editorials
2. Messerli FH, Bangalore S. Treatment-resistant hypertension:
another Cinderella story. Eur Heart J 2013;34:1175-7.
3. Radio waves to kidneys lower persistent high blood pressure. Press release of the American Heart Association, Dallas,
December 17, 2012.
4. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based
renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;
373:1275-81.
5. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE,
Böhm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (the SYMPLICITY HTN-2 Trial):
a randomised controlled trial. Lancet 2010;376:1903-9.
6. Krum H, Schlaich MP, Sobotka PA, et al. Percutaneous renal
denervation in patients with treatment-resistant hypertension:
final 3-year report of the SYMPLICITY HTN-1 study. Lancet 2014;
383:622-9. [Erratum, Lancet 2014;383:602.]
7. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial
of renal denervation for resistant hypertension. N Engl J Med
2014;370:1393-401.
8. Elmula F, Hoffmann P, Larstorp AC, et al. Adjusted drug
treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension. Hypertension
2014 March 3 (Epub ahead of print).
9. Gottlieb S. The FDA wants you for sham surgery: there are
better ways to test medical devices than by having patients be
placebos who get fake operations. Wall Street Journal. February
18, 2014.
10. Mahfoud F, Bhatt DL. Catheter-based renal denervation: the
black box procedure. JACC Cardiovasc Interv 2013;6:1092-4.
DOI: 10.1056/NEJMe1402388
Copyright © 2014 Massachusetts Medical Society.
Fibrinolysis of Pulmonary Emboli — Steer Closer to Scylla
C. Gregory Elliott, M.D.
According to Homer, Odysseus was forced to
choose whether to steer his ship closer to Scylla,
a six-headed sea monster, or Charybdis, a shipswallowing whirlpool. Odysseus steered closer
to Scylla, risking the loss of a few sailors, rather
than risking an entire ship and crew.
Much like Odysseus, the physician treating a
patient with acute pulmonary embolism occasionally must navigate treacherous waters. The
risk of fatal thromboembolism stands on one side,
and the risk of fatal bleeding lies just opposite.
Unlike Odysseus, the physician has empirical
evidence to guide decisions, but tragic outcomes
occur sometimes, no matter how carefully the
physician navigates.
Acute pulmonary embolism is a common disorder with a wide clinical spectrum. Current estimates suggest that physicians diagnose pulmonary embolism in more than 200,000 patients
annually in the United States.1 Anticoagulant
agents provide effective and safe treatment for
the majority of patients with acute pulmonary
embolism.2 However, in a subgroup of patients
with pulmonary emboli, the risk of death is increased despite anticoagulant treatment. Therefore, current practice embraces risk stratification
of patients with pulmonary embolism, so that
higher-risk therapies are offered to patients with
the greatest chance of benefit.3
Not surprisingly, physicians have long recognized that hypotension or cardiac arrest predicts
high early mortality (>15%) associated with acute
pulmonary embolism.4 Authors of evidence-
based guidelines suggest that such patients undergo systemic fibrinolysis when a high risk of
bleeding is not present.2 The absence of hemodynamic decompensation identifies patients who
are unlikely to die from pulmonary embolism if
they receive anticoagulant therapy promptly. The
size of the emboli does not predict risk. In this
regard, the terms massive and submassive pulmonary embolism can mislead physicians.
Controversy remains over the role of fibrinolysis among normotensive patients with an intermediate risk of death after acute pulmonary embolism. Investigators have suggested that right
ventricular dysfunction detected with echocardiography, myocardial injury defined by elevated
biomarker levels, and the absence of hypotension characterize this intermediate-risk group.5
The increased risk of fatal bleeding conferred
by fibrinolysis and uncertainty about the risk of
death among patients with right ventricular dysfunction and myocardial injury have fueled debates about the treatment of such patients.6,7
In this issue of the Journal, Meyer et al. report
the main results of the Pulmonary Embolism
Thrombolysis (PEITHO) trial.8 In the PEITHO
trial, investigators at 76 centers randomly assigned 1006 patients who had acute pulmonary
embolism and right ventricular dysfunction, as
well as a positive cardiac troponin test, to initial
treatment with anticoagulants and fibrinolysis
or with anticoagulants and placebo. The primary
end point of death or hemodynamic decompensation within 7 days after randomization oc-
n engl j med 370;15 nejm.org april 10, 2014
1457
The New England Journal of Medicine
Downloaded from nejm.org at HELSEBIBLIOTEKET GIR DEG TILGANG TIL NEJM on June 15, 2014. For personal use only. No other uses without permission.
