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Andrew Peacock, MD
Scottish Pulmonary Vascular
Unit
Western Infirmary
Glasgow, United Kingdom
As new therapies emerge and reshape the future of management
in pulmonary arterial hypertension (PAH), the end points
used to diagnose PAH and evaluate the safety and efficacy
of these new treatments are also evolving. Although often
overshadowed by breakthroughs in therapy because of the
excitement generated by new treatment modalities, the
role of end points is nevertheless critical to the assessment
and success of any new agent. The search for more reliable
approaches to determine risk/benefit ratios of therapy
has shown promising results. A clearer picture is beginning
to emerge as to what end points may be used in the future,
what can be gained by applying them in clinical trials
and clinical practice, and what role may be assigned to
conventional end points currently used as the standard.
The challenge in redefining end points is in some respects
as formidable as developing new therapies. It is a task
complicated by a number of factors: the agents administered
for treatment usually target a disease process that is
located primarily in the pulmonary arterioles and that
is usually of unknown etiology. Because the disease itself
is sequestered beyond the reach of currently safe and
convenient methods of evaluation, relatively cumbersome
assessments of PAH are the primary tools relied on to
target organs and functions and investigate a relatively
remote pathophysiology. Unknown etiologies and cumbersome
methods limited to remote functions constitute the central
problems for investigators attempting to assess effects
of treatment.1
The enrollment of more than 1,000 patients with PAH during
the last two years into placebo-controlled trials has
provided important information on the validity of the
gold standard test - the 6-minute walk distance.2-6
Nearly all of these trials have used the unencouraged
6-minute walk distance and resting hemodynamics as end
points. Although results have been considered statistically
significant, they have not produced dramatic improvements
from a physiological perspective. The average increases
in 6-minute walk distances have ranged from 17 to 72 m,
and decreases in mean pulmonary artery pressure have never
exceeded a few mm Hg. Despite subjective improvements
reported by patients, survival has still been limited
and none of the newly introduced therapies has yet been
shown to reverse the pathological process. As new trials
are planned, two essential criteria are the trial design
and the choice of the appropriate primary and secondary
reinforcing end points.6,7
Additional end points are needed to more adequately describe
the changes that occur in PAH and the response to therapy.
Although quality of life is one of the most important
measures, this variable alone may not be compelling evidence
to convince most physicians involved with PAH care. Physiological
changes that accompany the change in quality of life,
whether these be changes in pulmonary hemodynamics, exercise
physiology, circulating hormones, or cardiopulmonary morphology,
tend to provide the most convincing results for physicians.
A conference earlier this year in Scotland brought together
internationally recognized experts on quality of life,
imaging, exercise physiology, pulmonary hemodynamics,
and the hormonal changes associated with PAH to redefine
end points in the disease. This meeting considered the
end points that have been used and examined other end
points potentially of value. The definition of "end
point" adopted was: a measurement used by investigators
conducting a drug trial to determine whether patients
with pulmonary arterial hypertension were benefited by
drug administration. Workshops at the End Points Scotland
Meeting Gleneagle focused on reaching a consensus on a
broad spectrum of topics. This paper reviews a few highlights
from this meeting.
Primary and Secondary Reinforcing
End Points: Requirements of Regulatory Agencies
Exercise capacity, time to clinical worsening, and mortality
are the only clinical end points widely recognized as
"primary" by regulatory agencies in Europe and
the United States. In contrast, pathophysiological variables
such as hemodynamics are considered "secondary."
Assessment of exercise capacity by the 6-minute walk test
may still be the most definitive test as a primary end
point particularly because it is useful in comparing the
results obtained with those obtained from previous trials.
Nevertheless, there is room for improvement. For example,
the 6-minute walk test could be enhanced if an index were
used that included the distance walked and the Borg dyspnea
index or the level of arterial desaturation during the
exercise. If the test also could accommodate a correction
for age and body weight, perhaps more of its critics could
be persuaded concerning its value. As the thinking evolves
on new end points, the following variables are being considered:
- Quality-of-life questionnaires. Although
such questionnaires have been proposed as a "primary
end point, several doubts surround their applicability,
particularly because validation has been lacking in
the clinical setting of PAH.
- Time to clinical worsening. As a combined
end point it has attracted support, yet it requires
standardization to make it more objective and comparable.
This variable is usually defined as the combination
of death, hospitalizations due to worsening of PAH,
and escalation of treatments (need for epoprostenol
or transplantation). If "objective" findings,
such as predefined cut-off levels for exercise capacity
and hemodynamic variable deterioration, were incorporated,
this variable might be considered to have greater value,
thus mitigating its heavy reliance on physician judgment.
- Hemodynamic variable have been considered
traditionally as "secondary" reinforcing end
points based on their prognostic value.7
Although this concept has been accepted by regulatory
agencies, resting hemodynamics optimally give only an
incomplete picture of impaired pulmonary vessels in
PAH. Hemodynamics under conditions of stress such as
exercise, dobutamine, or leg raising are likely to be
more useful. It may be that selected echocardiographic
variables could be considered as a substitute for invasive
hemodynamics but this concept needs to undergo further
study. In fact, some echocardiographic and Doppler variables,
such as Doppler-derived cardiac output, the right ventricular
(Tei) index, pericardial effusion size, etc, have been
shown to provide helpful prognostic information and
could be of value in determining the need for changes
in therapy.8-10
- Still investigational yet promising are biological
end points such as BNP, troponin, endothelin, etc.
