Other Pharmacotherapy Updates - Cleveland Clinic€¦ · Updates Joseph Saseen, Pharm.D., FCCP, BCPS Professor University of Colorado ... lawsuit seeking to remove any other versions

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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–16 (2.9%) were withdrawn from the market• Half within the first 2 years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)


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%


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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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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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


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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


Met statistical


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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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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)


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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)


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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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




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


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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

38

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)

39

Conclusions

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