(Circulation. 1998;97:940-941.)
© 1998 American Heart Association, Inc.
Echocardiographic Effects of Prostacyclin?
Ronald W. Day, MD
Division of Pediatric Cardiology,
University of Utah,
Salt Lake City, Utah
To the Editor:
I read with interest the manuscript by Hinderliter and other members of
the Primary Pulmonary Hypertension Study Group entitled
"Effects of Long-term Infusion of Prostacyclin (Epoprostenol) on
Echocardiographic Measures of Right
Ventricular Structure and Function in Primary
Pulmonary Hypertension."1 I was
disappointed that the authors stated conclusions with no supporting
data. Previously, these authors reported that a 12-week continuous
intravenous infusion of prostacyclin improved survival in
patients with severe primary pulmonary
hypertension.2 Hinderliter and associates now
claim that a 12-week period of prostacyclin therapy also had important
beneficial effects on right ventricular structure and
function in this same group of patients. Unfortunately, the results
were incompletely reported without appropriate statistical comparisons.
The baseline echocardiographic features of treated
patients and control subjects were well described. However,
corresponding measurements, 12 weeks after randomization, were not
reported. Furthermore, the authors reported none of the statistical
comparisons between baseline and follow-up measurements. By comparing
only the median differences between baseline and follow-up
echocardiographic variables, the authors arrived at
inappropriate and misleading conclusions. The median differences in
most echocardiographic variables were so small that
it is unlikely that significant "changes" in right
ventricular structure or function occurred in either
patient group. The authors have suggested that the effects of
prostacyclin on cardiac function may have contributed to improved
survival and exercise capacity. However, little attention was given to
the possibility of a type II error in overlooking a significantly
better baseline performance in the 6-minute walk for patients
treated with prostacyclin.
The Primary Pulmonary Hypertension Study Group should be
commended for their efforts in identifying a potential therapy for a
group of patients with little hope for a good quality of life and
long-term survival. Nonetheless, the results of their collaborative
efforts must be interpreted accurately in order to clearly confirm the
safety and efficacy of prostacyclin therapy.
References
1.
Hinderliter AL, Willis PW, Barst RJ, Rich S, Rubin LJ,
Badesch DB, Groves BM, McGoon MD, Tapson VF, Bourge RC, Brundage BH,
Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Koch G, Li S,
Clayton LM, Jöbsis MM, Blackburn SD, Crow JW, Long WA. Effects of
long-term infusion of prostacyclin (epoprostenol) on
echocardiographic measures of right
ventricular structure and function in primary
pulmonary hypertension. Circulation. 1997;95:1479–1486.[Abstract/Free Full Text]
2.
Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB,
Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D,
Keller CA, Murali S, Uretsky BF, Clayton LM, Jöbsis MM, Blackburn
SD, Shortino D, Crow JW. A comparison of continuous
intravenous epoprostenol (prostacyclin) with conventional
therapy for primary pulmonary hypertension. N Engl
J Med. 1996;334:296–301.[Abstract/Free Full Text]
Response
Alan L. Hinderliter, MD
Department of Medicine
Gary Koch, PhD
Department of Biostatistics
Tonya Sharp, MS
Department of Biostatistics
Park W. Willis, IV, MD
Departments of Medicine and Pediatrics
Walker Long, MD
Department of Pediatrics,
University of North Carolina,
Chapel Hill, North Carolina
We believe that the data published in our manuscript
entitled "Effects of Long-term Infusion of Prostacyclin
(Epoprostenol) on Echocardiographic Measures of Right
Ventricular Structure and Function in Primary
Pulmonary Hypertension"1 were
analyzed and interpreted correctly. Baseline
echocardiographic data were summarized as mean values
with standard errors for three purposes: (1) to fully characterize the
patients enrolled in the trial; (2) to illustrate that the patients
randomized to prostacyclin and conventional therapy were similar to
those randomized to conventional therapy alone; and (3) to demonstrate
the marked differences in echocardiographic
measurements between our patients and normal control subjects.
