New Drugs The Good, the Bad, and the Worthless OAFP 4/25/2014

Bill Origer MD woriger@samhealth.org 541-768-4558

Disclaimers

• No commercial financial support

• After the talk, you will understand why

• All is based on high quality published research

• References & boring details available

• Prices are approximate & may vary

• New information is continuous, anything could change, and I could be wrong

How did I get into this??

• Medical Director, Samaritan Health Plans 2000-06

• Wrote & managed formularies for Oregon Health Plan, Medicare & commercial insurance plans

• Used by >400 physicians who know where I live

• Oregon Health Resources Commission 2006-11, Chair, Pharmaceutical Subcommittee ‘08-11

• Oregon Preferred Drug List Committee 2010

• Oregon P & T Committee, Chair, 2012-14

Another disclaimer

• Research applies to populations

• Physicians treat individuals

• Medicine has thousands of unique & unusual people and situations

• There are times when the first or second choice are not appropriate

• Do the right thing for each patient

Using this in Health Care Reform

• Lowers cost – avoid overpriced brands

• Using evidence to improve outcomes

• Avoid things that do not work

New evidence on old stuff

Same efficacy & toxicity within category

May be differences in side effects, dosing, duration of action, price

• Alzheimer’s drugs • ACE Inhibitors • Angiotensin receptor blockers • ADHD stimulant drugs • Inhaled steroids for asthma • Inhaled nasal steroids • β agonists for asthma • α blockers for PBH • 5 α-reductase inhibitors- BPH • Estrogens for menopause • Oral contraceptives • Muscle relaxants

• Benzodiazepine receptor agonist sedatives

• NSAIDS • H2 blockers • PPIs • Statins (adjusted for potency) • Triptans for migraine • Anticholinergics & others for

overactive bladder • DPE-5 inhibitors for erectile

dysfunction • Second generation

antidepressants

New Anticoagulants for in Atrial Fib

• Factor Xa inhibitors: apixaban, betrixaban, darexaban, edoxaban, idraparinux, rivaroxaban. All drugs lumped together

• Cochrane review & meta-analysis 42,084 patients, 12-weeks to 1.9 years, ages 65-74

• Comparable to warfarin for stroke preventions & bleeding risk

• High heterogeneity of studies, insufficient data on individual drugs

New Anticoagulants for Atrial Fib

• This is favorable, BUT…

• Don’t know which one is best or safest

• Potential risks – short acting BID doses, could wear off if dose missed

• Still no way to reverse

• Results are preliminary, could change

• Few long term data

JAMA 3/19/2014

New Anticoagulants vs Warfarin

• DO NOT use for prosthetic heart valves.

• Option for those who cannot take warfarin

• Expect higher co-pay & out of pocket expense

• If warfarin is working, don’t change

• Stay tuned for more info

• Many references, most readable: Medical Letter 11/15/2010,

12/12/2010, 10/1/2012, 2/4/2013, JAMA 4/2/2104

It ain't what you don't know that gets you into trouble.

It's what you know for sure

that just ain't so.

Mark Twain

“Enough Is Enough: Stop Wasting Money on Vitamin and Mineral Supplements” Editorial Title Annals of Internal Medicine 12/17/2013

“We believe that the case is closed – supplementing the diet of well-nourished adults with most mineral or vitamin supplements has no clear benefit and might even be harmful.” Editorial Annals of Internal Medicine 12/17/2013

Worthless: non-statins for lipids

• Bile acid sequestrants, ezetimibe, fibrates, niacin, Ω-3 fatty acids

• “Alternatives” if intolerant to statins

• Studies are short & poor quality

• No decrease in cardiovascular events

• Why do something that does not work???

Annals of IM 4/1/2014

The Rise & Fall of Fish Oil

The rise: small short term studies showed benefit on surrogate markers

Lots of hype & pseudo-science

The plateau: larger studies of surrogate markers – mixed results

Nobody noticed

The fall: large meta-analysis of clinical endpoints – no benefit

The hype persists, ignoring facts

Vitamin D Remain skeptical

• Proposed to benefit almost everything • Mostly observational studies – cannot prove

causality • Most evidence is poor quality • Two systematic reviews of observational &

randomized trails: no convincing evidence of any benefit

• It’s possible that there may be some limited benefit in some populations – don’t know yet

BMJ 4/1/2014

Low T is high BS

• “Low-T Quiz” is the ultimate of hype • Claims: flagging endurance, poor performance at

sports, sleepiness after a big meal, and loss of height, as well as decreased libido could be signs of a “serious testosterone deficiency.”

• Facts: T increases libido and cardiovascular risk • Lean muscle mass vs fat – change <5% • Does not: improve strength, endurance, or mood • Won’t make anyone taller • Only proven uses: true hypogonadism: pituitary

ablation, radiation, chemo, genetic, etc JAMA Internal Medicine 8/26/2013

Pre-disease is not pathologic

No long term benefit of drug treatment for:

– Pre-diabetes1

• WHO discarded term in 1980 & 2008

– Pre-hypertension2

• JNC 8 eliminated this term

– Subclinical hypothyroidism3

Recommend lifestyle changes, not pills

1) J Am Coll Cardiol 2/14/2012; 2) JAMA 12/18/2013;

3)JAMA IM 10/25/2013

The GOOD

Benefits from routine vaccination

• In the past 10 years, vaccination has prevented 26 million cases of childhood diseases.

