PHARMACOTHERAPY UPDATE

BENJAMIN GROSS, PHARM D, BCPS, BCACP,CDE,BC-ADMUNIVERSITY OF TENNESSEE COLLEGE OF PHARMACY

DEPARTMENT OF CLINICAL PHARMACYCLINICAL PHARMACY DIRECTOR HOLSTON MEDICAL GROUP

Understand recent updates in drug therapy management

Review new medications that have recently come to market

Understand recent dosing changes and contraindications of common medication therapies

Discuss recent reported medication adverse reactions

OBJECTIVES

DISCLOSURE Advisory Board for

Sanofi Aventis

OFFICE◦ 423-578-1537◦ 105 WEST STONE DRIVE◦ KINGSPORT, TN 37660

EMAIL◦ BGROSS@UTHSC.EDU◦ GROSS.BEN@GMAIL.COM

CONTACT

HYPERLIPIDEMIA

HMG-CoA Reductase Inhibitors (STATINS)

↓LDL (18-63%) ↑HDL (5-15%) ↓TG (7-30%) Adverse effects

◦ Myopathy Myalgia Rhabdomyolysis

◦ Rash, headache◦ GI complaints◦ Vivid Dreams

DOSE LIMITIATION◦ FDA ISSUES SAFETY COMMUNICATION

80 MG DOSE INCREASED RISK OF MUSCLE DAMAGE ONLY USED IN THOSE WHO HAVE BEEN TAKING THE

MEDICATION 12 MONTHS OR LONGER WITHOUT EVIDENCE OF MUSCLE INJURY

DO NOT USE IN NEW PATIENTS

SIMVASTATIN

Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine (SEARCH) trial◦ 80mg vs 20 mg

With or without Vitamin B12 (1 mg) and folate (2mg) daily

Survivors of myocardial infarctions: 12, 064 patients Mean duration: 6.7 years Incidence of major vascular events

25.75% in the 20 mg group 24.5% in the 80 mg group

Am Heart J. 2007 Nov;154(5):815-23

SIMVASTATIN

SEARCH: Effects of more vs less STATIN on MORTALITY

Simvastatin allocation Risk ratio & 95% CICause of death 20mg80mg 80mg better 20mg better

(n=6033)(n=6031)

CHD 447 (7.4%) 438 (7.3%)

Stroke 57 (0.9%) 67 (1.1%)Other vascular 53 (0.9%) 56 (0.9%)

All vascular 557 (9.2%) 561 (9.3%) 0.7% SE 5.9reduction

Neoplastic 245 (4.1%) 266 (4.4%)Respiratory 74 (1.2%) 58 (1.0%)Other medical 75 (1.2%) 70 (1.2%)Non-medical 13 (0.2%) 14 (0.2%)

All non-vascular 407 (6.7%) 408 (6.8%) 0.2% SE 7.0reduction

All causes 964(16.0%) 969(16.1%) 0.5% SE 4.6reduction

0.6 0.8 1.0 1.2 1.4

Myopathy◦ 55 patients (0.9%) in the 80 mg group◦ 1 patient (0.02%) in the 20 mg group

Rhabdomyolysis◦ 22 patients (0.4%) in the 80 mg group◦ 0 patients in the 20 mg group

◦ Highest in the first 12 months of treatment

SIMVASTATIN

Increased risk◦ Older and female sex◦ Calcium channel blockers

Diltiazem

Analysis of FDA’s Adverse Event Reporting System (AERS) database and this trial was the basis of their safety communication

SIMVASTATIN

Previous Simvastatin Label New Simvastatin Label

Avoid Simvastatin with: Avoid Simvastatin with:

Itraconazole Itraconazole

Ketoconazole Ketoconazole

Erythromycin Erythromycin

Clarithromycin Clarithromycin

Telithromycin Telithromycin

HIV Protease Inhibitors HIV Protease Inhibitors

Nefazodone Nefazodone

Gemfibrozil

Cyclosporine

Danazol

AVOID USE

Previous Simvastatin Label New Simvastatin Label

Do not exceed 10 mg Do not exceed 10 mg

Gemfibrozil Amiodarone

Cyclosporine Verapamil

Danazol Diltiazem

Do not exceed 20 mg Do not exceed 20 mg

Amiodarone Amlodipine

Verapamil Ranolazine

Do not exceed 40 mg

Diltiazem

DOSE LIMITIATIONS

LOVASTATIN

Previous Lovastatin Label New Lovastatin Label

Avoid Lovastatin with: Contraindicated with Lovastatin :

