and the Worthless Bill Origer MD OAFP 2015 Disclosure No commercial financial support After the talk you will understand why worigersamheathcom 5417684558 Disclaimers Not a comprehensive study of diseases ID: 805554
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Slide1
New DrugsThe Good, The Bad, and the Worthless
Bill Origer MD
OAFP 2015
Slide2DisclosureNo commercial financial support After the talk, you will understand whyworiger@samheath.com541-768-4558
Slide3DisclaimersNot a comprehensive study of diseases All is based on high quality published research References & boring details available Prices are approximate & may varyNew information is continuous, anything could change, and I could be wrong
Slide4How did I get into this??Private practice Albany, OR 1977 - 1996Variety of administrative jobs since thenBeen doing drugs with the state since 2006Oregon Health Resources Commission 2006-11, Chair, Pharmaceutical Subcommittee ‘08-11Oregon Preferred Drug List Committee 2010Oregon P & T Committee, Chair, 2012-15My credibility in this world is the strength of evidence
Slide5Another disclaimerResearch applies to populations Physicians treat individualsMedicine has thousands of unique & unusual people and situationsDo the right thing for each patientThere are times when a 4th or 5th choice is the best option for that patient
Slide6Using this in Health Care ReformLowers cost – avoid overpriced brandsUsing evidence to improve outcomesAvoid things that do not work
Slide7New evidence on old stuff
Slide8Same efficacy & toxicity within category May be differences in side effects, dosing, duration of action, priceAlzheimer’s drugsACE InhibitorsAngiotensin receptor blockersADHD stimulant drugsInhaled steroids for asthmaInhaled nasal steroids β agonists for asthmaα blockers for PBH5 α-reductase inhibitors- BPHEstrogens for menopauseOral contraceptivesMuscle relaxantsNSAIDS
Benzodiazepine receptor agonist sedatives
Opioids for long term use
H
2
blockers
PPIs
Statins (adjusted for potency)
Triptans for migraine
Anticholinergics & others for overactive bladder
DPE-5 inhibitors for erectile dysfunction
2
nd
generation antidepressants
Slide9Nicotine Replacement – 8 weeks. Period Duration of nicotine replacement therapy–8 weeks same as 24 or 52 weeks.Only good end-point: continuous cessation at 1 yr. Cluttered with lots of meaningless secondary & post-hoc end points. Who cares if the time to relapse was a few days different from one treatment to another? JAMA Internal Medicine online 2/23/2015
Slide10Long Term OpiatesEvidence of Safety & EffectivenessThis page is intentionally blank
Slide11Long term Opiates No Data Proving BenefitThere are no studies of opioid vs placebo or non-opioid therapy lasting > one year on outcomes related to pain, function, or quality of life.Most randomized studies <6 weeksAnnals of IM online 1/13/2015
Slide12Long Term OpiatesAdverse EffectsIncreased risk of Death – 16,235 opioid OD deaths US 2013 Overdose, more w higher doses Fractures MI, especially with high doses Rx for testosterone & erectile dysfunction Motor vehicle accidents Addiction & diversionCDC mortality data 2015; Annals of IM online 1/13/2015
Slide13Comparison No evidence of risk or efficacy difference among productsMinimal difference in efficacy, no difference in adverse effects between short acting narcotics given on schedule and timed release productsOregon P & T Committee evaluation March 2014
Slide14Lunesta - FDA warningThe moth* bites back – FDA warning on Lunesta. Eszoplicone is a benzodiazepine receptor agonist with a long half-life - a good reason not to use it. 3mg dose can cause impairment of driving, memory, and co-ordination for up to 11 hours. FDA warning - starting dose 1 mg for both men & women. *The Lunesta advertisement “butterfly” is a nocturnal moth Actias luna native to the eastern US. The adult lives 10 days, does not eat, mates, & dies. It’s a good mascot for a drug that should only be used short term.
The
Medical Letter 6/9/2014
Slide15Tamiflu & InfluenzaNeuraminidase inhibitors do little for influenza Early studies (1999) showed minor benefit – reducing recovery time by a day. Roche and GSK suppressed publication of company research 4½ year legal battle, the Cochrane Collaboration and BMJ obtained 160,000 pages of documents. The results? Same as in 1999. Oseltamivir reduced duration by 19 hours in adults, 29 hours in kids. Zanamivir reduced duration by 14.4 hours in adults, none in kids. No reduction in sinusitis, pneumonia, hospitalization, or death by either Modest effect if used for prevention, NNT 30-50.
