Transcript New Drugs 2016 - Oregon Academy of Family Physicians

New Drugs 2016
The Good, the Bad, & the
Worthless
Bill Origer MD
OAFP
March 11, 2016
Disclosure
• No commercial financial support
• After the talk, you will understand why
[email protected]
541-812-4577
Disclaimers
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Not a comprehensive study of diseases
Based on high quality published research
References & boring details available
Prices are approximate & may vary
New information is continuous
– anything could change
– I could be wrong
Another disclaimer
• Research applies to populations
• Physicians treat individuals
• Medicine has thousands of unique & unusual
people and situations
• Do the right thing for each patient
• There are times when a 4th or 5th choice is the
best option for that patient
How did I get into this??
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20 yrs private practice Albany, 1977 – 1996
Variety of admin jobs & part-time practice 1997-2015
Faculty, Samaritan Family Medicine Residency, Corvallis
Oregon Health Resources Commission 2006 -11,
– Chair, Pharmaceutical Subcommittee ‘08-’11
– Oregon Preferred Drug List Committee 2010
• Oregon P & T Committee, Chair, 2012-16
• My credibility in this world is the strength of evidence
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 anti-cholinergics
β agonists for asthma
Inhaled nasal steroids
α blockers for PBH
5 α-reductase inhibitors- BPH
Estrogens for menopause
Oral contraceptives
Muscle relaxants
NSAIDS
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Ophthalmic steroids
Ophthalmic anti-inflammatories
Growth hormone products
Benzodiazepine receptor agonist
sedatives
Opioids for long term use
H2 blockers
PPIs
Statins (adjusted for potency)
Triptans for migraine
Anticholinergics & others for
overactive bladder
DPE-5 inhibitors for erectile
2nd generation antidepressants
The Good
Newer anticoagulants
• Safety & efficacy same as warfarin for stroke
prevention with atrial fib, and acute DVT in
uncomplicated patients
• Concerns: no way to monitor, bid dose (dabigatran &
apixaban) caution w renal impairment, high cost
(~$300/mo)
• Edoxaban (Savaysa) no comparative data to others
• Only dabigitran is reversible
• 90% of OHP patients still on warfarin
• Oregon P & T Sept 2015; Medical Letter 3/15/2015
Idarucizumab (Praxbind)
Antidote for dabigatran (Pradaxa)
• Human monoclonal antibody
• Binds to dabigatran w higher affinity than
dabigatran binds to thrombin
• Works only for dabigitran.
• Immediate onset, blood levels <20 ng/ml
– 93% at 12 hr, 79% at 24 hrs.
• Dose - IV bolus 5 gm, $3500/dose
• Limited data – single arm trial, 90 patients, 92%
had normal hemostasis for surgery
• The Medical Letter 11/23/2015
Drugs past expiration date
• Dates written by legal department
• Single episode of toxicity of expired drug – tetracycline 1963
• Dept Defense Study: 3005 lots of 122 meds, ave. 66 mo. past
date
• Solid drugs, unopened container, room temperature >90% of
potency 5 yrs past date
• Heat & humidity speed aging
• Solutions, suspensions less stable, especially to freezing
• Epi-pens loose potency after expiration
• The Medical Letter 12/7/2015
Albuterol powder MDI (ProAir RespiClick)
• Existing albuterol inhalers - dilute solution w propellant.
Requires coordination between actuation of the device and
inspiration, or the use of a spacer
• Dry powder inhalers are breath-actuated, and do not
require an initial priming dose. The patient must be able to
take a rapid deep inhalation to activate the inhaler.
• Contains a dose counter
• Opening the mouthpiece prepares a dose for use & causes
the counter to count down one dose. Closing the cap
without inhalation wastes that dose.
• Price $50 per inhaler (200 doses,) similar to other albuterol
MDIs. This device may be easier for some patients to use.