Itraconazole Itraconazole

Ketoconazole Ketoconazole

Erythromycin Erythromycin

Clarithromycin Clarithromycin

Telithromycin Telithromycin

HIV Protease Inhibitors HIV Protease Inhibitors

Nefazodone Nefazodone

Posaconazole

Boceprevir

Telaprevir

Avoid Lovastatin with:

Cyclosporine

Gemfibrozil

Previous Lovastatin Label New LovastatinLabel

Do not exceed 20 mg Do not exceed 20 mg

Gemfibrozil Danazol

Cyclosporine Verapamil

Danazol Diltiazem

Niacin (>1g/day)

Other fibrates

Do not exceed 40 mg Do not exceed 40 mg

Amiodarone Amiodarone

Verapamil

Avoid Large Quantities of grapefruit juice (>1 quart daily)

Avoid Large Quantities of grapefruit juice (>1 quart daily)

Dosing Range

30-40% Reduction

FLUVASTATIN LESCOL 20-80 80

LOVASTATIN MEVACOR 20-40 40

PRAVASTATIN PRAVACHOL 20-80 40

SIMVASTATIN ZOCOR 20-80 20

ATORVASTATIN LIPITOR 10-80 10

ROSUVASTATIN CRESTOR 5-40 5

PITAVASTATIN LIVALO 1-4 2

STATINS

Ator Fluva Pita Lova Prava

Rosu Vytorin

Simva

%LDL Red.

40 1 20 20 10 30

10 80 2 40 or 80

40 20 38

20 4 80 80 5 10/10 40 41

40 10 10/20 80 47

80 20 10/40 55

40 10/80 63

RELATIVE EFFICACY

PITAVASTATIN (LIVALO) NEWEST STATIN DOSAGE: 2-4 MG LDL: 38-45% REDUCTION GFR: 30 to <60

mL/min/1.73m2, or hemodialysis◦ Initial dose: 1 mg◦ Max dose 2 mg initial daily

dose is 1 mg, max daily dose is

2 mg. Do not use if GFR <30

mL/min/1.73m2

Very few drug interactions◦ Avoid with cyclosporine◦ 1 mg with erythromycin◦ 2 mg with rifampin

Meta-analysis◦ Five studies◦ 40,000 patients◦ No evidence that the use of a statin increased risk

of developing type 2 diabetes Tendency toward reducing the risk with pravastatin Small, significant increased risk with other statins

Coleman et al. Curr Med Res Opin 2008: 1359-62

STATINS AND INCREASE RISK OF DIABETES

Jupiter Trial◦ 18, 000 patients: healthy, normal LDL levels◦ Rosuvastatin 20 mg for two years◦ Reduced primary end point of heart attack, stroke,

arterial revascularization or CV death was reduced◦ For every 167 patients treated one more case of

diabetes Six more cases per 1000 patients Were physician reported Protocol-specified fasting blood glucose did not differ

Ridker et al. NEJM 2008: 2195-2207.

STATINS AND INCREASE RISK OF DIABETES

Meta-analysis◦ Six studies◦ 60,000 patients◦ Statins not found to increase risk ◦ One of the studies excluded (WOSCOPS)

Small increase risk of diabetes

Rajpathak et al. Diabetes Care 2009: 735-42.

STATINS AND INCREASE RISK OF DIABETES

Meta-analysis◦ Five studies◦ 32,752 patients◦ Moderate dose versus intensive dose◦ High dose significantly more developed diabetes

2 additional cases for every 1000 patient-years 6.5 fewer cases of cardiovascular events

Priess et al. JAMA 2011: 2556-64.

STATINS AND INCREASE RISK OF DIABETES

2010 Lancet meta-analysis, which found a small but measurable risk for new-onset diabetes after all statin use.

Predictors of New-Onset Diabetes in Patients Treated with Atorvastatin◦ Analysis of three large randomized control trials

TNT Randomized to atorvastatin 80 mg vs. 10 mg 9.24% vs. 8.11%, p=0.226

IDEAL Randomized to atorvastatin 80 mg vs. 20 mg simvastatin 6.4% vs. 5.59%, p=0.072

SPARCL Randomized to atorvastatin 80 mg vs. placebo 8.71% vs. 6.06%, p=0.011

◦ Major cardiovascular events 11.3% with new-onset diabetes vs. 10.8% without new-onset diabetes,

(p=0.69)

JAAC 2011; 57:1535-1545

STATINS AND INCREASE RISK OF DIABETES

Routine periodic monitoring of liver enzymes no longer necessary◦ Before starting therapy and as clinically indicated◦ FDA has concluded that serious liver injury with

statins is rare and unpredictable and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury.

