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Is there evidence to Is there evidence to mandate mandate heparin heparin prophylaxis in medical inpatients?prophylaxis in medical inpatients?

Part 2Part 2

(Part 1: ACP/ASIM, (Part 1: ACP/ASIM, RochesterRochester MN 10/30/09)MN 10/30/09)

MinneapolisMinneapolisMinneapolisMinneapolisMedical CenterMedical CenterMedical CenterMedical Center

Rochester Rochester MN, 10/30/09)MN, 10/30/09)

Frank A. Lederle, MDFrank A. Lederle, MDProfessor of MedicineProfessor of Medicine

VA Medical CenterVA Medical CenterMinneapolis, MN 55417Minneapolis, MN 55417

Recap of Part I. Recap of Part I. The problem as it looked 15 years ago The problem as it looked 15 years ago

Lederle FA, Ann Intern Med 1998;128:768Lederle FA, Ann Intern Med 1998;128:768--7070

•• Low dose heparin prophylaxis Low dose heparin prophylaxis ↓↓ mortality in surgical mortality in surgical patients, & probably acute MI (? not via VTE)patients, & probably acute MI (? not via VTE)

•• Despite several guidelines, effectiveness uncertain for Despite several guidelines, effectiveness uncertain for h it li d l di l ti th it li d l di l ti t


hospitalized general medical patientshospitalized general medical patients

•• Heparin prophylaxis Heparin prophylaxis ↓↓ asymptomatic DVT asymptomatic DVT (+ screening test) in medical patients, but:(+ screening test) in medical patients, but:•• ~~10 times more common than clinically evident VTE 10 times more common than clinically evident VTE

•• surrogate outcome whose value has been questionedsurrogate outcome whose value has been questioned

•• must be balanced against ↑ risk of bleedingmust be balanced against ↑ risk of bleeding

What ‘What ‘Prompt’edPrompt’ed UsUs

•• One pseudoOne pseudo--randomized Israeli study: heparin randomized Israeli study: heparin prophylaxis prophylaxis ↓↓ allall--cause mortality in gen med pts. cause mortality in gen med pts. 2 days after 2 days after admadm: 39 v 19 deaths (45% of total #) : 39 v 19 deaths (45% of total #) ((HalkinHalkin, Ann Intern Med 1982), Ann Intern Med 1982)

•• Six later true RCTs, one (Six later true RCTs, one (GårdlundGårdlund ) with > 11,000 ) with > 11,000 ti t f dti t f d i ifi t t lit d tii ifi t t lit d ti


patients, found patients, found nono significant mortality reductionsignificant mortality reduction

•• “Interest” in this topic vastly increased after the “Interest” in this topic vastly increased after the advent of profitable LMW heparinadvent of profitable LMW heparin

•• Big issue: 13 million nonBig issue: 13 million non--surgical patients discharged surgical patients discharged each year from U.S. acute care hospitalseach year from U.S. acute care hospitals

PROMPTPROMPT

•• The Prophylaxis of Medical Patients for The Prophylaxis of Medical Patients for ThromboembolismThromboembolism (PROMPT) Study (VA (PROMPT) Study (VA Cooperative Study #438). LOI submitted 1995Cooperative Study #438). LOI submitted 1995

•• 25,000 patient RCT designed to determine 25,000 patient RCT designed to determine whether low dose heparin given throughoutwhether low dose heparin given throughout


whether low dose heparin given throughout whether low dose heparin given throughout hospitalization reduces 90hospitalization reduces 90--day mortality in day mortality in general medical patients (w/o AMI or CVA). general medical patients (w/o AMI or CVA).

•• Chart review indicated 25% of pts over age 60 Chart review indicated 25% of pts over age 60 admitted to VA medicine would be eligibleadmitted to VA medicine would be eligible

•• We reported the results of a 1We reported the results of a 1--year pilot study to year pilot study to assess feasibility of the full studyassess feasibility of the full study

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

De Facto ResultsDe Facto Results


7.6% eligible

28% of goal!


Meta-analysis of all-cause mortality, presented as a public service…


Le morte d’PROMPTLe morte d’PROMPT



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, but the mean was 8.2 days.

Fatal PE in the largest study


y , y

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!


Tim Wilt finds a way to respond!