Contradicts recommendations from the
CDC, WHO,
American
Academy of Pediatrics and others who should have known better.
>$
7
billion worldwide since
2003 stockpiling this stuff,
shelf-life 5-7 yrs
.
The
Medical Letter 10/8/1999; CDC Emerging Infectious Diseases 10/1999; BMJ 4/12/2014
Slide16Tramadol –why it does not always work It seemed like such a good idea….Parent molecule is SNRI, similar to venlafaxine, not a narcotic, andMetabolized by CYP2D6 into desmethyltramadol, which binds to μ opioid receptors, but…
Slide17Tramadol Expression of 2YP2D6 is highly variable7% of Caucasians have no CYP2D6 10% of Italians, Portuguese, and Greeks, and ⅓ of Arabians are ultra-rapid metabolizers & produce a high level of the drugDrugs inhibiting CYP2D6 will prevent formation of the active metabolite: fluoxetine, paroxetine, sertraline, bupropion, duloxetine, and cimetidineJAMA Internal Medicine 12/8/2014
Slide18Dabigitran (Pradaxa)Unsafe at any speed
Slide19Dabigitran (Pradaxa)Poor absorption 3-7%Two-step activation, hydrolysis, then glucuronide formation.Major accumulation with declining renal function.Small changes in any one of these variables can cause 500% fluctuation in serum levels on the same dose.BMJ 7/26/2014
Slide20Dabigitran (Pradaxa)Fluctuating serum levels can produce over or under anticoagulation.Data from the manufacturer - optimal serum level between 40 - 200 ng/mLNo commercially available test.This contradicts the advertising hype that promised no testing.JAMA 3/10/2015
Slide21Dabigitran (Pradaxa)Rivaroxiban (Xarelto) similar – wide variations in plasma concentrationsApixaban (Eliquis) has not had this problemJAMA 3/10/2015
Slide22Lipid GuidelinesLipid guidelines overestimate cardiac risk. Harvard researchers applied the risk to a known population, 27,542 women aged 45-79 from the Women’s Health Study Lipid measurements, + 10 years of FU for cardiac eventsThe calculator overestimates CV risk by at least 50%. Editorial criticized the American College of Cardiology and the American Heart Association and recommends prompt revision of the guidelines to conform to published evidence. JAMA IM 12/2014
Slide23Antiepileptic Drugs for Neuropathic PainSmall benefit at best. Ten Cochrane reviews of 91 randomized double-blind studies of 17,955 ambulatory adults with neuropathic pain or fibromyalgia Only gabapentin & pregabalin showed reduced pain w diabetic or postherpetic neuropathy. Small benefit: 7-25% of patients had pain reduction of ≥50% Pregabalin alone helped fibromyalgia, small benefit: 7-11% of patients had a 50% reduction in pain. No benefit or poor quality studies: clonazepam, phenytoin, carbamazepine, lamotrigine, oxcarbazepine, topiramate, and lacosamide. Side effects: 30% of patients
withdrew
by 12 weeks. Adverse effects
in
80% of
patients, usually dizziness
and somnolence.
JAMA
7/9/2014
Slide24The Good
Slide25This week in 1952 Measles declining, 29,518 cases this week, season total 439,297Polio at its lowest, 74 cases this week, seasonal total 28,692; this time last year 33,393 Anthrax: 4 human and 327 animal cases this week Four botulism deaths: 2 each in Oregon & California Rabies: 191 animal cases, one human death in Tennessee Scarlet fever: 2,916 cases, 82 cases in a hospital in Massachusetts Malaria: 41 cases in 20 states. Typhoid:
28
cases in 16
states.