NEW STATIN LABELING

Information about the potential for generally non-serious and reversible cognitive side effects (memory loss, confusion, etc.) Memory loss and confusion have been reported with

statin use. These reported events were generally not serious and went away once the drug was no longer being taken.

NEW STATIN LABELING

Crestor causing heart attacks◦ Commercial from law firm◦ Where does this come from?

Based on crestor causing rhabdomyolysis and thus weakening heart muscles

Public Citizen, independent watchdog group claims that crestor causes rhabdomyolysis 22 times more than its lowest dose competitor and 3 times more than its highest dose competitor

www.citizen.org/hrg1729

FDA findings Risk of serious muscle damage is similar with Crestor

compared to other statins

CRESTOR

Literature review The safety of rosuvastatin in comparison with other

statins in over 100,000 statin users in UK primary care 10, 289 patients on rosuvastatin

No cases of myopathy, rhabdomyolysis or acute liver injury

Use of multiple international healthcare databases for the detection of rare drug-associated outcomes: a pharmacoepidemiological programme comparing rosuvastatin with other marketed statins Associated with no significant difference in the incidence

of hospitalized myopathy, rhabdomyolysis, or acute renal failure

CRESTOR

Journal of the American College of Cardiology◦ Expert review panel

The dose of the statin is a greater predictor of myopathy, etc and not the potency of the statin

CRESTOR

More emphasis on diet and exercise Less emphasis on meds for most people For fasting triglyceride levels of 150 to

199 mg/dL, focus on diet and exercise first. For fasting triglyceride levels of 200 to 499

mg/dL, diet and exercise should still be considered first. However, this is the point at which non-HDL cholesterol levels should be considered as a secondary target to LDL cholesterol

Circulation May 24, 2011 123(20): 2292-2333

Triglyceride and Cardiovascular Disease: A Scientific Statement From the American Heart Association

For high non-HDL cholesterol, consider a statin or a dose increase for patients already taking a statin. Adding omega-3 fatty acids to the statin is also an option.◦ There is some evidence that a statin plus niacin can

reduce surrogate markers of cardiovascular disease, such as carotid artery intima-media thickness.

◦ If LDL cholesterol is controlled and non-HDL cholesterol is still high, a drug therapy for lowering triglycerides such as niacin, fibrates, etc. can be considered.

Circulation May 24, 2011 123(20): 2292-2333

Triglyceride and Cardiovascular Disease: A Scientific Statement From the American Heart Association

AIM-HIGH Study◦ Niacin (1500-2000 mg) and 40 mg Simvastatin

Primary outcome was time to first CHD death, nonfatal MI, ischemic stroke, acute coronary syndrome hospitalization, or symptoms requiring coronary or cerebral revascularization

3500 patients Stopped early due to lack of benefit of

Niacin/Simvastatin vs simvastatin alone Most patients had well-controlled LDL on a statin at

baseline LDL vs HDL

Am Heart J 2011; 161:471-77

NIASPAN

JUVISYNC◦ JANUVIA AND SIMVASTATIN

100/10, 100/20, 100/40 Same price as Januvia Same cautions, contraindications, adverse effects as

each component alone

NEW DRUG THERAPY

ANTIDEPRESSANTS

Celexa (citalopram) Should no longer be used at doses greater

than 40 mg/day Prolongation of the QT interval No benefit in doses higher than 40 mg/day

ANTIDEPRESSANTS

Increased risk◦ CHF◦ Bradyarrhythmias◦ Predisposition to hypokalemia or hypomagnesemia

Max dose: 20 mg◦ Hepatic impairment◦ >60 years old◦ CYP2C19 poor metabolizers◦ CYP2C19 inhibitors

Omeprazole, Cimetidine Not to exceed 20 mg escitalopram (Lexapro) Sertraline, paroxetine, and fluoxetine lower risk and

alternative agents

ANTIDEPRESSANTS

CYP2C19 INHIBITORS chloramphenicol

cimetidine citalopram delavirdine efavirenz esomeprazole ethinyl estradiol etravirine felbamate fluconazole fluoxetine fluvoxamine indomethacin isoniazid kavaketoconazolelansoprazole

letrozole moclobemide modafinil nicardipine omeprazoleoxcarbazepine pantoprazole rabeprazole telmisartan ticlopidine topiramate vilazodonevoricon

Switching between SSRIs◦ Usually overlap in their mechanism of action, and

the new SSRI will usually prevent discontinuation symptoms that may occur when the first SSRI is stopped.