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The Medical Letter 10/26/2015
Hepatitis C Facts
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Of 100 persons infected with HCV, approximately
75–85 will go on to develop chronic infection
60–70 will go on to develop chronic liver disease
5–20 will go on to develop cirrhosis over a period
of 20–30 years
• 1–5 will die from the consequences of chronic
infection (liver cancer or cirrhosis)
• CDC website accessed 2/22/2015
Beware of Hep C Guidelines
• American Association for the Study of Liver
Diseases (AASLD) Infectious Disease Society of
America (IDSA) Hepatitis C Guidelines
• Not evidence based
• Majority of members with conflict of interest
Levels of evidence
• 1A Meta-analysis of randomized controlled trials
• 1B At least one randomized controlled trial
• 2A At least one controlled study without
randomization
• 2B At least one type of quasi-experimental study
• 3 Descriptive studies, such as comparative studies,
correlation studies, or case-controlled studies
• 4 Expert committee reports or opinions and/or
clinical experience of respected authorities
American Association for the Study of Liver Diseases (AASLD)
Infectious Disease Society of America (IDSA)
Definitions of Evidence
Classification
Description
Class I
Conditions for which there is evidence and/or general
agreement that a given diagnostic evaluation, procedure, or
treatment is beneficial, useful, and effective
Class II
Conditions for which there is conflicting evidence and/or a
divergence of opinion about the usefulness and efficacy of a
diagnostic evaluation, procedure, or treatment
Class IIa
Weight of evidence and/or opinion is in favor of usefulness
and efficacy
Usefulness and efficacy are less well established by evidence
and/or opinion
Conditions for which there is evidence and/or general
agreement that a diagnostic evaluation, procedure, or
treatment is not useful and effective or if it in some cases may
be harmful
Class IIb
Class III
Guideline Myths
• Myth - Treat everyone
– <20% get cirrhosis over 20-30 yrs; <5% die from disease
– Cost would double total annual drug budget for OHP open card
• Myth - treat early
– Based on “modeling studies” – IE speculation
• Myth - Active drug abuse not a barrier
– Only study done on opioid addicts in treatment with suboxone
or methadone – they did well, but can’t extrapolate
– Anecdotal reports of re-infection in addicts after tx
• Myth – alcohol abuse not an obstacle
– Studies exclude active drug or alcohol users – no data
Priority - sickest
• Advanced fibrosis (METAVIR F3),compensated
cirrhosis (METAVIR F4) OR radiologic, lab, or clinical
evidence of cirrhosis without ongoing progressive
decompensation (MELD score 8 -11),
• Expected survival from other conditions >5 years
• Extrahepatic manifestations of hepatitis C
– Type 2 or 3 cryoglobulinemia with end-organ
manifestations (vasculitis)
– Proteinuria, nephrotic syndrome, or
membranoproliferative glomerulonephritis
Priority - sickest
• Patient is listed for a transplant and it is
essential to prevent recurrent hepatitis C
infection post-transplant
• Post-transplant patients with Stage 4 fibrosis
• Post-transplant patients with fibrosing
cholestatic hepatitis due to HCV infection
• Oregon P & T Jan 2016
Priority – best chance for success
• Abstinent from illicit drug, marijuana use, AND
alcohol abuse for 6 months or longer
• Able to participate & cooperate in treatment
• Consultation with hepatologist, GI or ID
specialist, or other physician with experience
in treatment of Hepatitis C
Hep C summary
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New drugs are better & less toxic
Studies are poor quality & short
Guidelines are not scientific
Competition dropping prices, but still outrageous
More drugs in the pipeline
Treat the sickest, no hurry for most
Naloxone auto injector (Evzio)
• Auto-injector syringes containing 0.4 mg
naloxone for opioid overdose
• Original price $250/pkg
• As of 2/24/2016: pkg of 2 syringes: $820
• Off-label: a standard dose, 0.4mg of injectable
naloxone ($17-22) may be used intranasally.
• The Medical Letter 6/9/2014; goodrx.com
Platelet inhibitors after PCI
• Dual antiplatelet therapy (DAPT) consisting of aspirin plus a P2Y12
receptor antagonist is after drug‐eluting stent (DES)
– 12 months by the Am Coll of Cardiology/Am Heart Asso (ACC/AHA)
– 6-12 months by European guidelines
– followed by aspirin monotherapy
• extended therapy (>12 months) compared with 12‐month therapy
– reduction in stent thrombosis (NNT 100‐250) and MI (NNT 50‐125),
but increased risk of major bleeding (NNH 111‐325).
– increase in all‐cause mortality with extended DAPT beyond one
year 2.0% vs. 1.5%; NNH 200 driven by non‐cardiovascular events.
• Further studies are needed the optimal duration of therapy
• DAPT one year in most patients receiving a DES
– high CV risk patients considering longer term use (up to 30 months)
– high bleeding risk consider <6 months.
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Oregon P & T July 2015
Newer drugs for Diabetes
• A recent systematic review found insufficient
evidence to compare health outcomes of the
newer diabetes medications and combinations
• Studies underway
• Be skeptical of single studies
• CV benefit of metformin, insulin, sulfonylureas
based on meta-analysis of large studies
• Evidence‐based Practice Center for the Drug Effectiveness Review Project.
