Other Pharmacotherapy Updates - Cleveland Clinic€¦ · Updates Joseph Saseen, Pharm.D., FCCP,...
Transcript of Other Pharmacotherapy Updates - Cleveland Clinic€¦ · Updates Joseph Saseen, Pharm.D., FCCP,...
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Other Pharmacotherapy
Updates
Joseph Saseen, Pharm.D., FCCP, BCPSProfessor
University of ColoradoAnschutz Medical Campus
School of Pharmacy and Medicine
Sir William OslerNew Drugs:New Drugs:
““Use them while they Use them while they are still safeare still safe””
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Timing of Black Box Warnings and Withdrawals for Prescription Medications
FDA approved drugs between 1975-1999
● 548 new chemical entities approved–81 (14.8%) major changes to drug labeling
–45 (8.2%) acquired 1 black-box warning(s)• Half within the first 7 years
–16 (2.9%) were withdrawn from the market• Half within the first 2 years
● 20% probability of withdrawal or new black-box warning over 25 years
JAMA 2002;287(17):2215-2220.
New Innovations and/or Information
with Gout
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Overview of Gout
● Gout is a broad term for a spectrum of several clinical conditions:–Gouty arthritis (acute and chronic)
–Interstitial kidney disease
–Uric acid nephrolithiasis
● Hyperuricemia: elevated serum uric acid–Often an asymptomatic condition
–Clinical manifestation is gout that may occur when the uric acid concentration is “super saturated” (generally > 7.5 mg/dL in serum)
Clinical Case…
● A 62-year-old man is diagnosed with acute gouty arthritis. His pain started 4 hours ago and is in his right great toe, which is red and very swollen. He has a past medical history of poorly controlled hypertension, and chronic kidney disease (serum creatinine is 2.0 mg/dL, and creatinine clearance is 20 mL/min).
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Polling Question…
● Which of the following treatments is most appropriate treatment to start today for his acute gouty arthritis?
Indomethacin 50 mg TID
Prednisone 60 mg daily
Colchicine 1.2 mg then 0.6 mg one
hour later
Acute Gouty Arthritis Pharmacotherapy
Colchicine● New colchicine product approved by FDA
(Colcrys) in 2009 has set standard for use:– Much lower doses than previously used
– Significantly less diarrhea, nausea, vomiting
● Use if within 48 hr. of symptom onset (best 24 hr.)– 1.2 mg initially, then 0.6 mg 1 hr. later
– If on dialysis, then dose is 0.6 mg once
– Wait a minimum of 3 days between courses of colchicine therapy for patients with CrCl 30 mL/min (if < 30 mL/min wait 2 weeks)
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Incentives for Drug Development:The Curious Case of Colchicine
● “In July 2009, the Food and Drug Administration (FDA) officially announced what physicians have long known — that the drug colchicine can effectively treat acute flares of gouty arthritis”
● “The implications of market exclusivity for the public health can be substantial. After the FDA approved Colcrys, the manufacturer brought a lawsuit seeking to remove any other versions of colchicine from the market and raised the price by a factor of more than 50, from $0.09 per pill to $4.85 per pill”
Kesselheim AS and Solomon DH. N Engl J Med 2010;362(22):2045-2047.
Acute Gouty Arthritis
Onset of symptoms < 48 hr?
Contraindication to NSAID?
Number of joints involved?
Use an NSAID
Inadequate response
Use Oral Colchicine
Yes No
YesNo
< 48 hr
Inadequate response
48 hr
Joint accessible to injection?
only 1 multiple
Contraindication to systemic corticosteroids?