◦ Substituting a new SSRI at the relatively equivalent dose of the former SSRI is typically well-tolerated

SWITCHING ANTIDEPRESSANTS

AGENT DOSE

Fluoxetine 20 mg

Paroxetine 40 mg

Sertraline 50-75 mg

Citalopram 20 mg

Escitalopram 10 mg

Fluvoxamine 100 mg

Venlafaxine 75 mg

DOSE EQUIVALENTS

Switching from SSRI to TCA◦ Cross-taper◦ Fluoxetine and Paroxetine

Strong inhibitors of the p450 enzyme 2D6 Sertraline, citalopram, and escitalopram are milder inhibitors Enzyme involved in metabolism of many TCAs Inhibition increase levels and increased risk of toxicity

◦ TCAs should be started at low doses when cross-tapering with an SSRI, particularly with fluoxetine and paroxetine

Inhibition of p450 2D6 will be present to some degree until the SSRI is completely cleared◦ Most in 5 days; fluoxetine up to 5 weeks

SWITCHING ANTIDEPRESSANTS

SSRI to venlafaxine or duloxetine ◦ Both have strong serotonergic properties ◦ Switching immediately from most SSRIs to the

equivalent dose Well tolerated If higher dose of an SSRI, consider cross-taper Caution when switching from fluoxetine or

paroxetine, because venlafaxine and duloxetine are metabolized by p450 2D6 Start at lower dose

SWITCHING ANTIDEPRESSANTS

Venlafaxine or duloxetine to antidepressants ◦  Venlafaxine is associated with uncomfortable

discontinuation symptoms upon cessation. ◦ Recommend cross taper as well as duloxetine

Cross-taper also when switching to or from Mirtazapine (Remeron)

SWITCHING ANTIDEPRESSANTS

Bupropion to or from antidepressants◦ Does not have significant serotonergic properties◦ Switching from an SSRI, a TCA, venlafaxine, duloxetine,

mirtazapine to bupropion Cross-tapering off the former medication over a one to two

week period Two to three weeks for venlafaxine and duloxetine

Bupropion itself is not frequently associated with discontinuation symptoms◦ Tapered off over one week while initiating new

antidepressant◦ Avoid prescribing high-dose bupropion concomitantly with

paroxetine, fluoxetine, or fluvoxamine due to metabolism of Bupropion

SWITCHING ANTIDEPRESSANTS

DIABETES

Avandia – CV events including MI TZD’s - ↑ fractures Byetta and Januvia – pancreatitis Byetta- kidney problems Lantus-cancer?

DM med related adverse drug event issues

Epidemiological study conducted in France◦ French National Health Insurance Plan data◦ 1.5 million patients with diabetes◦ Followed for 4 years◦ Statically significant increase risk of bladder

cancer in patients Increased risk with cumulative dose >28,000 mg and

exposure for longer than one year Increased risk in males

PIOGLITAZONE (ACTOS)

FDA reviewed data from an 5-year interim analysis of an ongoing 10-year epidemiological study◦ Kaiser Permanente Northern California health

plan data◦ 193,099 patients◦ New diagnosis of bladder cancer

No overall increased risk Noted increased risk

Longest exposure (greater than 1 year) Highest cumulative dose

PIOGLITAZONE

Not to use pioglitazone in patients with active bladder cancer

Use with caution in patients with a prior history of bladder cancer

FYI: Bladder cancer is estimated to occur in 20 per 100,000 persons per year in the U.S.◦ Higher in diabetics????