MinneapolisMinneapolisMinneapolisMinneapolisMedical CenterMedical CenterMedical CenterMedical Center End of Part 1

Begin Part 2:


Data ExtractionData Extraction•• RCTs with clinical outcomesRCTs with clinical outcomes

•• Excluded trials ifExcluded trials if•• pseudopseudo--randomized randomized

•• also used another AC or thrombolytic also used another AC or thrombolytic

•• heparin studies of acute MI (old & irrelevant)heparin studies of acute MI (old & irrelevant)


p ( )p ( )

•• Included data to 120 (90) days after randomization Included data to 120 (90) days after randomization

•• Excluded surrogate outcomes (Excluded surrogate outcomes (asymptasympt. DVT). DVT)

•• Included all events after randomization (intentIncluded all events after randomization (intent--toto--treat), even if excluded by original authors treat), even if excluded by original authors

•• Excluded DVT & PE not confirmed by testingExcluded DVT & PE not confirmed by testingMinneapolisMinneapolisMinneapolisMinneapolisMedical CenterMedical CenterMedical CenterMedical Center

>36,000 patients>2800 deaths



[For illustration. Not our data]



Major BleedingMajor Bleeding

•• Fatal, required surgery, in critical location or Fatal, required surgery, in critical location or caused permanent injury, or “overt + >2u blood”caused permanent injury, or “overt + >2u blood”

•• Stroke studies: hemorrhagic transformation = Stroke studies: hemorrhagic transformation = bl di if t ti j bl dibl di if t ti j bl di


bleeding; if symptomatic = major bleeding bleeding; if symptomatic = major bleeding



apples = oranges


SummarySummary

•• In all nonIn all non--surgical patients combined surgical patients combined (18 studies involving 36,122 patients), (18 studies involving 36,122 patients), heparin prophylaxis resulted in:heparin prophylaxis resulted in:•• 3 fewer PE per 1000 pts treated (with ? of 3 fewer PE per 1000 pts treated (with ? of publpubl bias)bias)

•• 4 more episodes of major bleeding per 1000 pts treated4 more episodes of major bleeding per 1000 pts treated


•• 4 more episodes of major bleeding per 1000 pts treated4 more episodes of major bleeding per 1000 pts treated

•• A nearA near--significant 6 fewer deaths per 1000 pts treatedsignificant 6 fewer deaths per 1000 pts treated

•• No important differences between UFH & LMWHNo important differences between UFH & LMWH

•• Mechanical Mechanical prophproph → skin damage, 39 per 1000 pt→ skin damage, 39 per 1000 pt

PostPost--Heparin Rebound Thrombosis?Heparin Rebound Thrombosis?

GårdlundGårdlund: 11,693 : 11,693 randomized to heparin prophylaxis randomized to heparin prophylaxis for up to 21d (mean 8.2d) for up to 21d (mean 8.2d)


PostPost--Heparin Rebound Thrombosis?Heparin Rebound Thrombosis?-- 22

•• “Rebound thrombin generation after heparin therapy “Rebound thrombin generation after heparin therapy in unstable angina. A randomized comparison in unstable angina. A randomized comparison between UFH and LMWH. JACC 2002;39:811between UFH and LMWH. JACC 2002;39:811--7”7”

•• Levi: 1994 pt RCT of SQ heparin Levi: 1994 pt RCT of SQ heparin prophproph in pts on in pts on d t id t i h lf SQ h i b f d thh lf SQ h i b f d th


drotrecogindrotrecogin, half on SQ heparin before rand, those , half on SQ heparin before rand, those who went from heparin → placebo had ↑ mortalitywho went from heparin → placebo had ↑ mortality

Them:


Us:



The big disappointment:


←themus→

We didn’t write this letter…


On the bright side…


The month after our paper came out…




It’s like they were at Part 1!




Final thoughtsFinal thoughts

•• Heparin prophylaxis in medical inpatients prevents Heparin prophylaxis in medical inpatients prevents no more PE than it causes major bleedsno more PE than it causes major bleeds

•• There is some reason to believe that these 2 There is some reason to believe that these 2 conditions are about equally badconditions are about equally bad

•• The strongest argument for prophylaxis may beThe strongest argument for prophylaxis may be


The strongest argument for prophylaxis may be The strongest argument for prophylaxis may be mortality, but no one has tried to make itmortality, but no one has tried to make it

•• Heparin prophylaxis in medical inpatients appears Heparin prophylaxis in medical inpatients appears to be a tossto be a toss--upup

•• SanofiSanofi--Aventis has greatly influenced the debateAventis has greatly influenced the debate

•• TossToss--ups should not be JCAHO measures (!)ups should not be JCAHO measures (!)

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