Use Intraarticular Corticosteroid
Yes No
Use Analgesic and joint rest +/- Oral
Colchicine
Yes No
Use Parenteral or Oral Corticosteroid +/-
intraarticular corticosteroid
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Prophylactic Gout Pharmacotherapy
Indicated in:
● Patients with frequent attacks (≥2 attacks annually)
● Patients undergoing aggressive chemotherapy
● After the first episode only if one the following criteria are met:
● Severe attack– Uric acid > 10 mg/dL
– 24-hour urinary uric acid excretion > 1000 mg/day
– Presence of uric acid lithiasis
Not indicated:
● In patients with hyperuricemia but without gout
● In most patients following their first episode of gout
Xanthine Oxidase Inhibition
Richette P and Bardin T. Lancet 2010; 375: 318–28
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Febuxostat (Uloric)
● Xanthine oxidase inhibitor
● FDA approved in 2006
● Dosing:–40 mg once daily, increase to 80 mg daily if uric
acid is not lower than 6 mg/dL after 2 weeks
–No need to adjust dose based on kidney function; however, not recommended if CrCl is < 30 mL/min
● Transaminase elevations can occur; periodic LFT monitoring is needed
Xanthine Oxidase Inhibitors
AllopurinolPro’s
●Traditional drug of choice
●Can use in any degree of chronic kidney disease
Con’s
●Skin rashes
●Allopurinol Hypersensitivity Syndrome (rare)
●Requires renal dose adjustments
FebuxostatPro’s:
●Greater degree of uric acid lowering
Con’s
●Higher rate of thromboembolic events
●Cannot be used in severe chronic kidney disease
●Brand-name only
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Mobilization Gout
● Uric acid lowering drugs may precipitate acute gout when they are first started; this can be minimized by:1. Start antihyperuricemic drugs at low-doses,
titrating up slowly
2. Start antihyperuricemic drugs several weeks (6-8 wks) after an acute attack is resolved
3. Concurrent use of low-dose colchicine, or an NSAID for 3 months (may be used up to 6-12 months in severe cases)
New Innovations and/or Information
with Oral Contraceptives
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Contraceptive Effectiveness● Implants, Injections, Intrauterine
devices, SterilizationFewer
Pregnancies
More Pregnancies
Fewer than 1 pregnancy per 100 women in 1 yr
85 or more pregnancies per 100 women in 1 yr
10-20 pregnancies per 100 women in 1 yr
● Birth Control Pills● Skin Patch● Vaginal Ring with hormones
● Condoms● Diaphragm
● No sex during fertile days of the monthly cycle
● Spermicide● Withdrawal
● No birth control
FDA Drug Safety Communication: Updated information about the FDA-funded study on risk of blood clots in women taking birth control pills containing drospirenone
● Safety Announcement [10-27-2011]–The U.S. Food and Drug Administration (FDA)
is continuing its review of the potential increased risk of blood clots with the use of birth control pills containing drospirenone.
http://www.fda.gov/Drugs/DrugSafety/ucm277346.htm
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Approved Oral Contraceptives Containing Drospirenone
Names Generic nameOcella, Syeda, Yasmin, Zarah
Drospirenone 3 mg and ethinyl estradiol 0.03 mg
SafyralDrospirenone 3 mg,
ethinyl estradiol 0.03 mg, and levomefolate calcium 0.451 mg
BeyazDrospirenone 3 mg,
ethinyl estradiol 0.02 mg and levomefolate calcium 0.451 mg
Gianvi, Loryna, YazDrospirenone 3 mg and ethinyl estradiol 0.02 mg
Advantage of drospirenone: Low androgenic progestin
Polling Question…
● Do you avoid prescribing drospirenone containing oral contraceptives due to fear of blood clots?
Yes
No
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Six Studies
StudyOR (95% CI) for ThromboembolismDrospirenone vs. Levonorgestrel
Contraception 2007;75:344-54
1.0 (0.6-1.8)European prospective cohort study
Obstet Gynecol 2007;110:587-93
0.9 (0.5-1.6)US health insurance database
BMJ 2009;339:b28901.6 (1.3-2.1)
Danish national registry cohort study
BMJ 2009;339:b29211.7 (0.7-3.9)
Netherlands case-control study
BMJ 2011;340:d21393.2 (1.5-7.0)
