention

• In 2018, the FDA approved three new monoclonal antibodies that block the activity of CGRP: - - Fremanezumab OHSU- • Meds administered SC, q 1-3 months CGRP Antagonists

• Do not need dose titration • No liver or kidney concerns • Rapid onset of action, although may take up to 3 months for full effect • May be combined with other oral or OHSUinjectable treatments for migraine

Headache 2019;59:1-18 How well do these new CGRP OHSUdrugs work? Migraine Prevention Trials - CGRP

• Inclusion - 4 -14 migraine HA/month (episodic) or ≥ 15 migraine headaches/month (chronic) - Maintain a headache diary

• Exclusion OHSU- Pts who had tried and failed ≥ 2 migraine prophylactic agents

1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 OHSU Baseline characteristics

• ~ 85% of participants were women • Migraine duration ~ 20 yrs •OHSUMajority not currently on preventive meds

1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 Migraine Days/month Drug Baseline Low dose High Dose Placebo Erenumab (70 mg/140mg) (n=955) Fremanezumab (675mg quarterly vs 675mg + 225mg monthly) (n=1130) Fremanezumab (225mg/675mg) (n=875) GalcanazumabOHSU (120mg/240mg) (n=858)

1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 Migraine Days/month Drug Baseline Low dose High Dose Placebo Erenumab (70 mg/140mg) 8.3 (n=955) Fremanezumab (675mg quarterly vs 675mg + 225mg monthly) (n=1130) Fremanezumab (225mg/675mg) (n=875) GalcanazumabOHSU (120mg/240mg) (n=858)

1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 Migraine Days/month Drug Baseline Low dose High Dose Placebo Erenumab (70 mg/140mg) 8.3 5.1 4.6 6.5 (n=955) Fremanezumab (675mg quarterly vs 675mg + 225mg monthly) (n=1130) Fremanezumab (225mg/675mg) (n=875) GalcanazumabOHSU (120mg/240mg) (n=858)

1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 Migraine Days/month Drug Baseline Low dose High Dose Placebo Erenumab (70 mg/140mg) 8.3 5.1 4.6 6.5 (n=955) Fremanezumab (675mg quarterly vs 13.1 675mg + 225mg monthly) (n=1130) Fremanezumab (225mg/675mg) (n=875) GalcanazumabOHSU (120mg/240mg) (n=858)

1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 Migraine Days/month Drug Baseline Low dose High Dose Placebo Erenumab (70 mg/140mg) 8.3 5.1 4.6 6.5 (n=955) Fremanezumab (675mg quarterly vs 13.1 8.9 8.2 10.8 675mg + 225mg monthly) (n=1130) Fremanezumab (225mg/675mg) (n=875) GalcanazumabOHSU (120mg/240mg) (n=858)

1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 Migraine Days/month Drug Baseline Low dose High Dose Placebo Erenumab (70 mg/140mg) 8.3 5.1 4.6 6.5 (n=955) Fremanezumab (675mg quarterly vs 13.1 8.9 8.2 10.8 675mg + 225mg monthly) (n=1130) Fremanezumab (225mg/675mg) 9.0 (n=875) GalcanazumabOHSU (120mg/240mg) (n=858)

1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 Migraine Days/month Drug Baseline Low dose High Dose Placebo Erenumab (70 mg/140mg) 8.3 5.1 4.6 6.5 (n=955) Fremanezumab (675mg quarterly vs 13.1 8.9 8.2 10.8 675mg + 225mg monthly) (n=1130) Fremanezumab (225mg/675mg) 9.0 4.9 5.3 6.5 (n=875) GalcanazumabOHSU (120mg/240mg) (n=858)

1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 Migraine Days/month Drug Baseline Low dose High Dose Placebo Erenumab (70 mg/140mg) 8.3 5.1 4.6 6.5 (n=955) Fremanezumab (675mg quarterly vs 13.1 8.9 8.2 10.8 675mg + 225mg monthly) (n=1130) Fremanezumab (225mg/675mg) 9.0 4.9 5.3 6.5 (n=875) GalcanazumabOHSU (120mg/240mg) 9.1 (n=858)

