(Circulation. 1998;98:825-826.)
© 1998 American Heart Association, Inc.
Treatment of Pulmonary Embolism With Thrombolysis
Mark Metersky, MD
Assistant Professor University of Connecticut School of
Medicine,
Farmington, Conn
To the Editor:
I have read with interest the article by Dr Konstantinides and
colleagues1 regarding clinical outcomes after
treatment of pulmonary embolism (PE) with either heparin or
thrombolysis. Although not a randomized trial,
appropriate multivariate analysis was performed
so that although not the "final word," the results might have some
validity.
Unfortunately, as published, this study has a tremendous design flaw
that could potentially result in a selection bias that is not addressed
by the multivariate analysis. Specifically,
27% of the patients did not have confirmation of PE by either
ventilation/perfusion scanning or pulmonary angiography. The
use of only clinical criteria to diagnose some of these patients (we
don't know how many of this group had other studies, such as
Doppler ultrasound) is fraught with difficulty. In the Prospective
Investigation of Pulmonary Embolism Diagnosis (PIOPED) study,
only about a third of patients with suspected PE were found to have PE
at angiogram.2
How, then, does this issue result in selection bias? It is probable
that physicians would be less likely to give
thrombolytic agents to patients without a confirmatory
ventilation/perfusion scan or pulmonary angiogram. Because it
is almost certain that some of these patients were inaccurately
diagnosed with PE, they may not have been receiving appropriate care
for their true problem. Therefore, it is possible that patients with
cardiopulmonary disease other than PE, who may have been more
likely to die secondary to inaccurate diagnosis, were more frequently
treated with heparin as opposed to thrombolysis. Given
the relatively low number of deaths, there need not have been many such
patients to skew the results.
Fortunately, there is an easy way to address this concern.
Reanalysis of the data excluding patients without definitive
diagnosis of PE should be performed. If the results remain compelling,
then the evidence in support of thrombolytic therapy
for major PE is much stronger. If the results, however, fail to reveal
a benefit of thrombolysis, the readers of
Circulation deserve to know this, given the increased cost
and bleeding risk associated with thrombolytic
therapy.
References
-
Konstantinides S, Geibel A, Olschewski M, Heinrich F,
Grosser K, Rauber K, Iversen S, Redecker M, Kienast J, Just H, Kasper
W. Association between thrombolytic treatment and the
prognosis of hemodynamically stable patients with major
pulmonary embolism: results of a multicenter registry.
Circulation. 1997;96:882–888.[Abstract/Free Full Text]
-
PIOPED Investigators. Value of the
ventilation/perfusion scan in acute pulmonary embolism.
JAMA. 1990;263:2753–2759.[Abstract]
Response
Stavros Konstantinides, MD
Universitätsklinik, Innere Medizin III, Kardiologie
Manfred Olschewski, PhD
Medizinische Biometrie und Statistik Albert Ludwigs University,
Freiburg, Germany
Dr Metersky's letter gives us the opportunity to stress some
important issues regarding the management of acute major
pulmonary embolism (PE):
It is not correct to question the diagnosis of acute PE in 27% of our
patients just because they did not undergo pulmonary
angiography or ventilation/perfusion lung scan. In fact, all but 6 of
these 191 patients (97%) had echocardiographic
evidence of acute right ventricular pressure overload
and/or pulmonary hypertension according to the criteria listed
in the Methods section of our article.1 Bedside
echocardiography is a valuable noninvasive
diagnostic tool in patients with clinically suspected acute
major PE, especially in the emergency room or intensive care unit. The
diagnostic accuracy and reliability of
echocardiographic findings has been demonstrated
repeatedly by our work group2 3 as well as by
others.4 Besides,
echocardiography is particularly useful for risk
stratification and prognostic assessment of patients in the setting of
acute PE.5 Therefore, confirmation of major PE by
echocardiography "alone" is by no means a
"tremendous design flaw" or a factor causing selection bias, as Dr
Metersky suggests. In fact, rather the opposite is true: a study
including only patients who are able to undergo angiographic or
scintigraphic procedures would unavoidably select a clinically stable
patient group with favorable prognosis. This point of view is strongly
supported by the recently published results of the Management and
Prognosis of Pulmonary Embolism
Registry.6 In our study,1
statistical analysis focusing only on the subgroup of patients
with pulmonary angiograms or lung scans (n=528) would yield a
30-day mortality rate of 4.3% in patients given
thrombolytic treatment as opposed to 9.7% in
heparin-treated patients (P=0.05). Of particular importance,
however, is the fact that the independent effect of early
thrombolysis on death risk as assessed by multiple
logistic regression analysis would remain virtually unchanged
(odds ratio of 0.44 as opposed to 0.46 in the entire patient
population1 ). As might be expected, the 95%
confidence interval would become slightly larger (0.18 to 1.11) and the
P value slightly higher (0.08) due to the smaller number of
patients considered in such a statistical model.
In conclusion, it would be, in our opinion, inappropriate and
misleading to alter the inclusion criteria of the present registry
retrospectively, because we would only consider patients with better
in-hospital outcome without further improving the (already high)
diagnostic accuracy of cardiac ultrasound. On the other
hand, the association found between thrombolysis and
the prognosis of acute major PE remains compelling irrespective of
which diagnostic procedures were performed in each case.
Thus, our results do suggest a clinical benefit of
thrombolytic treatment for clinically stable patients
with acute major PE. Of course, a definite statement on this issue must
await the results of a prospective randomized trial, as already
stressed in our article.1
References
-
Konstantinides S, Geibel A, Olschewski M, Heinrich F,
Grosser KD, Rauber K, Iversen S, Redecker M, Kienast J, Just H, Kasper
W. Association between thrombolytic treatment and the
prognosis of hemodynamically stable patients with major
pulmonary embolism: results of a multicenter registry.
Circulation. 1997;96:882–888.
-
Kasper W, Meinertz T, Henkel B, Eissner D, Hahn K,
Hofmann T, Zeiher A, Just H. Echocardiographic findings
in patients with proven pulmonary embolism. Am
Heart J. 1986;112:1284–1290.[Medline]
[Order article via Infotrieve]
-
Kasper W, Geibel A, Tiede N, Bassenge D, Kauder E,
Konstantinides S, Meinertz T, Just H. Distinguishing between acute and
subacute massive pulmonary embolism by conventional and
Doppler echocardiography. Br Heart
J. 1993;70:352–356.[Abstract/Free Full Text]
-
Jardin F, Dubourg O, Bourdarias JP.
Echocardiographic pattern of acute cor pulmonale.
Chest. 1997;111:209–217.[Free Full Text]
-
Konstantinides S, Geibel A, Olschewski M, Kasper W,
Just H. Acute pulmonary embolism: the value of
echocardiography for identification of high-risk
patients. Circulation. 1997;96:I-25. Abstract.
-
Kasper W, Konstantinides S, Geibel A, Olschewski M,
Heinrich F, Grosser KD, Rauber K, Iversen S, Redecker M, Kienast J.
Management strategies and determinants of outcome in acute major
pulmonary embolism: results of a multicenter registry.
J Am Coll Cardiol. 1997;30:1165–1171.[Abstract]