• Parents of today do not know polio, measles, pertussis, diphtheria, rubella, mumps, or chicken pox

• Vaccination rates are declining

NEJM 11/28/2013

Time interval for 95% drop in disease

from vaccine

1924 Diphtheria 19 years

1948 Pertussis 17 years

1955 Polio 8 years

1963 Measles 5 years

NEJM 11/28/2013

Good - Varicella vaccine

Licensed in the US in 1995. Second dose added June 2006. Kaiser Permanente of N California: 14 year prospective

study of 7585 children who received initial vaccine in 1995.

Incidence of varicella in vaccinated children was 15.9/1000 person years, tenfold lower than pre-vaccine.

Cases were mild and occurred early after the first dose. No child developed varicella after the second dose. Effectiveness 90%. No decline in immunity at 14 years. Pediatrics May 2013

Bendectin Rises Again.

• Original Bendectin 1956: antihistamine doxylamine, pyridoxine (B6) and anticholinergic dicyclomine.

• 1976 dicyclomine removed. • 1983 voluntarily withdrawn due to lawsuits • No evidence of harm in over 30 million pregnant women. • Results: no decrease in birth defects, hospitalizations for

hyperemesis doubled. • Both components are available OTC, combined cost of

$0.15/dose. • Rx: Diclegis, timed release doxylamine 10mg & pyridoxine

10mg $4.75 per pill, 1-4 doses daily. • Resurrection is expensive. The Medical Letter 8/2/2013; Am J OB-Gyn 12/2010

Medical Therapy = Stenting with Stable Coronary Ischemia

• Meta-analysis of 4064 patients, ages 59-64, mostly male, follow-up 5 years

• Ischemia identified by stress testing (with or without imaging) clinically stable, ⅓ w diabetes, ⅓ w prior MI Most had >50% occlusion ≥ 2 coronary arteries

• Randomized to stenting plus medical therapy, or medical therapy alone: aspirin, β blockers, ACEI or ARBs, and statins.

• Endpoints: death, non-fatal MI, angina, or unplanned revascularization,

• No difference between groups in any end point.

JAMA Internal Medicine Feb 2014

Good with Reservations Hepatitis C

• Sofosbuvir (Sovaldi) nucleotide inhibitor, more effective, far fewer side effects

• With ribavirin & peginterferon for genotypes 1,3,4, with ribavirin genotype 2

• Also combined with other newer agents

• Expensive ~ $65-80,000 for 12 wks plus the cost of other drugs

• Cost is so high that treatment will have to be limited

The Reservations

• Cautions: studies are preliminary, details may change, new drugs are coming

• American Association for the Study of Liver Diseases (AASLD) Guideline Committee is industry dominated

• Coverage uncertain, target population unclear

• Need more practical guidelines

• Probably best to wait a year or two

Oregon P & T review 3/27/2014

Good –OTC Nasacort

• Triamcinolone nasal spray for allergic rhinitis

• 2 sprays each nostril once/day for adults

• Approximate price: $18-22/month

• Comparable to Rx nasal steroids at much lower price

The Bad

Bad Idea (SGLT2) inhibitors for diabetes

• Canagliflozin (Invokana) $289.10/mo • Dapagliflozin (Farxiga) $289.20/mo • Induce renal glycosuria, lower A1C 0.5 – 1.0% • Osmotic diuresis, weight loss, risk of hypovolemia,

renal failure, and hyperkalemia. • Genital mycotic infections

– Women 7.6% vs 1.5% w placebo RR 527%. – Men, 2.7% vs 0.3% w placebo RR 900%. – Are you scratching yet?

• The Medical Letter 5/13/2013, 2/17/2014

Bad Idea from FDA – Zohydro timed release hydrocodone

• FDA advisory panel voted 11 to 2 against approval

• FDA approved Zohydro, doses 10 to 50 mg per pill, no APAP, tablet is not tamper resistant, can easily be crushed, dissolved, & injected.

• The attorneys general of 29 states sent a letter to FDA in Dec asking the agency to reverse the approval.

• A bill has been introduced in Congess to reverse the approval

Medscape Medical News 12/12/2013

Remain skeptical

• Restless leg aka Willis-Ekbom Disease

• No objective findings for diagnosis or treatment. No mortality

• Diagnosed by questionnaire including telephone version

• Uncertain pathophysiology

• High placebo response

• Drugs with lots of side effects

• BMJ 1/4/2014

Dopamine Agonists

Pramipexole and Ropinirole

• Nausea, orthostatic hypotension and sedation

• Sudden episodes of sleep without warning

• Impulsive behaviors

• Augmentation – may cause worsening of condition

• Brands $200-300/mo

The Medical Letter 9/5/11,

11/28/11

Gabapentin

• Somnolence (20%) dizziness (13%).