M
eningococcal infections: 107
B
rucellosis
&
encephalitis:
27
each
Tularemia: 18
;
trichinosis: 5
MMWR
4/19/1952
Slide26Good - OTC Nasal SteroidsTriamcinolone acetonide (Nasacort Allergy 24HR)Fluticasone propionate (Flonase Allergy Relief)Same as Rx Drugs, but only $12/bottleRx brand names discontinued; still are Rx genericsThe Medical Letter 3/30/2015
Slide27Generic celecoxib (Celebrex)2 generic brands of celecoxib – Teva & MylanPrice still >$2/pill for 200 mg, >$3/pill for 400 mgBut who cares, since it is no better or safer than other NSAIDsBMJ 6/1/2002; FDA Bulletin 5/30/2014; GoodRx.com 3/31/2015
Slide28MRSA - IV, Inpatient Skin infections onlyGlycopeptidesVancomycin $115 7 daysDalbavancin – Dalvance $2980 Single doseOritavancin– Orbactiv $2900 Single doseTelavancin– Vibativ $2163 7 daysOxazolidinones Linezolid – Zyvox $2789 10 days Tedizolid phosphate – Sivextro $1410 6 daysOthers Ceftaroline fosamil – Teflaro $1260 5 daysDaptomycin – Cubicin
$2478 7 days
The
M
edical Letter 1/5/2015 – cost for shortest recommend treatment
Slide29Hepatitis C The Good Much better drugsHigh efficacy >90%Low toxicity/side effects < 5%Off the chart prices, so must select those most likely to benefit Treating all DMAP open card Hep C patients would double entire drug budgetOnly 5-20% will develop cirrhosis over 20 years
Slide30Hepatitis C Priority - Oregon Health Plan Open CardStage 3 and 4 fibrosis without decompensated cirrhosisThose receiving an organ transplantPatients with extrahepatic manifestations, including: Type 2 or 3 cryoglobulinemia with end‐organ manifestations (vasculitis) Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritisPatients prescribed medication by or in consultation with a hepatologist or gastroenterologist with experience in Hepatitis C.Oregon P & T Committee 3/26/2015
Slide31Hepatitis C DrugsHarvoni (ledipasvir and sofosbuvir)Genotype 1 Sovaldi (sofosbuvir)Genotypes 1, 2, 3, 4Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets)Genotype 1 Cost variable- $50,000 - $120,000
Slide32Naloxone Auto-injector Brand Evzio, kit for patient use in narcotic OD. Two prefilled auto-injector syringes containing 0.4 mg naloxone About $250, similar to Epi-pen, another cheap drug in an expensive package. Cheaper, but off-label: 0.4mg of injectable naloxone (about $20) used intranasally. The Medical Letter 6/9/2014
Slide33Placebo for cough in infants & toddlersPlacebo works for cough in infants and toddlers Randomized controlled blinded study of nonspecific cough in 125 children ages 2-47 months. Agave nectar cough syrup compared to placebo & no treatment. Agave - sweet taste & consistency similar to honey. Endpoints: parent questionnaires rating the severity, frequency, and bothersomeness of cough, congestion, and rhinorrhea, quality of sleep of child and parent, and a combined score of effectiveness. Placebo and agave nectar- same improvement, all scores: 1.5- 3 out of 7 points. Both better than no treatment
.
