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Lytics for Normotensive Submassive PE
1. Cardiology Division MorningCardiology Division Morning
ReportReport
Michael G. Katz, MD
Fellow in Cardiovascular Disease
University of Rochester
August 8, 2011
2. 2
45 year old WF
• Generally healthy
• Obese, Sleep apnea (home CPAP/BiPAP with good compliance), GERD,
and migraines
• Presented to OSH with 5 days of sub-acute DOE
• Cannot pin-point onset, but there was a distinct inability to exert
herself one day to the next
• Profound SOB after walking approx 50 feet on flat ground
• Associated with band-like upper chest pressure
• No associated diaphoresis, nausea, or vomiting
• Denies frank pain or discomfort.
3. PE
VS: afbrile 80s 140s/70s 92% on 2L NC (placed per ACS protocol)
WF, NAD
JVP 12 cm H2O (visible at angle of jaw at 45 degrees)
CTA B
RRR no r/m/g
Obese, NT/ND/+BS no HSM
No edema
Cardiac biomakers negative.
3
10. Focus on management - Show of hands!
•Anticoagulation
•? Heparin
•? LMWH
•? Thrombolytics
•? IVC filter (not going to talk about)
•(I’m not going to address IA lytics or
embolectomy) 10
14. Thrombolytics
PE may be response for approximately 300,000 deaths per
year in US
As of 2009, only 11 RCT of lytics vs conventional
anticoagulation
• Only 1 of 11 powered to detect mortality endpoint
In contrast: lytics were studied in thousands of patients before
acceptance to standard clinical practice for AMI.
15
Chest 1999;115:1695–1707
Lancet 1994;343:311–322
15. Historical perspective
Streptokinase
• 1930s – discovered that β-hemolytic streptococci produce
streptokinase and lyses fibrin clots
• 1950s – animals studies on rabbits
Urokinase
• 1957 - Maurice Guest, a physiologist at the University of Texas
1957, Lederle Laboratories manufactured streptokinase, and its first
successful use in treating acute myocardial infarction
16
16. 1968 - Hirsh and colleagues:
• 21 Australian patients with major PE proven by pulmonary angiography
• 18 tx with an IV streptokinase vs 3 with IV heparin
• Marked angiographic improvement was noted only 24 h after
streptokinase infusion with a discernable increase in peripheral
pulmonary vascular perfusion.
• 3 pts tx with heparin alone
• Pulmonary arteriography findings after 24 h of heparin therapy
were unchanged from baseline, demonstrating persistent high-grade
obstruction of the main, right, and left pulmonary arteries.
1970s - recombinant tissue plasminogen activator (rt-PA) was discovered
17
17. Lytics Agents
Plasminogen activators that set the
fibrinolytic system into motion
• high affinity for binding plasminogen, which is
bound to plasmin either in the circulation or on
the clot surface
• when thrombolytic agents bind the
plasminogen/plasmin complex, they activate
plasminogen and hydrolyze a peptide bond to
form free plasmin.
• Free plasmin in the circulation is rapidly
neutralized by the inhibitor α-antiplasmin;
however, fibrin-bound plasmin is protected
from this rapid inhibition and hydrolyzes
several key bonds within the clot matrix
18
18. Agents that preferentially activate plasminogen on the clot surface, such as rt-PA, are considered fibrin
specific
• no clear clinical benefit has been proven
3 agents currently FDA approved for treatment of PE
• Streptokinase is cheap but it is antigenic, and so recent streptococcal infection and previous
exposure to streptokinase may result in severe allergic reactions.
• A 2005 metaanalysis aimed at identifying differences among thrombolytic regimens failed to exhibit
any statistically significant differences related to efficacy
• ACCP guidelines suggest using the thrombolytic regimen with the shortest infusion time, which is
currently rt-PA.
19
Circulation. 2011;123:00-00
Eur Respir J 2005; 26:864–874
20. Bleeding Risk
Registry Data
• International Cooperative Pulmonary Embolism Registry
• 21.9% of pts who received thrombolytics for the treatment of PE had a major
bleeding complication, with 3% demonstrating intracranial hemorrhage, compared
with 0.3% in the heparin-treated group.