UK general practice research database
BMJ 2011;340:d21512.3 (1.6-3.2)
US claims data (PharMetrics)
Ongoing FDA-funded study Preliminary findings: 1.5-fold ↑ risk
Study Design
● Case-control study nested in population of current users of OCs containing drospirenone (case) or levonorgestrel (control)
● Base population–Women age 15-44 years with at least one
prescription for study drug from January 2002 through December 2008
–Excluded women with risk factors for VTE• History of cancer• Renal failure• Chronic cardiovascular disease• Inflammatory or autoimmune conditions
BMJ 2011;340:d2151
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Results: Overall Study486 potential cases
285 non-idiopathic cases
186 cases of non-fatal VTE 681 controls without VTE
n = 121 (65%) Drospirenone
n = 65 (35%) Levonorgestrel
n = 313 (46%) Drospirenone
n = 368 (54%) Levonorgestrel
ExposureCrude OR (95% CI)
Adjusted OR (95% CI)
Levonorgestrel 1.0 1.0
Drospirenone 2.3 (1.6-3.2) 2.4 (1.7-3.4)
BMJ 2011;340:d2151
Results: Age Category
Exposure Patient Years
Incidence rate (95% CI) per 100,000 person
years
Incidence Rate Ratio(95% CI)
Drospirenone/ethinyl estradiol• Age <30 (n=63) 253,895 24.8 (19.1 to 31.7) 4.6 (2.6 to 8.2)
• Age 30-39 (n=42) 107,701 39.0 (28.1 to 52.7) 2.1 (1.3 to 3.3)
• Age 40-44 (n=16) 31,248 51.2 (29.3 to 83.2) 2.4 (1.2 to 4.8)
Levonorgestrel/ethinyl estradiol 20 mcg or 30 mcg• Age <30 (n=14) 259,522 5.39 (2.94 to 9.05) 1.0
• Age 30-39 (n=35) 187,017 18.7 (13.0 to 26.0) 1.0
• Age 40-44 (n=16) 75,284 21.3 (12.1 to 34.5) 1.0
BMJ 2011;340:d2151
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Results: Levonorgestrel Dose
ExposureCrude OR (95% CI)
Adjusted OR (95% CI)
Levonorgestrel 20 mcg
• Levonorgestrel-20 1.0 1.0
• Drospirenone 2.7 (1.6-3.2) 2.4 (1.7-3.4)
Levonorgestrel 30 mcg
• Levonorgestrel-30 1.0 1.0
• Drospirenone 2.1 (1.4-3.1) 2.2 (1.5-3.4)
BMJ 2011;340:d2151
Results: Overall VTE Incidence
● 392,844 woman years – drospirenone–Incidence rate 30.8/100,000 woman years
• Age 15-29 years: 24.8/100,000• Age 30-39 years: 39/100,000• Age 40-44 years: 51.2/100,000
● 521,824 woman years – levonorgestrel–Incidence rate 12.5/100,000 woman years
• Age 15-29 years: 5.39/100,000• Age 30-39 years: 18.7/100,000• Age 40-44 years: 21.3/100,000
BMJ 2011;340:d2151
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Putting This Into Perspective…
PopulationIncidence of VTE
(per 100,000 woman yrs.)Relative
Risk
Young women – general 4-5 1
Pregnant women 48-60…up to 123 25
OC with ≥50 mcg EE 24-60 12
OC with <50 mcg EE 12-20 4
Levonorgestrel-containing OC 27.1 5
Norgestimate-containing OC 30.6 6
Desogestrel-containing OC 53.5 10
Levonorgestrel-containing OC 12.5 3
Drospirenone-containing OC 30.8 6
Speroff L, Fritz M. Clinical Endocrinology and Infertility, 7th ed. Contraception 2006;73(6):566-70.
ABSOLUTE RISK
Pregnancy: 0.12% OC with levo: 0.01% OC with dros: 0.03%
New Innovations and/or Information
with Oral Anticoagulants
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Reflective Question…
When do you use an oral anticoagulant in patients with
atrial fibrillation
CHADS2 Risk Stratification Scheme
Risk Factors Score
C Recent congestive heart failure 1
H Hypertension 1
A Age 75 years 1
D Diabetes mellitus 1
S2 History of stroke or transient ischemic attack (TIA) 2
J Am Coll Cardiol. 2004;43:929-935.
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J Am Coll Cardiol. 2006;48:854-906.
CHADS2 Risk Criteria for Stroke in Nonvalvular AF
Warfarin
Stroke Risk in Patients With Nonvalvular AF Not Treated With Anticoagulation According to the CHADS2 Index
5
65
220
337
523
463
120
Patients (N = 1733) (95% CI)
66
55
44
33
22
11
00
CHADS2 Score
Adjusted Stroke Rate (%/year)
Polling Question…
● Which of the following do you find to be the most problematic issue when treating patients with chronic warfarin therapy?
Drug interactions
Risk of INR fluctuations
Need for frequent monitoring
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Ann Intern Med 1999;131:927.