OHSU Portland, OR. 2014.
Ophthalmic steroids & antiinflammatories
• High quality evidence - no difference in
efficacy/effectiveness or in safety between
ophthalmic corticosteroid agents
• High quality evidence - no difference in
efficacy/effectiveness or in safety among
ophthalmic nonsteroidal anti‐inflammatory
drugs
• Oregon P & T 5/28/2016
Asthma/COPD
• Tiotropium/olodaterol (Stiolto™ Respimat®)
insufficient evidence of comparative efficacy or
safety between tiotropium-olodaterol and other
drugs for the management of COPD
• Olodaterol - lack of quality evidence for clinical
effectiveness.
• Fluticasone furoate (Arnuity™ Ellipta®) same as
any other inhaled steroid
• Oregon P & T Sept 24, 2015
Insulin glargine (Lantus)
Insulin detemir (Levemir)
• Insufficient comparative evidence that evaluates
long‐term outcomes (ie, vascular outcomes,
mortality or cancer) between insulin detemir and
glargine products
• No clinically relevant difference in efficacy or
safety of the two long acting agents
• Insulin degludec (Tresiba) is noninferior to insulin
glargine & insulin detemir in lowering HbA1c
• Oregon P & T Nov 2015; Medical Letter 12/7/2105
Insulin degludec (Tresiba)
• 8 open‐label, randomized controlled trials
• Comparisons included insulin glargine, insulin
detemir, and sitagliptin
• Low strength evidence - non‐inferior to insulin
glargine or detemir at A1c reduction
• Open‐label study design prohibits a fair
comparison for adverse effects
• Insufficient evidence to show any effect on
mortality, or vascular outcomes.
Insulin degludec and insulin aspart
Ryzodeg®
• Similar A1c lowering as detemir/aspart
• Insufficient evidence to determine the effect
of degludec/aspart on mortality, & vascular
outcomes
• Oregon P & T Dec 2015
Fluoroquinolones
• Moderate quality evidence: no difference
in effectiveness of fluoroquinolones to
susceptible bacteria
• Ofloxacin - highest risk of tendon injury
levofloxacin - least risk
Oregon P & T 5/28/2015
Topical analgesics
• Moderate quality evidence: topical NSAIDs are safe and
effective for acute musculoskeletal pain over 1 to 2 weeks
• Insufficient evidence to compare efficacy or safety among
topical analgesics.
• Topical 8% capsaicin improves neuropathic pain more than
lower concentrations
• Evidence of long‐term safety is insufficient
• Insufficient evidence exists for efficacy of 5% topical
lidocaine patches for neuropathic pain
• Insufficient evidence to compare topical VS oral NSAIDS for
efficacy or safety
• Oregon P & T Nov 2015
Maybe good
Flibanserin (Addyi)
• Hypoactive sexual desire in menopausal women
• Mechanism unknown
– Agonist serotonin-HT1A Antagonist serotonin-HT2A
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100mg daily at hs, $800/month
Somnolence, sedation, fatigue 21%
Hypotension & syncope, worse w alcohol
Concurrent alcohol use contraindicated
Flibanserin (Addyi)
• Three 24-week studies, DAISY, VIOLET, BEGONIA
• End points on self-rating scales:
• Increase in satisfying sexual events over 4 wks:
0.8 to 1.0 compared to placebo (p<0.05)
• Mean increase in peak sexual desire score at 24 wks: not
significant 2 studies, 3rd study: increase over placebo 0.3
on 6 point scale (p<0.05)
• Overall response rate 8-13% compared to placebo
• Long term safety & efficacy unknown
• Medical Letter 9/28/2015
Sacubitril/valsartan (Entresto)
• New category of drug neprilysin inhibitor
• Neprilysin degrades natriuretic peptides
• Natriuretic peptides prevent progression of
ventricular dysfunction & remodeling in animals
• Neprilysin also degrades angiotensin, endothelin1, opioids, bradykinin, & amyloid-β peptide.
• JAMA 12/7/2015
Sacubitril/valsartan
Theoretical risks
• Neprilysin also degrades angiotensin, opioids,
endothelin- 1, bradykinin, & amyloid-β peptide
• Used with ARB due to degradation of angiotensin
• Amyloid-β peptide has protective effects on
Alzheimer's & macular degeneration
• Long term studies of neurocognitive effects due
in 2022. I think we can wait.