Providing corresponding descriptive statistics 12 weeks after
randomization would be of little value and could be misleading, since
12-week means would not include values from some of our original
sample; data loss occurred because of patient deaths, transplantation,
and, in a few instances, unavailable or uninterpretable follow-up
ultrasound studies. The Wilcoxon rank sum test was utilized to
compare the effects of prostacyclin and conventional therapy with
conventional therapy alone for changes in
echocardiographic variables. The results of these
analyses are reported in Table 5 of the article. Data
analyzed using nonparametric statistics are
appropriately summarized as median values, as shown in Table 5. We
concur with Dr Day's observation that the differences between
treatment effects in the two groups, although statistically significant
in some instances, were small in magnitude. Additional assessments for
within-group change through the Wilcoxon signed rank test
indicated significant (P<.05) worsening of the group
treated with conventional therapy for all
echocardiographic variables in Table 5 except right
ventricular percent change in area; for the group
randomized to prostacyclin and conventional therapy, no
echocardiographic variable had significant
worsening, and diastolic eccentricity index had significant
improvement.
Dr Day correctly points out that the patients randomized to
prostacyclin and conventional therapy had a better performance
on the 6-minute walk than those randomized to conventional therapy
alone, although this atypical random difference was not significant
(P>.05). This raises the possibility that patients treated
with prostacyclin were less impaired for this factor at baseline by
chance, although they could by chance be more impaired for one or more
other factors. This possibly confounding factor was discussed in detail
in the previous report by Barst et al,2 and the
improved exercise performance and survival observed in patients
treated with prostacyclin was statistically evident, independent of
baseline 6-minute walk results. We did not adjust for baseline exercise
capacity in our analyses of treatment effects on
echocardiographic parameters since this
difference between groups was unexpected and there was no a priori
reason to expect that changes in echocardiographic
measurements would be influenced by initial 6-minute walk results.
However, in response to Dr Day's concerns, we have examined our data
with adjustment for baseline 6-minute walk through a rank ANCOVA for
each echocardiographic variable. The variables
with the lowest unadjusted probability values (diastolic
eccentricity index and maximal tricuspid regurgitant jet velocity)
remained statistically significant after this adjustment, but those
with more marginal unadjusted probability values (right
ventricular end-diastolic area and
systolic eccentricity index) had adjusted probability values
that were in the range of .05 to .15. These results are
consistent with those of the unadjusted analyses,
although they should be recognized as having some bias against the
group treated with prostacyclin.
In summary, we agree with the observations that differences between
treatment groups in the echocardiographic changes
observed over the 12 weeks of therapy were small in magnitude and that
the small difference between the two groups in baseline exercise
capacity complicates interpretation of the data. Nonetheless,
analyses reported in our manuscript are appropriate and support
the interpretation that improved right heart structure and function may
play a role in the clinical improvement and prolonged survival noted in
patients treated with prostacyclin.
References
1.
Hinderliter AL, Willis PW IV, Barst RJ, Rich S, Rubin LJ,
Badesch DB, Groves BM, McGoon MD, Tapson VF, Bourge RC, Brundage BH,
Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Koch G, Li S,
Clayton LM, Jöbsis MM, Blackburn SD, Crow JW, Long W, for the
Primary Pulmonary Hypertension Study Group. Effects of infusion
of epoprostenol (prostacyclin) on echocardiographic
measures of right heart structure and function in primary
pulmonary hypertension. Circulation. 1997;95:1479–1486.
2.
Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB,
Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D,
Keller CA, Murali S, Uretsky BF, Clayton LM, Jöbsis MM, Blackburn
SD, Shortino D, Crow JW, for the Primary Pulmonary Hypertension
Study Group. A comparison of continuous intravenous
epoprostenol (prostacyclin) with conventional therapy for primary
pulmonary hypertension. N Engl J Med.. 1996;334:296–301.