Warfarin for Atrial FibrillationLimitations lead to under treatment
VIIa
Xa
IXaXIa
XIIa
New Oral AnticoagulantsTissue factor
II
FibrinFibrinogen
IIa(thrombin)
Dabigatran
RivaroxabanApixaban
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Dabigatran (Pradaxa)Direct thrombin inhibitor
● Indication: To reduce the risk of stroke and systemic embolism non-valvular atrial fibrillation
● Dose: CrCl >30 mL/min: 150 mg twice dailyCrCl 15-30 mL/min: 75 mg twice daily
● Most common adverse reactions (>15%) are gastritis-like symptoms and bleeding
Pradaxa Package Insert. Boehringer Ingelheim Pharmaceuticals, Inc; November 2011
Rivaroxaban (Xarelto)Factor Xa inhibitor
● Indications: 1) to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation
2) prophylaxis of DVT (or PE) in knee or hip replacement surgery
● A.fib Dose: CrCl >50 mL/min: 20 mg daily*CrCl 15-50 mL/min: 15 mg daily*
● DVT ppx Dose: 10 mg daily with or without food
● Box Warning – risk of spinal/epidural hematoma*with evening meal
Xarelto Package Insert. Jannsen Pharmaceuticals, Inc.; November 2011
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New Anticoagulants: Pharmacokinetics
Property Rivaroxaban ApixabanDabigatran
etexilateTarget Factor Xa Factor Xa Thrombin
Tmax (hr) 2.5-4 3 2
Half-life (hr) 9-13 8-15 14-17
Monitoring Not needed Not needed Not needed
Dosing Daily Twice Daily Once or Twice Daily
Bioavailability (%) 60-80% 50-85% 5-6%
Renal Excretion 33% 25% 80%
Drug Interactions Potent CYP3A4 Inhibitors
Potent CYP3A4 Inhibitors
Proton Pump Inhibitors; P-gp
inhibitors
New Anticoagulants in Atrial Fibrillation
DabigatranRE-LY
●18,113 patients randomized to adjusted-dose warfarin (open-label) or fixed dose dabigatran 110 mg or 150 mg BID (blinded)
●Mean CHADS2 score 2.1
RivaroxabanROCKET-AF
●14, 171 patients randomized, double-blind, to rivaroxaban or adjusted dose warfarin
●Rivaroxaban dose adjusted to CrCl
●Mean CHADS2 score 2.1
N Engl J Med 2009;361:1139-51.N Engl J Med 2011; 365:883-891.
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RE-LY: Primary Endpoint
N Engl J Med 2009;361:1139-51.
RE-LY: Results
N Engl J Med 2009;361:1139-51.*< 0.001 both non-inferior
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RE-LY: Results
N Engl J Med 2009;361:1139-51.
ROCKET-AF: ResultsPrimary End Point - stroke or systemic embolism
Rivaroxaban Warfarin
Hazard Ratio
(95% CI)
Primary Endpoint -on treatment
1.70 2.150.79
(0.65-0.95)
Primary Endpoint –intention to treat
2.12 2.420.88
(0.74-1.03)
Hemorrhagic stroke 0.26 0.440.59
(0.37-0.93)
Ischemic stroke 1.34 1.420.94
(0.75-1.17)
Event rate per 100 patient-years
N Engl J Med 2011; 365:883-891.
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Rivaroxaban:DVT prevention Studies
● RECORD 1: Oral rivaroxaban compared with subcutaneous enoxaparin for extended thromboprophylaxis after total hip arthroplasty
● RECORD 2: Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis with low molecular weight heparin after total hip arthroplasty
● RECORD 3: Rivaroxaban – an oral, direct Factor Xa inhibitor – for the prevention of venous thromboembolism in total knee arthroplasty surgery
N Engl J Med 2008; 358:2765-2775.Lancet 2008;372:31-39.
N Engl J Med 2008; 358:2776-2786.
Rivaroxaban in Hip SurgeryRECORD 1 (n=4541) RECORD 2 (n=2509)
N Engl J Med 2008; 358:2765-2775.Lancet 2008;372:31-39.
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Rivaroxaban in Knee SurgeryRECORD 3 (n=2531)
N Engl J Med 2008; 358:2776-2786.