1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 Migraine Days/month Drug Baseline Low dose High Dose Placebo Erenumab (70 mg/140mg) 8.3 5.1 4.6 6.5 (n=955) Fremanezumab (675mg quarterly vs 13.1 8.9 8.2 10.8 675mg + 225mg monthly) (n=1130) Fremanezumab (225mg/675mg) 9.0 4.9 5.3 6.5 (n=875) GalcanazumabOHSU (120mg/240mg) 9.1 4.4 4.5 6.3 (n=858)

1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 Percentage achieving a Drug 50% Reduction in Migraine Days Low dose High Dose Placebo Erenumab (70 mg/140mg) (n=955) Fremanezumab (675mg quarterly vs 675mg + 225mg monthly) (n=1130) Fremanezumab (225mg/675mg) OHSU(n=875) Galcanazumab (120mg/240mg) (n=858) 1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 Percentage achieving a Drug 50% Reduction in Migraine Days Low dose High Dose Placebo Erenumab (70 mg/140mg) 43 50 27 (n=955) Fremanezumab (675mg quarterly vs 38 41 18 675mg + 225mg monthly) (n=1130) Fremanezumab (225mg/675mg) 48 44 28 OHSU(n=875) Galcanazumab (120mg/240mg) 62 61 39 (n=858) 1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 CGRP Antagonists – Adverse Events

• Major adverse events were rare and did not differ from placebo

• Minor injection site reactions (redness, induration, itching) were more common OHSUwith CGRP drugs

1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 CGRP Antagonists – Quality of Life

• QOL and disability scores improved with CGRP compared to placebo

CGRP antagonists - 7-8 fewer headache-weeks per year OHSUPlacebo - 3-5 fewer headache-weeks per year

1. N Engl J Med 2017;377:2123-2132 2. N Engl J Med 2017;377:2113-2122 3. JAMA 2018;319:1999-2008 4. JAMA Neurol 2018;75:1080-1088 How do CGRP antagonists compare to other preventive OHSUtreatments for migraine? Common prophylactic agents

• No direct comparisons yet • In general, most people experienced a 50-75% reduction in migraine frequency with use of traditional agents, but side OHSUeffects were often limiting

N Engl J Med 2002;346:257-270 Percentage achieving a Drug n ≥50% Reduction in Migraine Days Active Drug Placebo Topiramate 100 mg1-3 468 49 23 469 54 23 498 48 22 as a class3 1341 49 20 Divalproex sodium3 579 47 21 Amitriptyline 25-100 mg4 100 55 34 OHSUCandesartan 16 mg5 72 43 23

1. JAMA 2004;291:965-973 2. Arch Neurol 2004;61:490-495 3. ACP J Club 2005;142:21 4. Arch Neurol 1979;36:695-699 5. Cephalgia 2014;34:523-532 Are there any new therapies for OHSUtreatment of acute migraine? New meds for acute migraine

• “Gepants” - FDA approved (Dec 2019) and (Feb 2020), oral CGRP receptor antagonists

• “” OHSU- FDA approved (Oct 2019), a selective Serotonin 1F agonist OHSU Freedom from Migraine Pain at 2 Drug hours (%) Low dose High Dose Placebo Ubrogepant (50 mg vs 100 mg PO) 22 21 14 (n=1,465) Ubrogepant (50 mg vs 100 mg PO) 19 21 12 (n=1,672)

Rimegepant (75mg PO) OHSU(n=1,072) Rimegepant (75 mg) (n=1,351)

1. JAMA 2019;322:1887-1898 2. N Engl J Med 2019;381:2230-2241 3. N Engl J Med 2019;381:142-149 4. Lancet 2019;394:737-745 Freedom from Migraine Pain at 2 Drug hours (%) Low dose High Dose Placebo Ubrogepant (50 mg vs 100 mg PO) 22 21 14 (n=1,465) Ubrogepant (50 mg vs 100 mg PO) 19 21 12 (n=1,672)

Rimegepant (75mg PO) - 20 12 OHSU(n=1,072) Rimegepant (75 mg) - 21 11 (n=1,351)