JAMA
Pediatrics October
2014
Slide34Metoprolol = carvedilolMetoprolol is equal to carvedilol in preventing mortality in CHF patients. Danish retrospective review. Heart Failure Registry of 11,664 CHF patients Mean age 69.3 years, 71% male. Average follow-up 2.5 years. All had an EF <40%. Outcomes: all-cause mortality and CV mortality. Mortality 18% for both groups. Study limits: retrospective not randomized. JAMA IM 8/2014
Slide35The Bad
Slide36Alzheimer’s Rip-offs Aricept 23 mg same modest efficiency, but more side effects $475/mo. Generic $12/mo Forest Labs planned to discontinue Namenda 5 & 10 mg & force switch to Namenda XR 7-14-21-28 mg Patent on 5 & 10 mg expires in Oct 2015Switch stopped by court order Memantine hydrochloride extended-release + donepezil hydrochloride (Namzaric) approved, not marketed. Worthless combination.Oregon P & T Committee, August 2014; FDA news Drug Daily Bulletin
Slide37Diabetes(SGLT2) inhibitors Induce renal glycosuriaOsmotic diuresis, dehydration, weight loss, renal failure, and hyperkalemia.Genital mycotic infections♀7.6% RR 527%. ♂, 2.7% vs 900%.Dapagliflozin (Farxiga) empagliflozin (Jardiance) dapagliflozin + metformin hydrochloride (Xigduo XR) & other combinationsBAD IDEAOregon P & T Committee 3/2015
Slide38Suvorexant (Belsomra) for Insomnia - Bad IdeaNew category orexin receptor agonistOrexin neurons in lateral hypothalamusActive during wakefulness & silent during sleepLoss of orexin neurons in narcolepsy (cataplexy & hypnogogic hallucinations)Drugs block orexin neuropeptides from binding to receptorsDoses: 5,10,15,20 mg, $10/pillTime to T MAX 1-2 hrs fasting, 3 hrs fedLong half life - 12 hrs
Slide39Suvorexant (Belsomra)Efficacy: dose related, lower value for 10 mgSleep onset: 2-20 minutes < placeboSleep duration: 15-40 min > placeboAdverse effects:Somnolence/daytime sleepiness 13-20%Narcolepsy sx: (0.013-0.018) 26-36x expected rateSlow onset, long half-life, and might induce narcolepsySeems like a bad idea The Medical Letter 2/2/2015; Lancet Neurology 5/2014;Biologic Psychiatry 10/23/2014
Slide40The Worthless
Slide41Particularly WorthlessDroxidopa (Northera) for orthostatic hypotensionNo study showed efficacy beyond 2 weeks of treatment100-600 mg tid $1,000 - $8,800 monthly costOregon P & T Committee; GoodRx
Slide42Still Worthless Ω- 3 Omega-3-carboxylic acids (Epanova)EFFICACY —No convincing evidence that fish oil supplements either prevent cardiovascular disease or improve outcomes in patients who already have it.Medical Letter Treatment Guidelines Jan 2014
Slide43Niacin Bombs OutASCVD prevention– increased risk no benefit. 26,673 adults with vascular disease - niacin vs placebo added to statin.Primary endpoint: 1st CV event- nonfatal MI, coronary death, stroke, or revascularization Men and women ages 50-80, previous MI, stroke, peripheral artery disease, or diabetes with evidence of coronary artery disease. No benefit in preventing CV events Increased the rate of diabetes, poor diabetic control, infections, serious bleeding, plus GI, musculoskeletal, & skin side effects. NEJM 6/17/2014
Slide44Long-acting Injectable PaliperidoneInjectable paliperidone (Invega Sustenna) vs haloperidol inj. 311 adult patients with schizophrenia. Median FU 466 days. Primary end point: efficacy failure, psychiatric hospitalization, crisis requiring stabilization, or increase in outpatient visits. Failure rates similar 32-34%Secondary outcomes: adverse medication events No differences in involuntary movements, tardive dyskinesia, or Parkinson’s symptoms. Haloperidol patients - more motor restlessness (akathisia.) Paliperidone pts ↑
6.04 kg
@
24 months, haloperidol
pts
↓
3.88 kg.
P
aliperidone
$859/month, haloperidol $32.