Sacubitril/valsartan
Clinical study
• 8399 pts randomized, CHF, EF 29%, NYHA
Class II or III, on diuretic and β blocker
• Comparison: enalapril 10 mg bid
• End points at 27 months: composite CV death
or admission for CHF; all cause mortality
• Single blind run-in for dose toleration. 20% of
subjects eliminated before randomization.
• NEJM 9/11/2014
Sacubitril/valsartan
Clinical study
• Terminated early, 27 vs 36 months
• CHF admission: 12.8% vs 15.6% control
Absolute risk reduction 2.8% NNT 36
• CV mortality: 16.5% vs 13.3% control
Absolute risk reduction 3.2% NNT 31
Sacubitril/valsartan
Clinical study- Problems
• Not comparable dose of enalapril – should be
20 mg bid
• Higher ARB dose could be reason for benefit
• 20% of both arms dropped out due to drug
intolerance (in addition to 20% eliminated at
run-in)
• Large single study, not replicated
• Long term toxicity unknown
Sacubitril/valsartan analysis
• NNT 36 patients for 27 months to prevent one
admission and one death. Assume $375/mo cost
• 36 pt x 27mo = 972 months x $375/mo = $364,500
– drug cost to prevent one hospitalization
• Medicare 2015 DRG payments for CHF
hospitalization $3,966 to $8,855
• Total drug cost is 41-92X more than cost of
hospitalization.
• Oregon State Drug Review Dec 2015; cost: Goodrx.com
2/16/2016
Sacubitril/valsartan
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Interesting concept
Not ready for general use
Need more/better studies
Standard therapy better studied, costs 100X
less
Rifaximin for hepatic encephalopathy
• Low quality evidence - adding rifaximin 550 mg bid to
lactulose is superior to lactulose alone at preventing HE
• Low quality evidence -adding rifaximin to lactulose in
hospitalized patients with HE is superior to lactulose alone
• Studies have not been conducted in the U.S. - off label use
• Insufficient evidence for the use of rifaximin without
lactulose for prevention or treatment
• Cases reports of Clostridium difficile infection - uncommon,
but incidence unknown.
• $1,800/month, lactulose $50/mo
• Oregon P & T 5/28/2105
Fidaxomicin (Dificid) for C diff
• Moderate evidence - oral vancomycin is superior to oral
metronidazole in mild and severe C difficile infection (CDI)
• Moderate evidence - oral vancomycin and oral fidaxomicin same
for first episode of CDI
• Insufficient evidence to compare metronidazole and fidaxomicin.
• Insufficient evidence to support fidaxomicin alone for complicated
or fulminant CDI
• First recurrence – repeat previous tx
• Moderate quality evidence fidaxomicin is superior to oral
vancomycin at preventing recurrences of CDI
• Insufficient evidence for the combination of 2 oral antibiotics
• Fidaxomicin $3,500 - $3,700 for 10 days
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Oregon P & T 5/28/2016
The BAD
Ivabradine (Corlanor) for CHF
• Slows heart rate by inhibiting cardiac pacemaker If current. No
effect on ventricular repolarization or myocardial contractility
• Does not reduce all‐cause or CV mortality compared to placebo
• Low quality evidence - ivabradine may reduce hospitalizations
for CHF by 4.7% compared to placebo (15.9% vs. 20.6%.)
• Majority of patients were in Eastern European countries with
higher rate of hospitalization for CHF than USA. Cannot
extrapolate results to US.
• Increases risk for atrial fibrillation. Do not use in patients with
atrial fibrillation, discontinue if a fib develops
• $380 - $400/month
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Oregon P & T July 2015
Eluxadoline (Viberzi) for irritable bowel
• Mu-opioid receptor, Schedule IV narcotic $960/mo
• 2 unpublished studies 26-52 weeks, vs placebo reported
12 week endpoints, 75 & 100 mg doses
• Primary endpoint: improvement in the daily worst
abdominal pain score by ≥30% as compared to the
baseline weekly average AND a reduction in the Bristol
Stool Score to <5 on at least 50% of the days in a 12-week
time interval. Improvement in daily worst abdominal pain
in the absence of a concurrent bowel movement was also
considered a response day.
