Disclosure. Overview. Objectives. Five Noteworthy Outpatient Publications. Factors Affecting Antibiotic Prescribing 7/24/2013

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1 47 th Annual Meeting August 2-4, 2013 Orlando, FL Five Noteworthy Outpatient Publications R. Vandervoort, Pharm.D. Disclosure I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation 2 Objectives Upon completion of this activity, the participant should be able to: Summarize and critique current literature and its application to current practice Identify current topics and breakthroughs in internal medicine Discuss recent guidelines and their impact on patient care Overview Amoxicillin for acute lower respiratory tract infection in primary care when pneumonia is not suspected: a 12 country, randomised, placebo controlled trial Oral Rivaroxaban for Symptomatic Venous Thromboembolism and for PE n 3 Fatty Acids in Patients with Multiple Cardiovascular Risk Factors Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs Invasive and Standard Blood Pressure Targets in Patients with Type 2 Diabetes Mellitus Lancet Infect Dis 2013;13:123 9 NEJM 2010;363: & NEJM 2012;366: NEJM 2013;368: BMJ 2012;345:e4388 Arch Intern Med 2012;172(17): Antibiotics for Lower Respiratory Tract Infection Factors Affecting Antibiotic Prescribing Patients with recent onset cough (less than 3 weeks) as their main symptom without suspicion of pneumonia are broadly diagnosed with acute bronchitis Whether to prescribe antibiotics for patients such as this has long been controversial This paper deals with patients who do not have complicating factors such as coexisting COPD or features consistent with influenza Lancet Infect Dis 2013;13:

2 Introduction Randomized, Placebo controlled trial of 2061 patients in 12 European countries Patients were adults with acute cough (<28 days) diagnosed with acute lower respiratory infection and who did not carry a clinical diagnosis of pneumonia Because many clinicians err on the side of treating older patients, post hoc analysis included stratification by age Patients were given either amoxicillin 1 gram TID or placebo Primary outcome was duration of symptoms rated moderately bad or worse 7 Age: 49 Women: 59% Baseline characteristics (all similar between groups) Illness duration: 9.4 days Sputum production: 80% Discolored sputum: 50% 8 Results Primary Outcome No differences statistically significant Median time to resolution for Amoxicillin group was 6 days and for placebo was 7 days No trend suggestive of additional benefit in older patients Mean Symptom Severity Score (0 6) on days 2 4 Worsening of Illness (%) Amox Placebo P NNT Total Age> Age < Lancet Infect Dis 2013;13: Lancet Infect Dis 2013;13: Adverse Effects The authors report that in aggregate: nausea, rash, or diarrhea was reported in 28.7% of amoxicillin patients vs 24% of placebo patients (NNT 21, p=0.025) Two placebo and one amoxicillin patient were admitted for respiratory or CV issues One amoxicillin patient had anaphylaxis This is by far the largest study of its kind to date The authors caution against extrapolating the results to generally unwell elderly patients as these weren t well represented For most otherwise healthy patients, the study demonstrates little if any benefit from amoxicillin and an incidence of AE that may outweigh this benefit These results support current recommendations against routine AB use

3 Resources The CDC mpaign materials/infosheets/adult acute coughillness.html Part of their Get Smart Campaign deals with this topic and free materials are provided, including small posters for physicians offices Resources Smith SM, Fahey T, Smucny J, Becker LA. Antibiotics for acute bronchitis. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD DOI: / CD pub2 There is limited evidence to support the use of antibiotics in acute bronchitis. Antibiotics may have a modest beneficial effect in some patients with acute bronchitis though data on subsets of patients who may benefit more from treatment is lacking. However, the magnitude of this benefit needs to be considered in the broader context of potential side effects, medicalisation for a self limiting condition, increased resistance to respiratory pathogens and cost of antibiotic treatment Resources Chronic Cough Due to Acute Bronchitis. ACCP Evidence Based Clinical Practice Guidelines CHEST 2006 DOI: /chest Guidelines for the Management of adult lower respiratory tract infections full version Clin Microbiol Infect 2011;17(suppl 6):E Rivaroxaban for Treatment of DVT and PE Rivaroxaban is a Factor Xa inhibitor previously approved for a fib and DVT prophylaxis in orthopedic surgery The EINSTEIN Studies compared Rivaroxaban (15mg BID x 3 weeks, then 20mg daily) with standard therapy (LMWH and VKA) in patients with VTE It is now the first of the new oral anticoagulants to compete with warfarin for the long term management of VTE NEJM 2010;363: & NEJM 2012;366: Introduction Potential Causes/Risks for VTE (%) Einstein DVT 3449 patients Proximal DVT w/o PE Treated for 3,6,or 12mo Primary Outcome Recurrent VTE Einstein PE 4382 patients Acute PE Treated for 3,6,or 12mo Primary Outcome Recurrent VTE DVT Study PE Study Rivaroxaban Placebo Rivaroxaban Placebo Unprovoked Surgery or Trauma Immobilization Estrogen Cancer Known Thrombophilia Previous VTE NEJM 2010;363: & NEJM 2012;366:

4 Results DVT Study (%) Results PE Study (%) Primary Outcome HR: 0.68 (p=0.08) Major Bleeding HR: 0.65 (p=0.21) Net Clinical Benefit HR: 0.67 (p=0.03) AE incidence 62.7 vs 63.1, serious AE 12.0 vs 13.6 Primary Outcome HR: 1.12 (p=0.57) Major Bleeding HR: 0.49 (p=0.003) Net Clinical Benefit HR: 0.85 (p=0.28) AE incidence 80.5 vs 79.1, serious AE 19.7 vs 19.5 NEJM 2010;363: NEJM 2012;366: It would be nice to see a TTR analysis of this data While the studies didn t agree completely regarding their findings, it appears that rivaroxaban is similarly efficacious to standard therapy Regarding bleeding, both studies showed at least a trend toward less bleeding with rivaroxaban The current CHEST guidelines were prepared in October 2011 and published in They state: we give a weak recommendation in favor of VKA and LMWH therapy over dabigatran and rivaroxaban They do state also that this is based largely on the paucity of data available and the lack of post marketing safety data Omega 3 Fatty Acids for Primary Prevention of CV Events The American College of Cardiology recommends 1gram of omega 3 fatty acids daily for secondary prevention of CV events (IIB) Whether there may be benefit in primary prevention patients is uncertain This topic is not to be confused with higher doses of omega 3 s for lowering of triglycerides NEJM 2013;368: Introduction NEJM 2013;368: Double blind, randomized, placebo controlled trial in 12,505 patients from 860 general practitioners offices in Italy Patients were deemed high risk for CV events but could not have had a previous MI (see next slide) Assigned to 1gm n 3 fatty acids daily or placebo, consisting of at least 85% DHA and EPA Followed for median of 5 years 24 4

5 Risk Status Assessment Diabetes plus 1 CV Risk Factor 47.9% of patients History of Atherosclerotic Disease 29.5% of patients Four Risk Factors other than DM 20.8% of patients Endpoint Intrigue Originally the primary endpoint was supposed to be a composite of death, nonfatal MI, and nonfatal stroke An events assessment at 1 year showed fewer events than expected, warranting a reappraisal of the study s power Pursuant to this the endpoint was changed to include hospitalization for CV causes Patient Characteristics Results Primary Endpoint Both groups also had similar consumption of fish Triglycerides dropped by 8.1mg/dL in the treatment group compared with placebo Omega Placebo 3 Age Male 62.3% 60.6% B Blocker ACE/ARB Statin Antiplatelet Age < Age > Male 1.04 Female 0.82 CV Disease 1.02 No CV Disease 0.94 Total 0.98 NEJM 2013;368: Results Other Endpoints CV Death 1.03 Death or CV event 1.03 CV Hospitalization 0.98 HF Admission 0.65 NEJM 2013;368: The unexpected findings regarding HF and in women are consistent with other trials (one showing benefit of n 3 FA in heart failure patients and another showing CV event benefit in mostly women) but no known explanation exists for either finding, and the study was not prospectively designed to assess those elements This trial is very large. Certainly in men there appears to be no warrant for this type of supplementation at this time 30 5