1. JAMA 2019;322:1887-1898 2. N Engl J Med 2019;381:2230-2241 3. N Engl J Med 2019;381:142-149 4. Lancet 2019;394:737-745 Adverse effects

• Adverse events were rare and mild - Ubrogepant1-2 Nausea (2-4%), dizziness (1.4-2.1%), somnolence (2.3%) and dry mouth (2.1%) - Rimegepant3-4 Nausea (1.8-2%) and UTI (1-1.6%) OHSU• No signals of medication overuse headache

1. JAMA 2019;322:1887-1898 2. N Engl J Med 2019;381:2230-2241 3. N Engl J Med 2019;381:142-149 4. Lancet 2019;394:737-745 Ditans

• Highly selective oral 5-HT1F receptor agonists that block trigeminal nociception • Unlike , ditans do not cause vasoconstriction, so may be safer in OHSUmigraine sufferers with CV risks

1. Neurology 2018;91:e2222-e2232 2. Brain 2019;142:1894-1904 Freedom from Migraine Pain at 2 Drug hours (%) 100 mg 200 mg Placebo Lasmiditan1 (n=1,856) 28 32 15

Lasmiditan2 (100 mg vs 200 mg PO) 31 39 21 OHSU(n=3,005)

1. Neurology 2018;91:e2222-e2232 2. Brain 2019;142:1894-1904 Adverse effects

• Adverse events were mild to moderate - Dizziness (12-16%), parasthesias (6-8%), somnolence (5-6%) and nausea (3-5%) • Cardiovascular AE did not differ OHSUbetween lasmiditan and placebo

1. Neurology 2018;91:e2222-e2232 2. Brain 2019;142:1894-1904 How do other drugs fare in OHSUtreatment of acute migraine? Freedom from Migraine Drug n pain at 2 hrs (%) Active drug Placebo Sumatriptan 6 mg SC 2,522 59 15

Oral Triptans 24,089 59 30

Aspirin 1,000 mg 2,027 24 11 OHSUIbuprofen 400 mg 1,615 26 12 Naproxen 275-825 mg 1,241 17 8

1. Cochrane Database Syst Rev 2014;5:CD009108 2. Cephalgia 2002;22:633-658 3 Cochrane Database Syst Rev 2013;4:CD008041 4. Cochrane Database Syst Rev 2013;4:CD008039 5. Cochrane Database Syst. Rev. 2013;4:CD009455 Costalot Costalot Costalot Costalot

Costalot® OHSU(migrainumab injection) Expensivo OHSU(Robsublindemab injectable) Drug Monthly Cost

Erenumab $678

Fremanezumab $676

Galcanazumab $676

Ubrogepant $1,026

OHSURimegepant $865

Lasmiditan $653

Goodrx.com price at Costco pharmacy - accessed Oct 21, 2020 Traditional migraine meds - Cost Drug Monthly Cost

Propranolol $24

Timolol $10

Topiramate $12 OHSUDivalproex sodium $28 Amitriptyline $4

Goodrx.com price at Costco pharmacy - accessed Feb 20, 2020 Pitfalls of newer migraine agents

• Unknown efficacy vs traditional migraine therapies • Absence of longterm safety data OHSU• Cost Clinical Bottom Line

• CGRP inhibitors and the ditans are new classes of medications that may successfully reduce migraine frequency and/or relieve acute migraine symptoms • In addition to lifestyle interventions, traditional migraine agents should OHSUremain first-line for prevention and treatment OHSU Patient 2

• A 32-year-old woman with history of migraine headaches comes in to meet you as a new patient after moving from Colorado

OHSU• She asks you to approve medical marijuana for migraine prophylaxis Marijuana and migraines

• Use of marijuana for medical purposes is legal in 40/50 states • About ¼ of medical marijuana prescriptions are prescribed for people OHSUwith migraine headaches

J Headache Pain 2018;19:37 OHSU Does marijuana help patients OHSUwith chronic migraine? Marijuana to prevent migraines

• Retrospective cohort of 121 migraineurs advised to try medical marijuana (vaping, edible, smoking) for migraine prevention • 68% were current or former MJ users • Outcome: change in monthly migraine OHSUfrequency • Mean follow up: 22 months