Currently Unapproved Uses:New Oral Anticoagulants
● Acute treatment of DVT or PE
● Prevention in patients with recurrent VTE
● Use in patients with hyper coagulation disorders
● Use in patients with severe chronic kidney disease
● Use in children or pregnancy
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New Innovations and/or Information
In Pulmonary Disease
National Asthma Education and Prevention Program Expert Panel 3 (http://www.nhlbi.nih.gov/guidelines/asthma/)
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Leukotriene Antagonists as First-Line or Add-on Asthma-Controller Therapy● Study program with two overall studies:
–First-line controller therapy trial:• Asthma patients with symptoms deemed by their
physician to require initiation of controller therapy
• 306 patients randomized, open-label, to either leukotriene receptor antagonist (LTRA) or inhaled corticosteroid (ICS) for 2 yrs
–Add-on trial• Asthma patients with symptoms requiring increase
in therapy despite ≥12 weeks of ICS therapy
• 352 patients randomized, open-label, to either an LTRA or long acting beta-agonist (LABA) for 2 yrs
N Engl J Med 2011;364:1695-707
Primary Endpoint: ResultsFirst-line Controller Therapy Study
N Engl J Med 2011;364:1695-707
Failed to meet statistical
definition of equivalence
Met statistical
definition of equivalence
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Other ResultsFirst-line Controller Therapy Study
N Engl J Med 2011;364:1695-707
LTRA ICS P-valueMean # of
Exacerbation0.44 0.35 0.23
Median Adherence 65% 41% 0.11
Change in drug treatment at 2
years31% 21%
Not calculated
Primary Endpoint: ResultsAdd-On Therapy Study
N Engl J Med 2011;364:1695-707
Failed to meet statistical
definition of equivalence
Met statistical
definition of equivalence
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Other ResultsAdd-On Therapy Study
N Engl J Med 2011;364:1695-707
LTRA LABA P-valueMean # of
Exacerbation0.62 0.61 0.9
Median Adherence with ICS
74% 46% 0.007
Median Adherence with Add-on Drug
76% 64% 0.26
Change in drug treatment at 2 years
25% 0Not
calculated
Indacaterol (Arcapta)Long Acting Beta-Agonist Inhalation Powder
● Indication: Maintenance bronchodilator treatment of COPD, including chronic bronchitis and/or emphysemaNot indicated for asthma
● Dose: 75 mcg capsule inhaled daily using the NEOHALER device
● Clinical Data: Better than placebo
● Side effects: Typical of inhaled LABA therapy
● Box Warning: Asthma-related death (class warning)
Arcapta Package Insert. Novartis Pharmaceuticals Corp; July 2011
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GOLD 2011 UpdateStable COPD: Pharmacologic Therapy
Patient Group
First Choice
Second Choice
Alternative Choice
A • SA Anticholinergic prn• SABA prn
• LA Anticholinergic• LABA• SABA + SA Anticholinergic
• Theophylline
B • LA Anticholinergic• LABA
• LA Anticholinergic + LABA• SABA +/- SA
Anticholinergic • Theophylline
C • ICS + LABA• LA Anticholinergic
• LA Anticholinergic + LABA
• Phosphodiesterase 4 inhibitor
• SABA +/- SA Anticholinergic
• Theophylline
D • ICS + LABA• LA Anticholinergic
• ICS + LA Anticholinergic• ICS + LA Anticholinergic + LABA• ICS + LABA + Phosphodiesterase 4
inhibitor• LA Anticholinergic + LABA• LABA + Phosphodiesterase 4
inhibitor
• Carbocysteine• SABA +/- SA
Anticholinergic • Theophylline
http://www.goldcopd.org/
Tiotropium versus Salmeterol for the Prevention of Exacerbations of COPD
● 7376 patients with moderate-to-very-severe COPD
● Randomized, double-blind to tiotropium 18 mcg daily or salmeterol 50 mcg twice daily
N Engl J Med 2011;364:1093-1103
P<0.001
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Azithromycin for Prevention of Exacerbations of COPD
● 1142 patients with chronic COPD
● High risk for recurrent exacerbations (using oxygen, systemic corticosteroids in past year, ED or COPD hospitalization)