Eluxadoline (Viberzi) for irritable bowel
• Even if you understand what that means, it did not
work very well. At 12 weeks:
• Study 1: 24-25% responded to drug, 17% pcbo
• Study 2: 29-30% responded to drug, 16% pcbo
• 26 wks, 75 mg worse than placebo, 100 mg similar
to placebo
• No improvement in abd pain vs pcbo at 12 wks
• Medical Letter 1/4/2016; Viberzi package insert
Eluxadoline (Viberzi) for irritable bowel
• High dose - euphoria in 14-28% of patients, 0-5%
on placebo
• Sphincter of Oddi spasm 1%, if no gallbladder 4%
• Risk of pancreatitis if >3 drinks/day
• This drug has it all: High cost, high toxicity,
addiction risk, low efficacy!!
SGLT2 Inhibitors risks
• Induce renal glycosuria – risks: dehydration, hypotension,
hyperkalemia, mycotic genital infections, renal failure,
especially in elderly
• New FDA warnings - case reports of:
– Ketoacidosis, some with normal blood glucose. Mechanismincreased fat metabolism
– Pyelonephritis & urosepsis. Mechanism - glucosuria
– Loss of bone density & increased fractures. Mechanism –
increased renal reabsorption of phosphate
• Incidence & long term risk unknown
• Oregon State Drug Review Feb 2016. Medical Letter 10/12/2015
SGLT2 Inhibitors ? CV benefit
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Single study 7020 pts with DM-2 & CV disease
590 sites, 42 countries
Empagliflozin 10 or 25 mg vs placebo, 2.6 yrs
Same incidence of MI & stroke
Reduced CV death 3.7% vs 5.9 % placebo
Reduced hospitalization for CHF 2.7% vs 4.1%
Mechanism unknown
Remain skeptical. NEJM 11/26/2015
The Worthless
Rifaximin for irritable bowel
• Non-absorbable antibiotic - 550mg tid 14 days vs
placebo, 12 week study
• Primary endpoint is squishy:
• Self reported relief of symptoms 2 of the first 4
weeks of tx. Would we use that for angina?
• 40.8% drug - 31.2% pcbo
• Difference between tx & pcbo decreased w time.
Gone at 12 weeks in 4/5 endpoints
• $1,176
• Medical Letter 8/3/2015; NEJM 1/6/2011
Calcium & Vitamin D
• Mythology outweighs good studies by wide
margin
• Insufficient evidence on comparative efficacy
among the different calcium formulations and
among the different vitamin D formulations
• (USPSTF) recommends against routine screening
of vitamin D levels in asymptomatic adults
• Calcium and vitamin D supplements lack evidence
to support routine use
• Insufficient evidence to make strong conclusions
• Many references, Email me if you want specifics
Calcium supplements
• Small reduction in total fractures in women –
12 to 11%, vertebral fractures 1.5 to 1.3%. No
benefit in hip or forearm fx
• Small increase in bone density 0.7 to 1.8% in
hip, spine, femoral neck & forearm
• Decreases risk of pre-eclampsia &
hypertension in pregnancy
Vitamin D Benefits
• May reduce incidence of falls in elderly
women
Vitamin D does not
• Reduce mortally in healthy patients regardless
of baseline serum level
• Benefit cystic fibrosis, chronic pain scores,
depression or blood pressure
• Prevent recurrent adenomas of colon
• Reduce mortality in colon or any other cancer
• Improve HgbA1C in diabetics
Vitamin D risks
• Increases risk of nephrolithiasis,
hypercalcemia, and gastrointestinal effects
PCSK9 Inhibitors
Alirocumab (Praluent) Evolocumab (Repatha)
• Proprotein Convertase Subtilisin Kexin type 9 Inhibitor!
• Human monoclonal antibodies inhibit PCSK9 enzyme,
reducing degradation of the LDL receptor, lowering LDL‐C\
• Alirocumab and evolocumab, FDA approved.
Bococizumab - in phase 3 testing.
• Lowers LDL-cholesterol by ≥ 40% unpublished studies
• No studies of morbidly or mortality
• Both are injectable, $13,000/year
• Oregon P & T Nov 2015; Medical Letter 8/17/2015, 10/12/2015
Meloxicam (Vivlodex)
Generic meloxicam 7.5 & 15 mg, #30, $4.00
Vivlodex (meloxicam) 5 & 10 mg, #30, $638.00
Scrabble Effect
Names with unusual consonants are expensive
Drugs.com; fda.gov
Sumatriptan Nasal (Onzetra Xsail)
• Imitrex brand, 5mg, #6 unit dose $450
• Generic, 5mg, #6 unit dose $150
New FDA approval Jan 2016
Onzetra Xsail nasal powder
No release date or price
Expect Scrabble Effect
Similar efficacy to existing products
• Centerwatch website; Headache Jan 2015
Durlaza, $6 Aspirin
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For secondary prevention of MI or stroke
162.5-mg timed release capsules
Once daily, prescription only
No trials of clinical efficacy for preventing CV dz
Approval based on bioequivalence to regular ASA
“No evidence that Durlaza, is as safe or as
effective as low-dose immediate-release aspirin.”