Pharmacotherapy 2016;36:505-510 Marijuana to prevent migraines

• 85% of participants reported decrease in migraine frequency • Monthly migraine headache frequency decreased from 10.4 to 4.6 (p < 0.0001) • 12% had AE, mainly trouble controlling OHSUeffects from edibles

Pharmacotherapy 2016;36:505-510 Clinical Bottom Line

• Marijuana use is rapidly expanding

• Marijuana may play a role in migraine headache prevention, but further OHSUstudies are needed to clarify its role OHSU Patient 3

• A 64-year-old man with HTN and elevated lipids comes in to discuss chest pains that occur about once a week when he walks in the park to pick up his grandson from soccer practice. The pain goes away with OHSUresting for a couple minutes, and does not occur every time 64-year-old man with chest pains

• Meds: lisinopril 20 mg & atorvastatin 40 mg • BP: 130/77 mmHg HR: 72 bpm

• EKG: NSR with T-wave inversions in V3-V6

• Stress EKG: 1.5-2 mm of ST depression in OHSUV -V at 7 minutes correlating to symptoms 3 6 of chest discomfort Does revascularization reduce major CV events in patients with OHSUchronic stable angina? Revascularization for acute events

• Several studies have shown a reduction in mortality and reinfarction rates with early revascularization for unstable angina, acute MI, and left main OHSUcoronary artery disease COURAGE Trial

• 2,287 pts with chronic myocardial ischemia randomized to PCI + medical therapy vs medical therapy alone • No difference in death, MI, stroke or ACS at 4.6 years • 15-yr follow up data of the trial once again OHSUshowed no mortality difference2

1. N Eng J Med 2007;356:1503-1516 2. N Eng J Med 2015;373:1937-1946 Meta-analysis of RCTs of PCI

• 5,286 pts in 5 RCTs of PCI vs medical Rx in pts with chronic stable angina

• After 5 years avg follow up, PCI had no effects on death, nonfatal MI, unplanned OHSUrevascularization or angina symptoms

JAMA Intern Med 2014;174:232-240 PCI vs medical therapy for stable CAD with ischemia - Mortality OHSU

JAMA Intern Med 2014;174:232-240 PCI vs medical therapy for stable CAD with ischemia - MI OHSU

JAMA Intern Med 2014;174:232-240 Are there any new studies looking at revascularization vs optimal medical therapy (OMT) OHSUfor ischemic heart disease? The ISCHEMIA Trial - Design

• 5,129 patients with a cardiac stress test showing moderate to severe ischemia were randomized to: - Cardiac catheterization with subsequent PCI or CABG + OMT OHSUOr OMT alone

Am Heart J 2018;201:124-135 The ISCHEMIA Trial - Design

• 10 Endpoint - Composite of CV death, MI, hospitalization for unstable angina or resuscitated cardiac arrest

• 20 Endpoints OHSU- Quality of life - CV death or MI

Am Heart J 2018;201:124-135 The ISCHEMIA Trial - Design

• Inclusion Criteria - Moderate or severe ischemia by ETT, nuclear stress, stress ECHO or cardiac MRI

• Exclusion Criteria OHSU- NYHA class III-IV - Recent PCI or CABG - EF <35% - eGFR < 30mL/min - Severe angina - Left main > 50%

Am Heart J 2018;201:124-135 Study Design

• In prior trials, coronary anatomy was assessed first, and then select patients randomized to treatment groups • In ISCHEMIA, patients were randomized first, and then all patients underwent OHSUcoronary CT to assess degree of severity

Am Heart J 2018;201:124-135 Ischemia Trial – Baseline Anatomy OHSU The ISCHEMIA Trial - Results

• Pts: 5,179 (mean age 64 yrs, 23% female) • Mean follow up: 3.3 yrs

Intervention Invasive Optimal Medical Strategy Therapy (OMT) OHSUCardiac Cath 96% PCI or CABG 80%