These variables have to be validated in clinical studies
before they can be more widely considered for application.
On the Horizon: Emerging Concepts
in Establishing New End Points
Magnetic resonance imaging (MRI) may yield important
advantages in ultimately reducing the number of observations
needed to verify a research hypothesis. A major advantage
with MRI is the improved reproducibility of its results
compared with those obtained from echocardiography. However,
it will require new generations of software, permitting
semiautomatic evaluation of acquired data, to reduce the
excessive time currently needed even for relatively simple
measurements.
Spiral computed tomographic (CT) scanning using
recent multielement technology provides the highest resolution
of all imaging methods. However, i is limited in its ability
to provide insight into hemodynamics. CT evaluation of
diameters of proximal and distal pulmonary arteries may
be helpful to understand changes in pulmonary arterial
impedance with natural progression of the disease and/or
those caused by treatment.
Echocardiographic assessment of patients with PAH is
considered the best source of prognostic information to
be gathered from any imaging studies.8-11
These data indicate three groups of variable potentially
most useful as end points. Interestingly, rather than
being measurements of instantaneous hemodynamics, most
of them reflect long-term consequences of PAH. They are:
- Elevation of right atrial pressure by assessment of
the presence and score of pericardial effusion as well
as measurement of right atrial area/volume.
- Right ventricular dysfunction as assessed by calculating
Doppler indices of myocardial performance or, alternatively,
measuring the duration and flow velocity pattern of
right ventricular ejection. Surrogate assessment of
right ventricular ejection fraction by tissue Doppler
imaging or M-mode assessment of tricuspid annular systolic
motion could be of value.
- Decreased left ventricular preload by assessing left
ventricular eccentricity index or end diastolic area/volume
as well as by decreased left ventricular early diastolic
filling velocity. Improvement of left ventricular diastolic
dysfunction seems to best reflect the effects of treatment
of patients with PAH.
The aforementioned variables are simple and easy to obtain
from a single apical four chamber view in patients with
pulmonary hypertension studied with echocardiography.
Tissue Doppler imaging may facilitate the assessment
of dynamics of the heart and may assess indices of right
ventricular function from a single tracing. Although still
investigational, recent data suggest that myocardial acceleration
during isovolumic right ventricular contraction is load
independent and strongly correlated with end systolic
right ventricular elastance, the best measure of its contractility.
Stress studies using intravenous dobutamine,
exercise, or leg raising could be a more sensitive technique
for detecting abnormal hemodynamics and determining the
benefits of therapy. However, experience with this type
of assessment in patients with PAH is still limited.
Hemodynamics
A right heart catheterization with measurements of pulmonary
vascular pressures and blood flow quantify both the disease
process, or pulmonary vascular resistance (PVR), and its
main functional consequence (cardiac output limitation)
in PAH. Standard hemodynamic measurements in PAH are correlated
to clinical state, functional class, exercise capacity,
and prognosis12, 7,
13-15 but these correlations are
not well defined and often fail to reach significance.
however, it is still too early to omit invasive hemodynamics,
even as a secondary end point. Pulmonary hemodynamic measurements
do not appear to be strongly correlated with clinical
state in patients with PAH because of two factors:
- In most reported studies, the measurements are performed
at rest only, when right ventricular stress and related
symptoms are minimal.
- Mean Ppa and flow (Q) determinations may be insufficient
to measure right ventricular afterload.
These errors or approximations can be avoided by the
definition of PVR by a multipoint pressure/flow line.15
Improvement in exercise capacity with prostacyclin therapy
in PAH patients may not be associated with significant
changes in pulmonary hemodynamics at rest, while PVR defined
by a multi-point (Pps-Ppao)/Q plot shows a significant
decrease.16 Exercise or an
infusion of low-dose dobutamine can increase cardiac output.17
Exercise increases stress on the pulmonary circulation
because of decreased mixed venous oxygenation and sympathetic
nervous system activation.
Right ventricular afterload can be indirectly evaluated
by pulmonary artery pressure and flow waveform analysis.
Increased pulmonary arterial elastance and wave reflection
decrease the acceleration time and cause late or midsystolic
deceleration of pulmonary arterial flow waves as well
as increased pulse pressure and late systolic peaking
of pulmonary arterial pressure waves.18,
19
If 24-hour ambulatory monitoring is effective in evaluating
systemic hypertension, perhaps it can be applied also
in the definition of pulmonary hypertension. Its use could
identify the effects of changes in posture and exercise
on Ppa,20 and it could be
useful in better estimating increased afterload and consequent
right ventricular remodeling. Ambulatory pressure monitoring
has been reported using micromanometer-tipped catheters,20
but the method is expensive, invasive, and requires a
high level of expertise. It should thus be limited to
centers where results can be correlated with other, more
available, techniques.
