‘Top’ 5½ Papers in General Internal Medicine

1. ‘Top’ 5½ Papers in General Internal Medicine Glen Drobot, MD, FRCPC, DTM&H Assistant professor, Section of General Internal Medicine gdrobot@sbgh.mb.ca

2. Conflict of Interest Disclosure • Industry-funded trial: • Co-investigator, apixaban in VTE Bristol-Myers Squibb& Pfizer

3. Objectives At the end of the presentation, the attendee will be able to: 1) Develop strategies to stay abreast of recent literature 2) List the highlights of five (and one-half) recent studies and their impact on general internal medicine practice 3) Bombard the presenter with questions about the minutiae of the studies

4. Methods In my clinical life, I try to keep abreast of the medical literature in the following ways: • Emailed Table of Contents of the major IM journals (also cardiology, tropical medicine, HIV) • Emails from ‘news’ websites (theheart.org, Physician’s First Watch, Medscape) • Participate in McMaster Online Rating of Evidence (MORE) • Subscribe to ACP Journal Wise

5. Methods • I find TOCs to be too frequent to possibly keep up with • I do like to scan Physicians First Watch most days areas outside of internal medicine • MORE gives me really obscure articles to review! • ACP Journal Wise is very helpfulto peruse what’s new • Specific topic: UpToDate or Medline

6. Antihypertensive Meds at Night • 58-year-old female with DM 2, hypertension, and creatinine 120 µmol/L (eGFR 36 ml/min) is the following medications gliclazide MR 60mg daily EC-ASA 81mg daily hydrochlorothiazide 25mg daily lisinopril 20mg daily Amlodipine 10mg daily • Home BP usually shows readings <130/75 but sometimes morning BP is higher • Is there anything else she should do?

7. Bedtime dosing of antihypertensive medications reduces CV risk in CKD • RCT, blinded (outcome assessors) • Patients with HTN and CKD (eGFR <60 mL/ min and/or microalbuminuria) 1 antihypertensive at bedtime VS all antihypertensives taken upon awakening 1° outcome: total CV morbidity and mortality 2° outcome: major CV events Hermida RC et al. J Am Soc Nephrol 2011; 22:2313-2321.

8. Bedtime dosing of antihypertensive medications reduces CV risk in CKD n=661, mean age 59, 60% men, follow-up 5.4 yrs Hermida RC et al. J Am Soc Nephrol 2011; 22:2313-2321.

9. Antihypertensive Meds at Night • 58-year-old female with DM 2, hypertension, and CKD • Is there anything else she should do?  advised to move amlodipine to bedtime

11. Antibiotics for Appendicitis • Your 21-year-old son has a 12-hour history of anorexia, and then RLQ pain. Physical exam: afebrile, rebound tenderness. U/S confirms appendicitis. “Mom, I’m really scared of having an operation, ‘cos Granny didn’t wake up after her hip surgery” (Dr. Battad hadn’t seen her pre-op…) • You and the surgeon are insisting on surgery! • Smart-aleck older sister in Med 2 performs a lit search on her iPad and asks “why not just give the cry-baby some antibiotics?”

12. Safety and efficacy of antibiotics compared with surgery for appendicitis • Meta-analysis, 4 RCTs met inclusion criteria n=900 patients IV and/or oral antibiotics VS appendicectomy 1° outcome: complications secondary analysis: exclude 1 trial with crossover 2° outcome: LOS, readmissions, clinical outcomes Varadhan KK, Neal KR, Lobo DN. BMJ 2012; 344:2313-2321.

13. Safety and efficacy of antibiotics compared with surgery for appendicitis n=900 (470 antibiotics, 430 appendicectomy), ‘mean’ age 33 63% of patient in antibiotic arm  no surgery at 1 year 65 (20%) of patients had appendicectomy after readmission, 9 had perforated appendicitis, 4 had gangrenous appendicitis Varadhan KK, Neal KR, Lobo DN. BMJ 2012; 344:2313-2321.

14. Antibiotics for Appendicitis • 21-year-old male with appendicitis • Is there really an option for antibiotic therapy?  Admitted for 3 days of ceftriaxone/ metronidazole and discharged on 7 days of amoxicillin/clavulanate

16. Perioperative Statins and CV Events • 76-year-old male with hypertension, former 40-pack-year smoking history, and claudication, is going for cross-bifemoral bypass. O/E BP 128/76, HR 64 (regular), and ↓↓ lower extremity pulses. LDL cholesterol 2.1 mmol/L Lisinopril/HCTZ 10/12.5mg daily EC-ASA 81mg daily • Is there anything else you would recommend? Cardiac testing? Beta blocker? Statin?

17. Effect of perioperative statins on Death, MI, AFib and Length of stay • Meta-analysis, patients undergoing cardiac, vascular or other surgery Statin VS Control (placebo or lower-dose statin) Outcome assessed: death, perioperative MI & atrial fibrillation, and length of stay Chopra V et al. Arch Surg 2012; 147(2):181-9.

18. Effect of perioperative statins on Death, MI, AFib and Length of stay n=2292 patients in 15 trials (1 high vs low dose) Chopra V et al. Arch Surg 2012; 147(2):181-9.