N Engl J Med 2020;382:1395-1407 The ISCHEMIA Trial - Results

• Pts: 5179 (mean age 64 yrs, 23% female) • Mean follow up: 3.3 yrs

Intervention Invasive Optimal Medical Strategy Therapy (OMT) OHSUCardiac Cath 96% 28% PCI or CABG 80% 23%

N Engl J Med 2020;382:1395-1407 The ISCHEMIA Trial - Results

Outcome Invasive OMT p value Strategy 10 outcome 13.3% 15.5% 0.34

CV Mortality or MI 11.7% 13.9% 0.21

OHSUAll-Cause Mortality 6.4% 6.5% 0.67

N Engl J Med 2020;382:1395-1407 ISCHEMIA Subgroups OHSU

N Engl J Med 2020;382:1395-1407 Does revascularization improve OHSUangina in stable ischemic CAD? COURAGE Trial – Angina OHSU

1. N Eng J Med 2008;359:677-687 OHSU

JAMA Intern Med 2014;174:232-240 Ischemia trial - Angina OHSU Ischemia trial - Angina

daily weekly monthly daily weekly monthly daily weekly monthly OHSU Ischemia Trial – Medication use OHSU Were the angina score differences in COURAGE and ISCHEMIA due in OHSUpart to a placebo effect? RCT of PTCA – The ORBITA trial

• 200 pts with chronic stable angina with severe single vessel disease (≥ 70% stenosis) on optimal medical Rx • Randomized to PCI with drug eluting stent vs placebo procedure OHSU• 10 outcome: Exercise time • 20 outcome: angina score

Lancet 2018;391:31-40 PCI vs sham PCI – Clinically important differences?

Major bleeding occurred in OHSU2.2% OHSU

Better Health for Oregonians: Opportunities to Reduce Low-Value Care. July 2020 https://www.Oregon.gov/OHA/ Trends in Cardiac Revascularization

• There are ~950,000 cardiac caths performed each year in the US, and the OHSUnumbers appear to be increasing

Diagnostic and Interventional Cardiology epub. Sep 13, 2018 Clinical Bottom Line - 1

• A procedural approach to stable CAD pts with moderate to severe ischemia does OHSUnot reduce mortality or CV events Clinical Bottom Line - 2

• Optimizing medical therapy for symptom control should be considered first-line therapy for chronic angina

• Pts with refractory angina with daily or OHSUweekly symptoms should be considered for an invasive approach OHSU Patient 4

• A 58-year-old woman with chronic iron deficiency anemia has complaints of constipation and hematochezia • Recent colonoscopy - diverticular disease and angiodysplasia without obvious source of bleed OHSU• The GI doctor placed her on Ferrous sulfate 325 mg TID, which is making her feel bloated and constipated What is the optimal iron OHSUreplacement regimen? Iron Replacement

• Approximately 1 in 8 people in the world have iron deficiency anemia • IV iron is safe, convenient, and more effective than oral replacement, often correcting deficits in 1-2 sessions OHSU• Cost and physician unfamiliarity are the most common barriers to use of IV iron

Hematology Am Soc Hematol Educ Program 2016;1:57-66 What is the best method for oral OHSUreplacement of iron? Oral Iron replacement and Hepcidin

• Oral absorption of iron is tightly regulated by a protein called hepcidin, which reduces gut absorption of iron in response to high plasma iron levels • A study of 54 iron-deficient women OHSUshowed increased hepcidin and reduction in iron absorption with more than once daily dosing Blood 2015;126:1981-1989 QD vs QOD oral Iron

• 40 women with iron deficiency were randomized to daily vs every other day iron supplements, followed for 1 month

Measure Daily dosing QOD Dosing P value

Fractional Iron 16.3% 21.8% 0.0013 OHSUabsorption Cumulative total Iron 131 mg 175 mg 0.0010 absorption

Lancet Haematology 2017;4:e524-e533 Clinical Bottom Line

• For patients requiring oral iron replacement, every other day dosing enhances absorption while minimizing OHSUside effects and pill burden OHSU Patient 5

• 54-year-old man with a recent MI and HTN has the following lipids: • Total chol = 290 • LDL = 190 • HDL = 50 OHSUTG = 250 • • You start him on atorvastatin 80 mg 3-month follow up: A 54-year-old man with a recent MI and HTN • Pt started on atorvastatin 80 mg last visit