JAMA
5/21/2014, The Medical Letter Treatment Guidelines 6/2013
Slide45High-dose Flu VaccineTiny BenefitAfter age 65, the immune system declines. In theory, a higher dose flu vaccine might work better 31,989 patients mean age of 73 were randomized to receive either a standard flu vaccination or a high-dose vaccination Endpoint: laboratory confirmed influenza Rates: 1.9% with standard vaccine, 1.4% with high-dose vaccine Absolute risk reduction 0.5%. NNT 200 Complications such as pneumonia were rare but same in both populations Bottom line: 199 out of 200 elderly people will not benefit from the high-dose vaccine
NEJM
8/14/2014
Slide46Luliconazole cream (Luzu) for tineaOverpriced worthless new drug: luliconazole cream (Luzu) for tinea. 3 double blind studies, cure rates of 21-27%. Cost $380 for 2 weeksOlder OTC drugs such as clotrimazole, miconazole, & terbinafine, cure rates of 40-60% and cost < $10. Who buys this stuff? The Medical Letter 6/23/2014; Journal Family Practice 1/2002
Slide47Worthless - Tavaborole 5% (Kerydin)Topical for onychomycosis $491.20 for 4 cc ($3,481/oz.) Once/day 48 weeksComplete cure(clinical & mycological) 6.5-9.1%And the spin: a novel endpoint “Almost complete” cure 15.3-17.9%The Medical Letter 3/2/2015Suggests other endpoints: almost non-fatal MI, almost successful CPR…
Slide48Me-tooAvanafil (Stendra) another PDE-5 inhibitor for EDEsomeprazole strontium (Anneal) The 9th PPI generic $60/mo; brand at $200/mo. Why? OTC Prilosec & Prevacid $18/mo. Indomethacin (Tivorbex) 20 & 40 mghigh rate of GI side effects. “There is no good reason to use indomethacin in any dosage for treatment of mild to moderate pain.”Finafloxacin otic suspension 0.3% (Xtoro)Fluticasone furoate inhalation powder (Arnuity Ellipta) similar price to Flovent
The
Medical Letter
5/12/2014, 7/21/2014
Slide49Me-too, DiabetesGLP-1 agonistsAlbiglutide (Tanzeum) weekly inj $326/moDulaglutide (Trulicity) weekly inj $488/moLiraglutide (Saxenda) – also approved for “chronic weight management” not available yet, recycled Victoza (daily inj)
Slide50Brimonidine gel (Mirvaso) for RosaceaTopical -2 adrenergic blockerTopical vasoconstrictor Temporarily reduces rednessNo effect on pustules or pathology of disease About $300 for 30 gramsThe Medical Letter 10/14/2013
Slide51Inhaled Insulin (Afrezza) Microspheres of carrier, rapidly absorbed in the lungsOnly regular insulin, no long-acting formulation 2 sizes, 4 or 8 units. Multiple inhalations for larger doses Reduced A1C by half compared to insulin aspart (NovoLog) (0.2% versus 0.4%.) Patients with good control (A1C <7%) also half (13.8% versus 27.1%.) 25% of patients w cough, reduces FEV1 in normal patients 40 cc, significance unknown. C
ontraindicated with
asthma, COPD,
&
other lung conditions.
Long-term
safety
& efficacy unknown
Cost: 2-5X NovoLog. Save
your breath
.
Clinical
Therapeutics
8/2014
; Afrezza package
insert; Price: Goodrx.com 2/27/2015
Slide52Roflumilast (Daliresp) Oral drug added to long-acting beta agonists and inhaled steroids to prevent COPD flares. Mechanism of action is similar to theophylline. Reduced exacerbations by 13.2% vs placebo. Defined as an episode requiring steroids, hospital admission, or was fatal. 1 yr study, placebo patients had 0.927 exacerbations/yr vs 0.805/yr w drug. Prevents 0.122 exacerbations/yr. IE prevents 1 exacerbation over 8.19 years. Reduces hospitalizations by 0.075 exacerbations/yr vs placebo. 13.15 yrs to prevent 1 hospitalization,
if the
patient lived that long.
C
ost about
$
300/mo. $
29,484
to prevent
one
exacerbation; $
48,000 to prevent one hospitalization.
67
% of patients receiving roflumilast
w adverse
drug effect.
Lancet
online 2/13/2015
Slide53Vytorin 10mg ezetimibe + 40mg simvastatinIMPROVE-IT study 18,144 high risk patients w acute STEMI, NSTEMI, or unstable angina w previous MI, previous CABG, or diabetes. Randomized to simvastatin 40 mg or Vytorin daily. Add-on, not a substitute for statins. Endpoints: composite of CV death, nonfatal MI or stroke, hospitalization for unstable angina, or coronary revascularization. Duration 7 yearsAbsolute risk reduction was 2%, from 34.7% to 32.7%. NNT 50 to prevent one event over 7 years. Vytorin is $210 per month, $2,520 per year. High-dose atorvastatin 40 or 80 mg is $17 per month, $204 per year.
Hype
warning:
Full
data not
published
.
Small
benefit to a narrow population. Remain skeptical.
