New Drugs
The Good, the Bad,
and the Worthless
OAFP 4/25/2014
Bill Origer MD
woriger@samhealth.org
541-768-4558
Disclaimers
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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
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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 wellnourished 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
1948
1955
1963
Diphtheria
Pertussis
Polio
Measles
NEJM 11/28/2013
19 years
17 years
8 years
5 years
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 prevaccine.
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?
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• 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
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“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