• Total chol = 290 T Chol = 190 • LDL = 190 LDL = 130 OHSU• HDL = 50 HDL = 55 • TG = 250 TG = 245 Secondary Prevention Goal

• Despite statin therapy, > 60% of high- risk patients go on to have a CV event1

• The ACC/AHA guidelines recommend institution of maximally tolerated statins OHSUto achieve ≥ 50% reduction in LDL2

1. Am J Med 2006;119;676-683 2. J Am Coll Cardiol 2018;Nov 10:epub ahead of print When should we consider therapies beyond statins? OHSUWhich agents should we choose? 2019 ACC/AHA Updated Guidelines for add-on therapy

• When LDL targets fall short on a high dose statin, consider adding one of these:

1. Ezetimibe OHSU2. Bile Acid sequestrant 3. PCSK9 Inhibitor

J Am Coll Cardiol 2019;March 17:epub ahead of print http://www.onlinejacc.org/content/accj/early/2018/11/02/j.jacc.2018.11.003.full.pdf Ezetimibe

• Inhibits intestinal cholesterol absorption • IMPROVE-IT (n=18,144)1 - Addition of ezetimibe 10 mg daily to a statin resulted in significant reduction in MACE* (NNT = 50 over 6 years) - Cost = $9/month2

OHSU* MACE = CV death, MI, unstable angina, stroke or revascularization 1. N Engl J Med 2015; 372:2387-2397 2. Goodrx.com accessed 10/24/2020 PCSK9 Inhibitors

• PCSK9 is a protein responsible for removal of LDL receptors from the cell surface1

Drug LDL Reduction 39-62% OHSUEvolocumab 47-56%

1. N Engl J Med 2015;373:1588-1591 PCSK9 Inhibitors

• FOURIER (n=27,564) - Addition of to statin reduced MACE* (NNT = 67 over 2.2 yrs)

• ODYSSEY (n=18,924) - Addition of alirocumab to statin reduced MACE* OHSU(NNT = 63 over 2.8 yrs)

* MACE = CV death, MI, unstable angina, stroke N Engl J Med 2017;376:1713-1722 or revascularization Lower your LDL and retirement income

Armandaleg® (PennilessumabOHSUinj.) PCSK9 Inhibitors - Cost

Drug Monthly Cost Yearly Cost

Evolocumab $462 $5,544 OHSUAlirocumab $622 $7,464

Goodrx.com price at Costco pharmacy - accessed 10/24/20 Who sets the pricing on drugs? OHSU Who sets the pricing on drugs? OHSU How much would it cost to prevent one CV event by adding A PCSK-9 inhibitor to statin therapy?*

• FOURIER trial - OHSU• ODYSSEY trial -

* Based on Primary composite event rate How much would it cost to prevent one CV event by adding A PCSK-9 inhibitor to statin therapy?*

• FOURIER trial - $ 835,758 OHSU• ODYSSEY trial - $ 1,293,138

* Based on Primary composite event rate OHSUAny new drugs targeting lipids? Bempedoic Acid

• Novel oral drug that blocks cholesterol synthesis at an upstream site from statins (ATP citrate lyase = ACL Inhibitor) • RCT of 2,230 pts with ASCVD, bempedoic acid added to a statin resulted in a 16.5% OHSUfurther reduction in LDL without AE • FDA approval in Feb 2020 • CV outcomes study (CLEAR) due late 2022

N Engl J Med 2019; 380:1022-1032 Fish Oil

• Meta-analyses of RCTs have failed to OHSUshow convincing CV benefits1-4 1. JAMA 2012;308:1024-33 2. N Engl J Med 2013;368:1800-1808 3. Cochrane Database Syst Rev 2018;7:CD003177 4. JAMA Cardiol 2018;3:225-234 Fish oil components

• Fish oil contains two major Omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)

EPA DHA  TG  TG OHSUNo effect on LDL ↑ LDL No effect on HDL ↑ HDL

J Clin Lipidol 2015;9(S6):S1-S122 EPA + Statin

• JELIS trial (n=18,645) - When added to statin, EPA resulted in a significant reduction in MACE* (NNT=142 OHSUover 4.6 years) * MACE = CV death, MI, unstable angina, or revascularization Lancet 2007;369:1090-1098 EPA + Statin