AHA
Scientific Sessions, 11/19/2014. Prices: good
Rx.com
Slide54Intra-articular Hyaluronic Acid –wide use, little benefit Meta-analysis, Archives IM 2012 - minimal clinical benefit American Academy of Orthopedic Surgeons 2013 Practice Guideline: “We cannot recommend using hyaluronic acid for patients with symptomatic osteoarthritis of the knee.” 2012 Medicare Part B paid for 1,161,924 intra-articular hyaluronic acid injections. Mean rate 39 injections /1000 Half the national rate in the Portland area10% below the national rate in Bend & Eastern Oregon10% above the national rate in Eugene, Albany, & Corvallis2-3 times the national rate in Salem area
JAMA
Internal Medicine 8/25/2014
Slide55Vitamin DUSPSTF recommends against screening for vitamin D deficiency Current evidence is insufficient to demonstrate benefit (or harm) of screening for vitamin D deficiency in asymptomatic adults. Annals of IM 11/25/2014
Slide56And finally….. The Strange
Slide57Contrave - Diet Pill, A Strange CombinationDo believe in magic? Another diet pill So far no pill for weight loss is both safe and effective long-term., Contrave, combines opioid antagonist naltrexone with the antidepressant bupropion. Weight loss of 3-5% more than placebo at 1 yr. No longer studies. Most previous drugs lost effectiveness 2nd year. Side effects: ⅓ of patients had nausea. Also, headache, constipation, dizziness, and dry mouth. Interacts with inhibitors of CYP2B6, such as antidepressants, antipsychotics, beta blockers, ticlopidine, and clopidogrel.
Naltrexone
can be used only by the portion of population not on Vicodin.
The
Medical Letter 11/10/2014
Slide58Strange FDA ApprovalPeramivir (Rapivab): IV drug for influenzaNeuraminidase inhibitor, similar to oseltamivir (Tamiflu)FDA approved only for treatment of uncomplicated influenza Not approved for use in hospitalized or critically ill patients Did not significantly reduce the time to clinical resolution in hospitalized patients600 mg IV once $950.00Why??The Medical Letter Feb 2, 2015
Slide59Zecuity Sumatriptan Battery Powered Patch“Coming soon” since 2001 Efficacy same as oral
Slide60Zecuity
Slide61Adasuve, inhaled loxapine for acute agitation
Slide62Adasuve, inhaled loxapine for acute agitation in schizophrenia & bipolar1st generation antipsychotic from 1975Generic tabs, about $1.50, rarely usedSingle use $140 device. Vaporizes 10 mg of the drug, inhaled, absorbed via lungsDownside: bronchospasm and respiratory distress, especially in patients with asthma or COPD.
Slide63AdasuveA special safety program is required. (I did not make this up, honest!) 1) Ask the patient if he/she has asthma or COPD or is taking a medication for either, and/or check records 2) Examine for respiratory abnormalities 3) Open Adasuve foil packet & remove inhaler4) Pull tab to activate. A green light will go on when it is ready. Administer in 15 minutes, or the battery dies5)If the light goes out, it will not work, so open another
Slide64Adasuve6) Patient exhales fully to empty the lungs 7) Patient inhales a steady breath through the mouthpiece 8) After full inhalation, patient holds breath 10 seconds. 9) If inhalation successful, green light goes out. It the light is still on, repeat with same inhaler. 10) Monitor, including chest auscultation every 15 minutes for one hour. 11) If bronchospasm occurs, treat with short acting beta agonist. May administer once in 24 hours
Slide65AdasuveHow to do this with an acutely agitated psychotic patient is not explained Simpler alternative: injectable Haldol, $1.90/dose. Adasuve package insert & website; The Medical Letter 4/14/2014, price: Goodrx.com.
Slide66Vitamin D does not reduce the adverse impact of earthquakes on healthy adults.Vitamin D is purported to benefit mental health. A series of earthquakes started 9/4/2010 in Christchurch, NZ lasting months, widespread destruction, no fatalities. The VIDARIS study of vitamin D and respiratory infections was underway in Christchurch at the time322 healthy adults were randomized to high-dose Vit D or placebo for 18 months from Feb 2010 - Nov 2011308 participants completed an earthquake impact questionnaire about psychological after effects, comparing vitamin
D
users to placebo users
The
incidence of fatigue, stress, anxiety, and insomnia did not differ between the vitamin D and placebo groups
.
BMJ 12/15/2014