6 2008: RCT suggests interaction with omeprazole on platelet activity Clopidogrel and PPIs 2009: In vitro Data suggests Pantoprazole not implicated. Observational outcomes data suggests class effect Principle and Triton Studies show kinetic interaction but no effect on outcomes Clopidogrel and PPIs 2011: FDA changed Plavix PI: no omeprazole or esomeprazole 2009: Observational studies show increased events in pts given omeprazole 2010:. FDA PI cautions re:omeprazole by name : COGENT* halted early: RCT showing no effect on outcomes N Engl J Med 2010;363: Introduction Analysis Specifics Two different analyses of a large database in the United Kingdom in which 24,427 patients were taking Plavix and aspirin and of those had exposure to a proton pump inhibitor Hospital records showing MI and death were examined to detect an association with PPI use Median follow up time was 303 days Cohort Study Patients enter cohort when prescribed clopidogrel and ASA Followed until event of interest or dc of plavix or ASA Follow up time classified based on whether pt was on PPI or not Self Controlled Case Series Patients who have MI or death are cases Controls are the same patients during times they weren t on PPIs Can detect an association that may otherwise be obscured by a nonrandomized study type BMJ 2012;345:e Primary Outcome Results Cohort Analysis BMJ 2012;345:e4388 Any PPI Omep, Esomep,Lansop Crude Adjusted Crude Adjusted 1.41 ( ) Mortality 1.44 ( ) MI 1.38 ( ) Nonvascular death 1.64 ( ) 1.37 ( ) 1.40 ( ) 1.30 ( ) 1.61 ( ) 1.43 ( ) 1.45 ( ) 1.37 ( ) 1.72 ( ) 1.39 ( ( ) 1.29 ( ) 1.71 ( ) Results Self Controlled Case Series For MI HR for association with any PPI exposure was 0.75 (0.55 to 1.01) relative to periods of no exposure For strong 2C19 PPIs, the HR was 0.77 (0.57 to 1.03) For ranitidine the HR was 0.57 (0.31to 1.06) BMJ 2012;345:e4388 Note: ranitidine HR: 1.20, 1.25,

7 Authors The authors believe the association observed in the cohort analysis is unlikely to be causative : 1. The within person design provided opposing results 2. Other drugs that shouldn t interact showed similar findings 3. Non vascular mortality was also higher with PPI use (unlikely due to this interaction) Authors 4. PPI users in the cohort study tended to be older and had more comorbidities; PPI use may be a surrogate for vulnerability (statistical adjustments cant account for severity of disease) 5. The authors believe that any interaction that exists between PPIs and clopidogrel does not result in clinical harm and is clinically unimportant Blood Pressure Targets in Diabetes Patients Antihypertensive Treatment Can Reduce Cardiovascular Events in Diabetic Patients Hypertension Optimal Treatment Study JNC VII establishes a goal of 130/80 for diabetic patients JAMA. 2003;289(19): In the text there is no rationale given, but the 2003 ADA guideline is cited The 2003 ADA guideline has a single paragraph addressing the issue in which they state that epidemiologically higher BPs (above 120) predict CV events. They also cite the HOT study as evidence for the lower diastolic goal. Diabetes Care 2003;26:S80 2 Target DBP Achieved SBP Achieved DBP Hansson L, et al. Lancet. 1998;351: Patients with Diabetes CV Events Per 1000 Patient-Years P = NNT=80 per year 39 Intensive and Standard Blood Pressure Targets in Patients with Type 2 Diabetes Mellitus Systematic Review and Meta Analysis Parallel RCTs Type 2 DM Prespecified BP targets Mortality, MI or stroke Analysis Details The authors compared standard with intensive targets across all five studies Four of the five studies used only diastolic targets. ACCORD was the only one to test different systolic targets Arch Intern Med 2012;172(17):

8 Relative Risk Impact for Intensive vs Standard BP Targets The ACCORD BP Trial N Engl J Med 2010; 362: Death MI Stroke ABCD H ABCD N HOT 80/ HOT 80/ ACCORD Combined Arch Intern Med 2012;172(17): ACCORD BP Results N Engl J Med 2010; 362: type 2 Diabetic patients Randomized to SBP goals of either <120 or <140 Achieved BP was 119/64 mmhg vs 133/70 mmhg Followed for mean of 4.7 years Primary outcome was stroke, MI or CV death Primary event rates were 1.87% and 2.09% HR=0.88, p=0.2 Stroke was reduced by 0.21%/year HR0.59, p=0.01, NNT 476/yr Serious AE 3.3% vs 1.7% P<0.001 For diastolic BP, a goal of 80mmHg seems reasonable compared to a goal of 90, though the evidence is less compelling than we may have assumed The NNT is likely around 80 for preventing stroke and it appears probable that other outcomes are prevented as well, to a smaller degree For systolic BP lower goals are tougher to sell as only one study has assessed this prospectively and it showed only a small absolute benefit on stroke and no hint of benefit on other outcomes 46 Where Does the ADA Stand Now? Diabetes Care 2013;36(suppl 1):s11 66 The goal for BP in diabetic patients is 140/80 Lower goals may be appropriate for some patients Long life expectancy High stroke risk not meant to downplay the importance of treating hypertension in patients with diabetes or to imply that lower targets are generally inappropriate 8