PIOGLITAZONE

BROMOCRIPTINE (Cycloset)◦ Dopamine agonist

Parlodel: Parkinson’s disease, acromegaly, hyperprolactinemia

◦ FDA-approved for Type 2 diabetics Mechanism unclear

May reverse metabolic changes associated with insulin resistance and obesity

Improve blood glucose control Without increasing insulin levels

A1C reduction: 0.1-0.6% (average of 0.4-0.5%)

NEW DRUG THERAPY

Starting dose 0.8 mg once daily◦ Increased 0.8 mg/day each week ◦ Max dose 4.8 mg/day◦ First thing in the morning within 2 hours of rising

Circadian rhythm If dosed missed, take it the next day

◦ Taken with food Nausea Also cause somnolence, hypotension, and syncope Aggravate psychotic disorders

◦ No increase risk of CV events◦ Drug-drug interactions◦ $$$$; will be generic within 5 years

NEW DRUG THERAPY

Tradjenta (Linagliptin)◦ DPP-IV inhibitor◦ Dosing

5 mg once daily No adjustment for renal or hepatic insufficiency

◦ Efficacy 0.5-0.8%

◦ Adverse effect Nasopharyngitis Pancreatitis has been reported

◦ No contraindications◦ Drug interaction: P-glycoprotein/ CYP3A4 inducer

Example: Rifampin

NEW DRUG THERAPY

Bydureon◦ Once a week exenatide◦ 2 mg daily◦ With or without meals◦ Administered immediately after the powder is

suspended Qnexa

◦ phentermine and topiramate◦ Once daily

NEW DRUG THERAPY

New Devices

RESPIRATORY

Levaquin went generic in June 2011

◦FDA approved application for 12 companies to manufacture generic versions of levofloxacin

◦ Infectious Disease Society of America/American Thoracic Society Consensus Guideline on the Management of Community Acquired Pneumonia

COMMUNITY ACQUIRED PNEUMONIA

No recent antibiotic therapy within the previous 3 months and no risk for drug resistant S. Pneumoniae

Macrolide or doxycycline

Comorbidities:COPD, diabetes, chronic heart, liver, lung or renal disease, malignancy, alcoholism, asplenia, immunosuppressing conditions or use of immunosuppressive drugs or use of antimicrobials within last three months

Respiratory fluoroquinolones or B-lactams plus a macrolide

In regions with a 25% or higher rate of infection with high level (MIC ≥16 µg/ml) macrolide resistant S. Pneumoniae (regardless of comorbidities)

Respiratory Fluoroquinolones or B-lactams plus a macrolide

COMMUNITY ACQUIRED PNEUMONIA

Recommendation 1: ACP, ACCP, ATS, and ERS recommend that spirometry should be obtained to diagnose airflow obstruction in patients with respiratory symptoms (Grade: strong recommendation, moderate-quality evidence). Spirometry should not be used to screen for airflow obstruction in individuals without respiratory symptoms (Grade: strong recommendation, moderate-quality evidence).

Recommendation 2: For stable COPD patients with respiratory symptoms and FEV1 between 60% and 80% predicted, ACP, ACCP, ATS, and ERS suggest that treatment with inhaled bronchodilators may be used (Grade: weak recommendation, low-quality evidence).

Recommendation 3: For stable COPD patients with respiratory symptoms and FEV1 <60% predicted, ACP, ACCP, ATS, and ERS recommend treatment with inhaled bronchodilators (Grade: strong recommendation, moderate-quality evidence).

COPD GUIDELINES

Recommendation 4: ACP, ACCP, ATS, and ERS recommend that clinicians prescribe monotherapy using either long-acting inhaled anticholinergics or long-acting inhaled β-agonists for symptomatic patients with COPD and FEV1 <60% predicted. (Grade: strong recommendation, moderate-quality evidence). Clinicians should base the choice of specific monotherapy on patient preference, cost, and adverse effect profile.

Recommendation 5: ACP, ACCP, ATS, and ERS suggest that clinicians may administer combination inhaled therapies (long-acting inhaled anticholinergics, long-acting inhaled β-agonists, or inhaled corticosteroids) for symptomatic patients with stable COPD and FEV1<60% predicted (Grade: weak recommendation, moderate-quality evidence).

COPD GUIDELINES

Recommendation 6: ACP, ACCP, ATS, and ERS recommend that clinicians should prescribe pulmonary rehabilitation for symptomatic patients with an FEV1 <50% predicted (Grade: strong recommendation, moderate-quality evidence). Clinicians may consider pulmonary rehabilitation for symptomatic or exercise-limited patients with an FEV1 >50% predicted. (Grade: weak recommendation, moderate-quality evidence).