• Fiumara and colleagues (Brigham and Women’s 1996-2004)
• major bleeding rate of 19.2% in rt-PA pts. Of these, one patient (5%) had proven
intracranial hemorrhage.
Meta-analysis of Trial Data- Pooled data from the 11 randomized trials
• Major bleeding: 9.1% for lytic tx vs 6.1% for heparin therapy (non-significant)
• Minor bleeding: 22.7% vs 10%, respectively (significant)
Lytics in AMI trials: Intracerebral bleeding 0.5%; t-PA (0.7%) is higher than
streptokinase (0.4%)
21
Lancet 1999;353:1386–1389
Am J Cardiol 2006; 97:127–129
Circulation 2004; 110:744–749
21. Who gets lytics? - Site of the debate
• Because of high mortality, massive PE associated with cardiogenic shock, given is a widely accepted
indication for lytics (despite lack of evidence).
• At the other extreme, the risks of thrombolysis are not justified in pts with an anatomically small PE
that causes no elevation in RV afterload
• In a meta-analysis of 5 studies involving 1302 pts with PE treated by heparin followed by
warfarin, rate of death due to PE was only 1.5%.
• Expected improvement in survival would be offset by the risk of life-threatening or disabling
hemorrhage with lytic tx
22
22. Submassive PE with evidence of RV
dysfunction – approx 30-50% of pts!
Argument that lytics are helpful centers on 2 main points:
1.RV dysfunction is a strong prognostic factor predicting
morbidity
2.Ability of thrombolytic agents to improve pulmonary
reperfusion and enhance RV function should translate into
clinical benefit.
(Because, as of yet, there is no definitive RCT demonstrating a mortality difference
between normotensive patients treated with lytics vs anticoagulation alone.)
23
23. Point 1: RV dysfunction is prognostic factor
24
27. Point 2A: Hemodynamic improvement should
yield clinical improvement
28
Maybe normotensive pts
aren’t actually
“hemodynamically stable?”
Maybe imaging and
biomarker evidence of RV
strain implies potential
hemodynamic crisis?
28. Early outcomes
Several trials report improvement in hemodynamics within hours and
days of lytic administration.
• Circulation 1973; 47(suppl):II1–II108
• BMJ 1974; 1:343–347
• Chest 1990; 97:528–533
• Lancet 1993; 341:507–511
Many trials have demonstrated a catch-up phenomena in heparin groups, with hemodynamic parameters
similar to the thrombolytic groups at 1 week of follow-up and beyond
• May indicate benefit for lytics with early hemodynamic deterioration, as opposed to those who
present for clinical evaluation >= 1 week after symptom onset
• Arch Intern Med 1997; 157:2550–2556
29
31. Part 2B (clinical outcomes?): MAP-PET 3
• 256 pts
• Clinical dx of acute PE, SBP > 90, and echo, CT, or EKG evidence of RV
strain followed by confirmation of PE by CTA or pulmonary angiography
• Randomized to thrombolysis with tissue plasminogen activator vs
placebo.
• all patients received continuous infusion intravenous unfractionated
heparin
• Prespecified end-point was defined as in-hospital death or clinical
deterioration requiring escalation of treatment
• catecholamine infusion, secondary thrombolysis, endotracheal
intubation, CPR, or emergency surgical embolectomy or thrombus
fragmentation by catheter.
32
N Engl J Med 2002;347:1143-50
32. 33
N Engl J Med 2002;347:1143-50
Treatment escalation occurred more than
twice as frequently in the heparin plus-placebo group.
No significant difference in mortality.
33. Main criticisms of MAP-PET-3
“end point is of debatable relevance and inadequately objective”
2 end points lytics are is intended to improve:
• Mortality: 2.2% in the heparin group compared with 3.4% in the
alteplase group
• Recurrent PE: 2.9% in the heparin group compared with 3.4% in the
alteplase group
Open label once pt was randomized
• Escalation driven by
• Secondary lysis more
Rates of intracrainial bleeding
• Lower than expected in tPA
34
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