• REDUCE-IT (n=8,179)1 - Icosapent ethyl, a purified EPA, when added to statin in high risk pts, resulted in significant reduction in MACE (NNT=20 over 4.9 years) - Critique of study – mineral oil was used as placebo, which raises LDL and CRP levels (LDL OHSUwas 7 points higher in placebo arm) • FDA approval in Dec 2019 for TG >1502

N Engl J Med 2019;380:11-22 www.fda.gov news and events December 13, 2019 Fish Oil - Cost

Drug 30-Day Cost

Generic Fish Oil1 $4

Prescription Fish Oil2 $23

OHSUIcosapent Ethyl2 $241

1. Costco.com accessed 2/24/2020 2. GoodRx.com accessed 10/28/2020 What is the cost to prevent one major event (CV death, MI or CVA) with use of icosapent ethyl over 5 years?

OHSU$640,000 Inclisiran

• Twice-yearly injectable drug that blocks messenger-RNA transcription of PCSK9 • Three trials (ORION -9,-10 & -11; n=3,660), yielded LDL reductions of ~50% at 1.5 yrs1,2 • No significant AE •OHSUCV outcomes (ORION-4) expected in 20243 • FDA approval pending

1. N Engl J Med 2020;382:1507-19 2. N Engl J Med 2020;382:1520-30 3. Future Cardiol. 2018;14:433-42 New lipid agents - Cost Drug Monthly Cost Yearly Cost

Evolocumab $462 $5,544 Alirocumab $622 $7,464 Bempedoic Acid $341 $4,092 Icosapent Ethyl $241 $2,892 OHSUInclisiran TBD TBD

Goodrx.com price at Costco pharmacy - accessed 10/24/20 New lipid agents - Cost Drug Monthly Cost Yearly Cost

Evolocumab $462 $5,544 Alirocumab $622 $7,464 Bempedoic Acid $341 $4,092 Icosapent Ethyl $241 $2,892 OHSUInclisiran

Goodrx.com price at Costco pharmacy - accessed 10/24/20 OHSU Can a Vaccine reduce CV events? OHSU Can a Vaccine reduce CV events?

• Researchers are studying a vaccine targeted against PCSK9

• Early results in animals show significant decreases in total (-30%) OHSUand LDL cholesterol (-50%) at 1 year

J Lipid Res 2012;53:1654-1661 Vaccine 2015;33(43):5747-5755 Drugs 2018;78(8):799-808 BMC Medicine 2019;17:223 CLINICAL BOTTOM LINE

• When additional lipid lowering is indicated for high-risk ASCVD patients: - Ezetimibe reduces CV events when added to statin therapy and should be first-line - PCSK9 inhibitors, bempedoic acid and icosapent ethyl also lower MACE and are OHSUprimarily limited by costs - Be on the lookout for inclisiran and perhaps a PCSK9 vaccine! CLINICAL BOTTOM LINE

• Going forward, we should leave all the fish alone and just make icosapent ethyl OHSUin a laboratory OHSU Patient 6

• A 68-year-old man was seen in the emergency department for right-sided flank pains and hematuria.

• US revealed a 7 mm right ureteral stone OHSUwithout evidence of hydronephrosis Nephrolithiasis

• Nearly 1 million emergency visits per OHSUyear for renal colic pain

J Urol 2014;191:90-96 Are there any medications that OHSUmight facilitate stone passage? Meds for nephrolithiasis

• In meta-analysis of 67 trials (n=10,509), patients given alpha-blockers were more likely to expel their stone (RR = 1.16) in a shorter time period (-3.4 days) • Alpha-blockers were most effective (RR = 1.45) for passage of large stones (>5 mm) OHSU• Decreased use of pain medications and need for hospitalization

Cochrane Database Syst Rev 2018;4:CD008509 68-year-old man with kidney stone

• The patient was placed on tamsulosin, but experienced frequent episodes of lightheadedness and felt compelled to stop the medication OHSU• His renal colic attacks continued What is the best analgesic OHSUfor renal colic? Renal Colic – NSAIDs vs Opioids