Copyright © 2014 Massachusetts Medical Society. All rights reserved.
editorials
curred in 13 of 506 patients (2.6%) in the fibrinolysis group and 28 of 499 patients (5.6%) in
the placebo group (P = 0.02). Hemodynamic decompensation occurred in 25 of 499 patients
(5%) in the placebo group and was responsible
for the difference in the primary end point between the two study groups. As expected, major
bleeding occurred more often in patients assigned to fibrinolysis. Although patients who
were at increased risk for major bleeding were
excluded, the rate of hemorrhagic stroke in the
fibrinolysis group (2.0%) was 10 times as high
as that in the anticoagulation group (0.2%).
This trial clarifies the risk of death among
patients with acute pulmonary embolism who
were initially normotensive and had myocardial
injury and right ventricular dysfunction. The rate
of death from any cause during the first 7 days
was low (1.2% in the fibrinolysis group and
1.8% in the placebo group, which included patients who received rescue fibrinolysis only if
hemodynamic decompensation had occurred).
The low mortality rate among patients who received anticoagulants is a key observation. The
trial data suggest that careful monitoring and
rescue fibrinolysis can minimize deaths from
pulmonary emboli. In this trial, only 17 of 500
patients (3.4%) who were assigned to initial
treatment with an anticoagulant and placebo received rescue thrombolysis. This approach averts
the increased risk of major bleeding, especially
hemorrhagic stroke, for the majority of patients.
Another approach to reduce bleeding risk that
has been studied in the management of myocardial infarction but not, as far as I know, in the
management of pulmonary embolism is the use
of half-dose fibrinolysis for patients 75 years of
age or older.9
Now, the critical question: What course should
physicians chart when confronted with a normotensive patient with acute pulmonary embolism?
Data from the PEITHO trial provide valuable
insight but no definitive answer. The data
strengthen the case for risk stratification and
for careful monitoring of patients who have an
intermediate risk of death. The data also show
the relative safety of withholding fibrinolysis
unless hemodynamic decompensation occurs.
Therefore, it may be that overall risk can be
minimized with a strategy of initial anticoagulation and rescue fibrinolysis for hemodynamic
decompensation. In the end, physicians must
guide their patients, since no strategy is perfect.
The goal, as the lesson of Scylla and Charybdis
teaches, is to steer toward the lower risk.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Department of Medicine, Intermountain Medical
Center, Murray, and the University of Utah School of Medicine,
Salt Lake City — both in Utah.
1. The Surgeon General’s call to action to prevent deep vein
thrombosis and pulmonary embolism. Rockville, MD: Office of
the Surgeon General, 2008.
2. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:Suppl:
e419S-e494S. [Erratum, Chest 2012;142:1698-704.]
3. Konstantinides S, Goldhaber SZ. Pulmonary embolism: risk
assessment and management. Eur Heart J 2012;33:3014-22.
4. Alpert JS, Smith R, Carlson J, Ockene IS, Dexter L, Dalen JE.
Mortality in patients treated for pulmonary embolism. JAMA
1976;236:1477-80.
5. Stein PD, Matta F, Janjua M, Yaekoub AY, Jaweesh F, Alrifai
A. Outcome in stable patients with acute pulmonary embolism
who had right ventricular enlargement and/or elevated levels of
troponin I. Am J Cardiol 2010;106:558-63.
6. Jiménez D. Point: should systemic lytic therapy be used for
submassive pulmonary embolism? Yes. Chest 2013;143:296-9.
7. Bilello KL, Murin S. Counterpoint: should systemic lytic
therapy be used for submassive pulmonary embolism? No. Chest
2013;143:299-302.
8. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients
with intermediate-risk pulmonary embolism. N Engl J Med 2014;
370:1402-11.
9. Armstrong PW, Gershlick AH, Goldstein P, et al. Fibrinolysis
or primary PCI in ST-segment elevation myocardial infarction.
N Engl J Med 2013;368:1379-87.
DOI: 10.1056/NEJMe1401025
Copyright © 2014 Massachusetts Medical Society.
apply for jobs at the nejm careercenter
Physicians registered at the NEJM CareerCenter can apply for jobs electronically.
A personal account created when you register allows you to apply for positions,
using your own cover letter and CV, and keep track of your job-application history.
Visit NEJMjobs.org for more information.
1458
n engl j med 370;15 nejm.org april 10, 2014
The New England Journal of Medicine
Downloaded from nejm.org at HELSEBIBLIOTEKET GIR DEG TILGANG TIL NEJM on June 15, 2014. For personal use only. No other uses without permission.
Copyright © 2014 Massachusetts Medical Society. All rights reserved.