Recommendation 7: ACP, ACCP, ATS, and ERS recommend that clinicians should prescribe continuous oxygen therapy in patients with COPD who have severe resting hypoxemia (Pao2 ≤55 mm Hg or Spo2 ≤88%) (Grade: strong recommendation, moderate-quality evidence).

COPD GUIDELINES

Chronic Azithromycin to prevent recurrent COPD exacerbations◦ 250 mg/day to standard COPD therapy reduces

the risk of acute exacerbations◦ 1 less exacerbation for every 3 COPD patients on

oxygen or with prior exacerbations that take azithromycin for one year

◦ Anti-inflammatory and immunomodulatory effects

◦ Place in therapy Severe COPD and frequent hospitalizations for acute

exacerbations

AZITHROMYCIN

Phosphodiesterase 4 (PDE 4) inhibitor Place in therapy

◦ Add-on therapy to maximized bronchodilators to decrease risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.

◦ Experts: More symptomatic and severe to very severe disease with frequent exacerbations showed greatest improvement

Dosage◦ 500 mcg daily

May require several weeks to reach effect◦ Not recommended in those with moderate to severe renal

impairment◦ Not studied in those with hepatic impairment

Contraindicated in severe hepatic impairment (Child-Pugh Class B or C)

Roflumilast (Daliresp)

Adverse effects◦ Diarrhea (9.5%)◦ Back pain Abdominal pain◦ Weight decrease (7.5%)◦ Influenza◦ Nausea (4.7%)◦ Dizziness◦ Headache (4.4%)◦ Decreased appetite◦ Some reports

Anxiety, depression and sleep disorders Rare: suicidal ideation and completed suicides

Roflumilast (Daliresp)

Drug interactions◦ Not recommended with strong inducers:

(decreased effectiveness) Rifampin, carbamazepine, phenytoin,

phenobarbital◦ Caution use with: (increased systemic exposure

and increase adverse effects) Erythromycin, ketoconazole, fluvoxamine,

cimetidine Pregnancy Category C; not to be used

during breastfeeding

Roflumilast (Daliresp)

Overall Evidence◦ 9349 patients studied in 8 RCT trials

Two trials showed rate of moderate or severe exacerbations reduced by 15-18%

Number of patient exacerbations per patient-year was 1.1 vs. 1.3 (placebo) and 1.2 vs. 1.5 (placebo); Absolute reduction was 0.2 and 0.3 exacerbations per patient year.

FYI◦ Originally the FDA advisory committee voted against approving

the medication in 2010 Only moderately improved FEV1 over baseline, concern about

d/c due to GI effects and psychiatric events Cancer events

218 patients 60% in roflumilast vs. 40% placebo

Roflumilast (Daliresp)

Long acting Beta-2 adrenergic agonists Indication

Treatment for COPD Inhalation powder hard capsule: 75 mg Inhaled once daily

Contraindications Asthma without use of a long term asthma control

medications Adverse effects

Cough, oropharyngeal nasopharyngitis, headache, nausea

Arcapta Neohaler: Indacaterol

MISCELLANEOUS DRUG INFORMATION

Angiotensin Receptor Blockers and Cancer

Vitamins Associated With Increased Risk Of Death In Older Women

Caffeine, Coffee, and Depression

Vitamin E Associated with Increased Prostate Cancer Risk

Aspirin reduces risk of cancer and prevent tumors from spreading

IN THE NEWS

Chantix and Cardiovascular events◦ Risk of serious adverse cardiovascular events

associated with varenicline: a systematic review and meta-analysis Results

Increase risk of serious adverse cardiovascular events compared to placebo

Absolute risk 1.06%(52/4908) vs 0.82% (27/3308) placebo

ODDs ratio 1.72 72% increase risk of any ischemic or arrhythmic adverse

cardiovascular event

Singh, et al. CMAJ July 2011

CHANTIX (VARENICLINE)

PALLAS Study◦ 65 year old with permanent A fib◦ Outcome : Major CV risk and death◦ Results

2 fold increase in death 2 fold increase in stroke and hospitalization for

heart failure◦ FDA advisory

Do not use in permanent A fib patients◦ Package insert has been changed 3 times recently

Concerns about safety Can increase INR

Dronedarone (Multaq)

QUESTIONS