Found: 30% of 25% eligible predicted by chart review; randomized: 28% of goal! Page 1

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1 Is there evidence to mandate heparin prophylaxis in medical inpatients? Part 2 (Part 1: ACP/ASIM, Rochester MN, 10/30/09) Frank A. Lederle, MD Professor of Medicine VA, MN Recap of Part I. The problem as it looked 15 years ago Lederle FA, Ann Intern Med 1998;128: Low dose heparin prophylaxis mortality in surgical patients, & probably acute MI (? not via VTE) Despite several guidelines, effectiveness uncertain for hospitalized general medical patients t Heparin prophylaxis asymptomatic DVT (+ screening test) in medical patients, but: ~10 times more common than clinically evident VTE surrogate outcome whose value has been questioned must be balanced against risk of bleeding What Prompt ed Us One pseudo-randomized Israeli study: heparin prophylaxis all-cause mortality in gen med pts. 2 days after adm: 39 v 19 deaths (45% of total #) (Halkin, Ann Intern Med 1982) Six later true RCTs, one (Gårdlund ) with > 11,000 patients, t found no significant ifi mortality reduction Interest in this topic vastly increased after the advent of profitable LMW heparin Big issue: 13 million non-surgical patients discharged each year from U.S. acute care hospitals PROMPT The Prophylaxis of Medical Patients for Thromboembolism (PROMPT) Study (VA Cooperative Study #438). LOI submitted ,000 patient RCT designed to determine whether low dose heparin given throughout hospitalization reduces 90-day mortality in general medical patients (w/o AMI or CVA). Chart review indicated 25% of pts over age 60 admitted to VA medicine would be eligible We reported the results of a 1-year pilot study to assess feasibility of the full study De Facto Results Found: 30% of 25% eligible predicted by chart review; randomized: 28% of goal! 7.6% eligible Page 1

2 Meta-analysis of all-cause mortality, presented as a public service Le morte d PROMPT Fatal PE in the largest study 1) Dentali took events to 21 days from Gårdlund s figure to be during anticoagulant prophylaxis. 2) Prophylaxis was given for up to 21 days, y, but the mean was 8.2 days. 3) Fatal PE was Gårdlund s 1 outcome, & they reported 15 v 16, not 3 v 12. 4) Dentali et al never mention their alteration of the original data. Mostly based on asx DVT, but now they can add: Both NS, but sound different! Page 2

3 Tim Wilt finds a way to respond! Begin Part 2: End of Part 1 Data Extraction RCTs with clinical outcomes Excluded trials if pseudo-randomized also used another AC or thrombolytic heparin studies of acute MI (old & irrelevant) Included data to 120 (90) days after randomization Excluded surrogate outcomes (asympt. DVT) Included all events after randomization (intent-to- treat), even if excluded by original authors Excluded DVT & PE not confirmed by testing >36,000 patients >2800 deaths Page 3

4 [For illustration. Not our data] Major Bleeding Fatal, required surgery, in critical location or caused permanent injury, or overt + >2u blood Stroke studies: hemorrhagic transformation = bleeding; if symptomatic ti = major bleeding apples = oranges Page 4

5 Summary In all non-surgical patients combined (18 studies involving 36,122 patients), heparin prophylaxis resulted in: 3 fewer PE per 1000 pts treated (with? of publ bias) 4 more episodes of major bleeding per 1000 pts treated A near-significant 6 fewer deaths per 1000 pts treated No important differences between UFH & LMWH Mechanical proph skin damage, 39 per 1000 pt Post-Heparin Rebound Thrombosis? Gårdlund: 11,693 randomized to heparin prophylaxis for up to 21d (mean 8.2d) Post-Heparin Rebound Thrombosis?- 2 Rebound thrombin generation after heparin therapy in unstable angina. A randomized comparison between UFH and LMWH. JACC 2002;39:811-7 Levi: 1994 pt RCT of SQ heparin proph in pts on drotrecogin, half on SQ heparin before rand, those who went from heparin placebo had mortality Them: Us: The big disappointment: Page 5

6 We didn t write this letter them us On the bright side The month after our paper came out It s like they were at Part 1! Page 6

7 Final thoughts Heparin prophylaxis in medical inpatients prevents no more PE than it causes major bleeds There is some reason to believe that these 2 conditions are about equally bad The strongest argument for prophylaxis may be mortality, but no one has tried to make it Heparin prophylaxis in medical inpatients appears to be a toss-up Sanofi-Aventis has greatly influenced the debate Toss-ups should not be JCAHO measures (!) Page 7