● Randomized to azithromycin 250 mg daily or placebo for 1 yr
N Engl J Med 2001;365:689-98
P<0.001
Rofumilast (Daliresp)Selective inhibitor of phosphodiesterase 4
● Indication: To reduce COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations
● Dose: 500 mcg daily
● Clinical Data: Absolute reductions in annual exacerbations was 0.2 to 0.3
● Side effects: Diarrhea, weight decrease, nausea, headache, insomnia, dizziness
● Warning: Does not cause broncodilation
Daliresp Package Insert. Forest Laboratories, Inc.; September 2011
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New Innovations and/or Information
with Low-Dose Aspirin
Summary of Primary Prevention Trials
Ann Intern Med. 2009;150:405-410
BMD PHS TPT HOT PPP WHSYear 1988 1989 1998 1998 2001 2005
PatientsMen
(Physicians)Men
(Physicians)Men with high
CV risk
Men & Women with hypertension
Men & Women with >1 CV risk
factor
Women (Health
Professionals)
N 5,139 22,071 5,085 18,790 4,495 39,876
Age (yrs)<60 (47%)
60-69 (39%)
70-79 (14%)
Mean 53 (range 40-84)
Mean 57.5 (range 45-69)
Mean 61.5 (range 50-80) <60 (29%)
60-69 (45%)
70-79 (24%)
Mean 54.6
45-54 (60%)
55-64 (30%)
≥ 65 (10%)
Duration (yrs)
5.8 5 6.8 3.8 3.6 10.1
Aspirin dose
500 mg/day325 mg every
other day75 mg/day 75 mg/day 100 mg/day
100 mg every other day
Placebo Control
No Yes Yes Yes No Yes
Blinding Open-label Double-blind Double-blind Double-blind Open-label Double-blind
Quality Fair Good Good Good Fair Good
BMD, British Male Doctors’ trial; HOT, Hypertension Optimal Treatment trial; PHS, Physicians’ Health Study; PPP, Primary Prevention Project; TPT, Thrombosis Prevention Trial; WHS, Women’s Health Study.
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Aspirin in Primary PreventionAntithrombotic Trialists’ (ATT) Collaboration Meta-Analysis
Lancet. 2009;373:1849–60.
RR: 0.82 (0.75-0.90)
RR: 0.86 (0.74-1.00)
RR: 0.97 (0.87-1.09)
RR: 1.32 (1.00-1.75)
Aspirin in Primary PreventionAntithrombotic Trialists’ (ATT) Collaboration Meta-Analysis
Major Coronary Event
Ischemic Stroke
P<0.05
P<0.05
Lancet. 2009;373:1849–60.
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USPSTF Recommendations 2009
Men Age <45 yrs Women Age <55 yrsDo not encourage aspirin use
(Grade D)
Men Age 45‒79 yrs Women Age 55‒79 yrsEncourage aspirin use when CV
benefit (MI) outweighs harmEncourage aspirin use when CV benefit (stroke) outweighs harm
Men Age 80 yrs Women Age 80 yrsNo Recommendation
(Grade I)
www.preventiveservices.ahrq.gov
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USPSTF Recommendations 2009: Risk level at which CVD events prevented
(benefit) exceeds GI harms
Men
10-yr CHD Risk
Age 45‒59 yrs 4%
Age 60‒69 yrs 9%
Age 70‒79 yrs 12%
Women
10-yr Stroke Risk
Age 55‒59 yrs 3%
Age 60‒69 yrs 8%
Age 70‒79 yrs 11%
www.preventiveservices.ahrq.gov
Evidence Evaluating Aspirin in Primary Prevention in Diabetes
● In the 6 major trials evaluating aspirin for primary prevention (e.g., PHS, HOT, WHS) only 4,281 of 90,971 (5%) had diabetes
● Trials evaluating only patients with diabetes:–Early Treatment of Diabetic Retinopathy Study
(ETDRS)
–Prevention Of Progression of Arterial Disease And Diabetes (POPADAD)
–Japanese Prevention of Atherosclerosis with aspirin for Diabetes (JPAD)
J Am Coll Cardiol. 2010;55:2878-86.
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Evidence Evaluating Aspirin in Primary Prevention in Diabetes
ETDRS JPAD POPADADYear 1992 2008 2008
N 3,711 2,539 1,276
Duration (yrs) 5.0 4.4 6.7
Aspirin dose 650 mg 81-100 mg 100 mg
CHD EndpointFatal +
nonfatal MI
Fatal +
nonfatal MICHD death + nonfatal MI
Results (control vs. aspirin):
•Endpoint Event Rate (%) 15.3 vs. 13.0 1.1 vs. 1.0 12.9 vs. 13.9
•RR (95% CI)0.85
(0.73‒1.00)
0.87
(0.40‒1.87)
1.09
(0.82‒1.44)
J Am Coll Cardiol. 2010;55:2878-86.