19. Perioperative Statins and CV Events • 76-year-old male with hypertension, former smoker going for cross-bifemoral bypass • Is there anything else you would recommend?  started 2 days pre-op and continued for 30 days post-op

21. Warfarin and new oral anticoagulants in atrial fibrillation • 77-year-old female with hypertension, former smoker, who had cross-bifemoral bypass, in atrial fibrillation for 6 months since operation O/E BP 136/70, HR 90 (irregular), and normal CV exam Lisinopril/HCTZ 10/12.5mg daily EC-ASA 81mg daily simvastatin 10mg daily “Oh dear. But I saw this ad for a blood thinner while watching ‘Dancing with the Stars.’ I think it’s made by Prada—can we get that in Canada?”

22. Efficacy and safety of new oral anticoagulants versus warfarin in AFib • Review of the 3 major trials comparing warfarin to dabigatran, rivaroxaban or apixaban new OAC VS warfarin ‘you mean rat poison’ 1° efficacy outcome: composite of stroke and systemic embolism 2° stroke, all-cause mortality, vascular mortality, MI 1° safety outcome: major bleeding, 2° hem stroke Miller CS et al. Am J Cardiol 2012; 110:453-60.

23. Efficacy and safety of new oral anticoagulants versus warfarin in AFib n=44,474 patients in 3 trials

24. Warfarin and new oral anticoagulants in atrial fibrillation • 77-year-old female with hypertension, recent cross-bifemoral bypass, and permanent AFib • What would recommend for anticoagulation? • Depends on patient preference, province, drug plan, ability to have INRs, risk of bleeding… ‘Even though I’d love that Prada, I guess taking another pill once a day isn’t that bad’

26. ASA for preventing the recurrence of VTE • 44-year-old female who has received 9 months of warfarin for acute PE, comes to your office asking about options at this point • She’s worried about the risk of bleeding, more worried about recurrence of a PE, but doesn’t like the hassle of getting blood tests • What are some of her options?

27. Aspirin for the prevention of recurrent of venous thromboembolism • RCT, blinded Aspirin 100mg daily VS Placebo 1° efficacy outcome: symptomatic, objectively verified recurrent of VTE 1° safety outcome: major bleeding 2° outcomes: DVT,PE, non-major bleeding, mortality Becattini C et al. N Engl J Med 2012; 366(21):1959-67. May 24

28. ASA for preventing the recurrence of venous thromboembolism n=403 patients, over 2 years

29. ASA for preventing the recurrence of VTE • 44-year-old female treated with warfarin for unprovoked PE • What are some of her options? • Risk stratify (clinically, D-dimer) • Continue warfarin at moderate or full intensity • Start EC-ASA 81mg daily • But wait… BREAKING NEWS

30. Low-dose aspirin for preventing recurrent venous thromboembolism • RCT, blinded, mostly Australia & New Zealand • Published in print November 22 (6 months later) Aspirin 100mg daily VS Placebo 1° efficacy outcome: symptomatic, objectively verified recurrent of VTE 2° outcomes: major vascular events 1° safety outcome: major or clinically relevant bleeding Brighton TA et al. N Engl J Med 2012; 367(21):1979-87.

31. Let’s talk cooperation! Protocols prospectively harmonized

32. Editorial in this issue of NEJM • Non-significant decrease in recurrent VTE 4.8% vs 6.5%/year, HR 0.74, p=0.09 • BUT significant decrease in major vascular events HR 0.66, p=0.01 • Pooling results for both trials (WARFASA, ASPIRE) Recurrence of VTE HR 0.68, p=0.007 Major vascular events HR 0.66, p=0.002 Warkentin TEN Engl J Med 2012; 367(21):2039-41.

33. Editorial in this issue of NEJM Warkentin TEN Engl J Med 2012; 367(21):2039-41.

34. ASA for preventing the recurrence of VTE • 44-year-old female treated with warfarin for unprovoked PE • What are some of her options? a continuum of treatment options Full dose moderate intensity aspirin OAC anticoagulation

35. Summary In patients with HTN and CKD, moving at least 1 anti-hypertensive medication to bedtime reduces CV events. Perioperative statin use is associated with significant reductions in MI and atrial fibrillation. Antibiotics are a reasonable, safe option in patients with uncomplicated appendicitis, preventing surgery in 2/3 patients. The newer oral anticoagulants are at least as efficacious and slightly safer than warfarin. Aspirin prevents about 1/3 of recurrences after first episode of unprovoked venous thromboembolism.

36. References Hermida RC et al. J Am Soc Nephrol 2011; 22:2313-2321. Varadhan KK, Neal KR, Lobo DN. BMJ 2012; 344:2313-2321. Chopra V et al. Arch Surg 2012; 147(2):181-9. Miller CS et al. Am J Cardiol 2012; 110:453-60. Becattini C et al. N Engl J Med 2012; 366(21):1959-67. Brighton TA et al. N Engl J Med 2012; 367(21):1979-87. Warkentin TEN Engl J Med 2012; 367(21):2039-41.

37. We have reached the end, er, summit