• Systematic review of 36 RCTs (n=4,887) comparing NSAIDs to opioids or OHSUparacetamol for acute renal colic

Eur Urol 2018;73(4):583-595 Opioids vs non-opioids for renal colic Clinically important differences? OHSU Renal Colic – NSAIDs vs Opioids

• Fewer patients taking NSAIDs required “rescue doses” of pain medication

• Greater number of adverse events seen OHSUwith use of opioids

Eur Urol 2018;73(4):583-595 Are there any non-pharmacologic interventions that may help pass OHSUa kidney stone? Dislodging renal calculi – a proof of concept study

• Three renal calculi (4.5, 13.5 and 64.6 mm3) were placed into the upper, middle and OHSUlower calyces of a urine-filled renal model

J Am Osteopath Assoc 2016;116:647-652 Pyelocalyceal Renal Model OHSU

J Am Osteopath Assoc 2016;116:647-652 Dislodging renal calculi – a proof of concept study

• Three renal calculi (4.5, 13.5 and 64.6 mm3) were placed into the upper, middle and lower calyces of a urine-filled renal model

• The pyelocaliceal model was placed into OHSUphysiologic position within a backpack and strapped into the seat of a rollercoaster

J Am Osteopath Assoc 2016;116:647-652 Big Thunder Mountain Railroad OHSU Placement of pyelocaliceal model OHSU Dislodging renal calculi - results

• 60 renal calculi rides were analyzed • 45% of all rollercoaster rides resulted in stone passage, with posterior seating resulting in greater passage rates (64%) • Side note: these guys figured out a way OHSUto get research funds to pay their entrance to Disneyworld!

J Am Osteopath Assoc 2016;116:647-652 What about other forms of OHSUphysical activity? Passage of Distal Ureteral Stones

• 75 patients with distal ureteral stones (average stone size ~ 5mm) were randomly assigned to 1 of 3 groups: - Sexual intercourse 3-4 times/week - Tamsulosin 0.4 mg daily OHSU- Usual medical therapy • Outcomes: Stone passage rate at 2 wks

Urology 2015;86:19-24 Passage of Distal Ureteral Stones

Group Renal Stone Passage Mean # days until (%) at 2 weeks stone passage

Sexual Intercourse 84 10 OHSUTamsulosin 0.4 mg/d 48 17 Control 35 18

Urology 2015;86:19-24 Sexual intercourse and stone passage

• A 2019 meta-analysis including 3 trials (n=240) confirmed increased stone expulsion with sexual intercourse at 2 OHSUweeks (OR 6.61, 95% CI: 3.66-11.94)

J Int Med Res 2019;47:497-504 CLINICAL BOTTOM LINE

• A romantic weekend getaway involving a trip to an amusement park may OHSUfacilitate passage of renal stones OHSU Quick Recap - Migraines

• CGRP Inhibitors and Ditans are a new class of drugs that may be helpful for migraine prophylaxis and acute treatment • Marijuana may play a role in migraine prevention • Traditional agents for migraine should OHSUremain first-line Quick Recap – Iron replacement

• Consider IV iron replacement in eligible patients with substantial iron deficit • Every other day dosing of iron appears to be more effective than daily iron and causes OHSUfewer side effects Quick Recap – CAD

• Avoid routine diagnostic testing for CAD in asymptomatic patients • For patients with CAD and severe ischemia, optimizing medical therapy is the preferred OHSUinitial approach Quick Recap – Lipids

• Ezetimibe is a useful adjunct to statin therapy for high risk patients • PCSK9 inhibitors, icosapent ethyl, bempedoic acid are newer agents that may be appropriate for very high-risk patients • Vaccines may play a role in CV disease OHSUprevention in the future • Stop squeezing fish into capsules Quick Recap – kidney stones

• Sex, drugs (tamsulosin) and rollercoasters may be helpful adjuncts for nephrolithiasis OHSU OHSU

Thanks for your kind attention! Questions/comments to [email protected]