• Balance disorder, edema, weight gain, blurred vision, disorientation, lethargy and vertigo

• Driving impairment 2 to14 hours after dosing.

• Branded timed release $200+/mo

• Same as placebo in 2 of 3 studies

Rip-off: Sitavig (acyclovir) for oral herpes

• “Mucoadhesive “ 50 mg tab

• Stick it on mucosa next to new lesion

• Theory: high local concentration

• Fact: rip-off

• Mean healing time Sitavig 7.05 days Placebo 7.62 days

• Price ??? Reference: Public Assessment Report submitted to FDA

12/18/2012

And now,

The Worthless

Overpriced & Mediocre paroxetine (Brisdelle) for hot flashes

• SSRIs have a very modest effect on menopausal hot flashes.

• Brisdelle 7.5 mg paroxetine, at bedtime.

• Reduced hot flashes from 7-8/day by 1.4 hot flash/day over placebo.

• Cost $135/month, vs. $4/month for generic paroxetine 10 or 20mg.

• The Medical Letter 10/28/2013

Overpriced & Mediocre vortioxetine (Brintellix) for depression

New serotonergic antidepressant. • Studies were short, under 8 weeks. Results were

mixed, some showed clinical benefit, and some did not.

• Sexual dysfunction – Women 34% vs 20% with placebo – Men 29% vs 14% with placebo.

• $218/month. • “Other antidepressants are preferred.”

The Medical Letter 11/25/2013

Worthless - Soy protein to prevent recurrence of prostate cancer.

• 177 men at high risk of recurrence after radical prostatectomy

• Intervention: 20 gram daily of soy protein isolate, or placebo. Randomized, double blind, seven US research sites

• End point: rise in PSA over two years

• Result: no difference from placebo.

JAMA 7/10/2013

Worthless -Saw palmetto for BPH

• Saw Palmetto compared to placebo or standard medications.

• Population: 5666 men, average age 65 in 25 RCTs, lasting 4 to 72 weeks.

• Endpoints: Self-rated symptoms scores, peak urine flow rate, nocturia, and physician symptom rating

• Results: improvement in self-reported symptoms, no change in urinary flow, physician assessment, or standardized rating scales.

• Cochrane Review 2012, cited in Journal Club, Archives of IM 5/21/2013

Worthless– SNRI antidepressant levomilnacipran (Fetzima)

• Isomer of milnacipran (Savella) which is modestly effective for fibromyalgia.

• Side effects of nausea, constipation, hyperhidrosis, palpitations, urinary hesitancy and erectile dysfunction 6-17% of patients.

• Six 8 week controlled studies: 6-10% better than placebo

• $203/month . Generic SSRI $4/mo.

• Medical Letter recommends using existing SSRIs and SNRIs instead of levomilnacipran.

The Medical Letter 12/23/2103; Int J Clin Pract 11/2013

Worthless -Cranberry products for UTI prevention in high risk populations.

• Cranberry products (tablets, capsules, juice, and concentrated juice extract)

• Compared to placebo, no treatment, antibiotic, or probiotic.

• Population: >2 UTIs in past year, elderly, patients w indwelling or intermittent catheters, pregnant women, and children with >1 prior UTI.

• Endpoint: documented symptomatic UTI. • Results: Cranberry - better than probiotics, same as

placebo. • Conclusion: “Cranberries should be recommended for

their culinary, rather than therapeutic potential.” Cochrane Review 2012, cited in Archives of IM 5/21/2013

Worthless

Metformin for childhood obesity.

• Used off-label in non-diabetic children for weight loss.

• Meta-analysis by OHSU of randomized trials of non-diabetic children with BMI >25 or BMI for age >85th percentile. 14 trials with 946 children, ages 10-16.

• Modest benefit at 6 months – wt loss 3.6% • No difference from controls at 12 months. JAMA Pediatrics Feb 2014

DPP-4 inhibitors for diabetes – no cardiovascular benefit

• Saxagliptin (Onglyza) and alogliptin (Nesina.)

• Added to standard treatment with other oral hypoglycemics and CV drugs.

• No CV benefit or risk over 1½ to 2 years. Rate of hospitalization for CHF was increased with saxagliptin.

NEJM 10/3/2013

Bad idea - expensive hydrocodone cough syrup

• 2 cheap components – 4mg chlorpheniramine and 5mg hydrocodone

• Brand name cough syrup (Vituz) $77 for 120cc.

• No clinical studies were required for FDA approval.

• “ Vituz might reduce coughing in some patients, but as with other similar combinations, its potential harms, especially in the elderly, outweigh its potential benefits.”

The Medical Letter 11/25/2013

Reliable Information

• The Medical Letter

• The Cochrane Collaboration

• Meta-analysis in peer-reviewed journals

• Oregon P & T Committee

http://pharmacy.oregonstate.edu/drug_policy/pharmacy-therapeutics

Click on

“Drug class reviews” and “Drug evaluations”

Remain Skeptical