Aspirin for Primary Prevention of CV Events in People With Diabetes
ADA/AHA/ACCF Scientific Statement
Recommendation #1:
● Low-dose aspirin is reasonable for adults at increased CVD risk (10-year risk > 10%) who are not at increased risk for bleeding
● Those at increased CVD risk include most men > 50 years and women > 60 years who have ≥ 1 additional major risk factors:–Smoking, hypertension, dyslipidemia, family
history of premature CVD, and albuminuria
AHA Level of Evidence: BJ Am Coll Cardiol. 2010;55:2878-86.
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Aspirin for Primary Prevention of CV Events in People With Diabetes
ADA/AHA/ACCF Scientific Statement
Recommendation #2:
● Aspirin should not be recommended for adults at low CVD risk (men <50 years and women <60 years with no major additional CVD risk factors; 10-year risk < 5%) as the potential adverse effects from bleeding offset the potential benefits
AHA Level of Evidence: C
J Am Coll Cardiol. 2010;55:2878-86.
Aspirin for Primary Prevention of CV Events in People With Diabetes
ADA/AHA/ACCF Scientific Statement
Recommendation #3:
● Low-dose (75 ‒ 162 mg/day) aspirin might be considered for those at intermediate CVD risk (younger patients with ≥1 risk factors, older patients with no risk factors, or patients with 10-year risk of 5-10%) until further research is available
AHA Level of Evidence: E
J Am Coll Cardiol. 2010;55:2878-86.
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http://abcnews.go.com/WNT/video/osteoporosis-drug-blamed-leg-breaks-10046260
Osteoporosis Drug Blamed for Leg Breaks
Commonly prescribed drugs meant to strengthen bones may
have the opposite effect03/08/2010
Atypical Fractures with Bisphosphonates
● Low trauma subtrochanteric or femoral shaft fracture
● Prodromal pain in thigh or groin
● Likely due to over/prolonged suppression of bone turnover and accumulated micro-damage
● Risk increased with use >5 years
● Absolute risk 5 cases per 10,000 patient-years
● For every 100 hip fractures prevented 1 atypical fracture occurs
N Engl J Med 2011;364:1728-37. JAMA. 2011;305(8):783-789
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Bisphosphonate Drug Holiday Recommendations
J Clin Endocrinol Metab, April 2010, 95(4):1555–1565
Patient’s Fracture Risk
Suggested Duration of Treatment Suggested Duration of Drug Holiday
Low(e.g., prevention)
Not needed n/a
Mildly Increased(e.g., younger, T-score just
below -2.5 with no additional risk factors,
osteopenia with risk factors)
Treat 3-5 years
Stop until BMD decreases significantly or fracture occurs
Moderately Increased(older, T-score below -2.5,
no fracture, some risk factors)
Treat 5-10 years
Stop for 2-3 years or until BMD decreases significantly or fracture occurs
High(older, very low BMD, multiple risk factors or
fractures)
Treat 10 years
Stop for 1-2 years or until BMD decreases significantly or fracture occurs; Possibly use alternate medication during holiday (i.e., teriparatide, raloxifene)
New Warnings or Indications
● Fracture risk and BMD reduction associated with PPIs
● Dronedarone increases CV death in high CV risk patients with permanent a.fib
● Daily vitamin D or calcium supplementation does not affect mortality, vascular disease, cancer mortality, or cancer incidence
● Abnormal heart rhythms associated with high doses of citalopram
● Once daily tadalafil (Cialis) 5mg daily for BPH
Pharmacotherapy 2012;32(1):67–79. N Engl J Med 2011;365:2268-76. Ann Intern Med. 2011;155:820-826.JCEM jc.2011-1309; doi:10.1210/jc.2011-1309. http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm
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Other New Drugs
● Spinosad (Natorba): Topical pediculocide
● Ticagrelor (Brilinta): Oral antiplatelet post ACS
● Azilsartan (Edarbi): Potent ARB, superiority versusolmesartan
● Fidaxomicin (Dificid): C. diff-associated diarrhea
New Fixed-Dose Combination Products
● Azilsartan/Chlorthalidone (Edarbyclor)
● Sitagliptin/simvastatin (Juvisync)
● Ibuprofen/famotidine (Duexis)
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Conclusions