• The Medical Letter 1/18/2016
Fluad –Influenza Vaccine for Older Adults
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Vaccine to counteract lower immune response in elderly
Will be available for NEXT season 2016-17
Surrogate endpoint – antibody response
Immunogenicity non-inferior to standard vaccine
Greater antibody response did not meet superiority
criteria
• More frequent tenderness at injection site
• SUMMARY: works the same, but hurts more
• Why bother?
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FDA ADVISORY COMMITTEE BRIEFING DOCUMENT 9/15/2015; The Medical Letter
1/18/2016
Alzheimer’s drugs
• ACH inhibitors and memantine - modest improvements in
cognition, activities of daily living, & behavior
• None stop or reverse the disease or impact clinical
outcomes - mortality, disability, or institutionalization
• Combination memantine ER + donepezil (Namzaric) Mixed
evidence - small improvement in cognition and behavior.
Magnitude low, clinical significance is uncertain
• No improvement in function compared to monotherapy.
Generic formulations of both individual products are
available
• Aricept 23 mg increased risk of adverse drug events.
• Anticholinergics decrease effectiveness of ACH inhibitors
• Oregon P & T Sept 24, 2016
Alzheimer's drugs – cost/month
• Namenda XR #30 (memantine 28mg) $360 -390
• Namzaric #30 (memantine ER and donepezil)
caps, $360 - $390
• Aricept 23, #30 (donepezil) $130 -$150
• Donepezil 10 mg #30, $8-$12
• Memantine 10 mg #60, $30-$40
• Goodrx.com 2/24/2016
Drugs for weight loss
Strange selections & combinations
• Lorcaserin (Belviq®) selective serotonin 2c agonist
Psychiatric effects, headache, dizziness, and
nausea
• Phentermine/Topiramate (Qsymia®) Increased
heart rate, paresthesias, and anxiety
• Naltrexone/Bupropion (Contrave®) Not for
patients on Vicodin or other opioids
• Liraglutide (Saxenda®) glucagon-like peptide-1
agonist for DM-2 that never sold well- injection
• OSU Drug review Nov 2015, Medical Letter 6/22/2015
Drugs for weight loss- cost/benefit
Same story as previous drugs
Wt loss at 1 yr vs placebo: 3-8.5% Average ~ 5%
No long term studies of safety or efficacy
No studies on clinical outcomes (morbidity,
mortality, disease prevention)
$200 - $240/month - oral meds
$1,000/month Saxenda
($1,000 per # lost - 240# with 5% loss at 1 yr)
Pioglitazone & stroke prevention
• “Pill to prevent strokes also prevents diabetes, study
shows” The Oregonian 2/22/2016
• 3876 patients, non-diabetic, with insulin resistance,
recent new CVA or TIA.
• Ave age 63.5, 65% male, 85% white
• Exclude: CHF, liver dz, anemia, dependent edema
• Pioglitazone vs placebo, ave. followup 4.8 yrs
• Standard care for htn, other dz, & stroke prevention
(statins, ASA, etc)
• Primary endpoint: first fatal or non fatal stroke or MI
• NEJM: 2/22/2016
Pioglitazone & stroke prevention
Primary outcome: lower composite & individual
rates of stroke & MI
BUT: Secondary outcomes:
Same rate: acute coronary syndrome
Same rate: composite of stroke, MI, or CHF
hospitalization
Are you confused? You should be…
Pioglitazone & stroke prevention
Smoke & mirrors
Study included only the first event
Patients with multiple events - only the first one
counted.
IE patient had MI, later had stoke, the stroke was
not counted. Number w multiple events unknown.
Results depend on which order events occurred,
not on total incidence of stroke or MI
Pioglitazone & stroke prevention
Adverse events
• Fractures: 6.9% vs 4.9% w placebo
• Edema: 35.6% vs 24.9% w placebo
• Wt gain >4.5 kg 52.2% vs 33.7% w placebo
• Wt gain >13.6 kg 11.4% vs 4.5% w placebo
• Progression to diabetes 3.8% vs 7.7% w placebo
Pioglitazone & stroke prevention
• Previous similar pioglitazone study –
PROactive – showed no difference from
placebo
Lancet 2005; 366:1279-89
Remain Skeptical