Exercise Capacity
Shortness of breath and fatigue result from the combined
effects of decreased O2 delivery to the tissues,
increased physiological dead space and arterial hypoxemia,
causing a decreased peak or maximum O2 consumption
(VO2), an early anaerobic threshold, and increased
ventilatory equivalents. Measurements of ventilation (VE),
VO2 and CO2 production (VCO2)
at progressively increased workload assess the physiological
severity of PAH. Several such cardiopulmonary exercise
testing (CPET)-derived measurements have been shown to
be correlated to outcome.21-24
An elevation of VE/VCO2 measured at the anaerobic
threshold25-29 appears to
be an excellent modality with which to assess the severity
of PAH.
Quality of Life
Doubts still remain about the validity of the standard
tests to assess the impact of PAH on quality of life.
Generic health status measures such as the SF-36,31
the Nottingham Health Profile (NHP),32
EuroQoL,33 and the Living
with Heart Failure Minnesota questionnaire are the methods
most commonly used.34 Although
results tend to improve or deteriorate along with changes
in clinical condition, functional state, and exercise
capacity, concern remains about their validity and sensitivity
in assessing those aspects of major concern to the patient.35
These pitfalls have encouraged efforts to collect information
directly from patients on impairments (symptoms), disability
(functioning), handicaps, and ultility.35,
36
Hormonal and Blood Studies
A few studies have indicated that markers of endothelial
cell and/or platelet dysfunction, such as endothelin-1,
von Willebrand factor, and D-dimers, may be prognostically
relevant. However, the data obtained so far have to be
confirmed in larger studies.
Markers of heart failure [A- and B-type natriuretic peptides
(ANP and BNP) and cyclic GMP] may be more relevant to
address prognosis and improvements with therapy37,
38 in the setting of PAH. In contrast, to ANP,
BNP is mostly excreted by overloaded myocytes of the ventricles.
Recent studies indicate that initial and follow-up supramedian
BNP plasma levels were independent markers of prognosis
in PAH. Because NT-pro BNP (its biologically inactive
alternative) is a more stable marker, it should be easier
to study. These biochemical markers, however, may indicate
merely that the disease process is already advanced. It
is still uncertain as to whether they can identify early
disease.
Chronic leakage of troponin T can be detected with high-sensitivity
tests in a subset of patients with severe PAH. In contrast
to other markers, troponin T indicates ongoing damage
of right ventricular contractile proteins, which may contribute
to progressive right ventricular failure. Torbicki and
colleagues have shown that elevation of troponin T was
related to poor survival in PAH.39
Clinical End Points
A 15-item clinical score has been developed4
and proved to be as sensitive to evaluating the active
treatment as the 6-minute walk distance.2
It deserves further study. Clinical events such as death,
hospitalization for right heart failure, and requirement
for alternative treatments have been used as secondary,
often combined, end points. Several papers have shown
that the active treatment reduced the incidence of these
clinical events after 3 to 4 months.12,
4, 5 A combined end point of clinical
events has the potential of a primary end point.
Discussion: Redefining the End
Point
Evaluation of outcomes in PAH is more problematic than
in systemic arterial hypertension. Because of the convenient,
accurate, inexpensive, inflatable cuff method to assess
pressure, systemic hypertension has been better defined
than pulmonary hypertension. Its natural history has been
described, early detection is possible, several different
etiologies have been identified; and guidelines for evaluation
of treatment are known. Several approaches have been used
to resolve problems associated with evaluating PAH. If
one assumes the following cascade in pulmonary arterial
disease: obstruction of flow through pulmonary arterioles,
pulmonary hypertension, reduction in pulmonary blood flow,
impairment of pulmonary circulation regulation, and impaired
oxygen transport, then each of these components may help
to evaluate the effects of PAH and potential benefits
of pharmacotherapy.
During the conference in Scotland, possible strategies
to evaluate the effects of treatment were presented. These
included measurements related to blood concentrations
of vasoactive substances (as markers of pulmonary endothelial
malfunction); invasive and noninvasive hemodynamics by
catheterization, ultrasound, and radiography (as markers
of pulmonary hypertension and pulmonary blood flow); ultrasound
and radiography (as markers of ventricular anatomy and
function); catriuretic factors (as markers of right heart
failure); pulmonary ventilation and exercise performance
(as markers of inadequate systemic oxygen transport);
quality of life assessment (as a marker of the patient's
response to disease); and finally, symptoms, frequency
and duration of hospitalization, and survival (as markers
of the effect of the disease on the patient).
Blueprint for Change: Special
Considerations for End Points
As new end points are proposed, the following recommendations
and considerations may help to clarify whether they will
be suitable for application in clinical trials. A clearer
definition of normal pulmonary hemodynamics is needed,
including the elucidation of normal mean pressures in
older children and adults. These definitions also need
to encompass flows and all pulmonary circulatory pressures
under differing conditions of position and activity. Data
on individual patients need to be more widely shared among
researchers, possibly through a research database. Variables
measured also need more precise quantitation, particularly
with respect to standards of oxygen costs (and arterial
oxygen transport) for patients evaluated with the 6-minute
walk. Periodic conferences should be encouraged to facilitate
a greater exchange of information by working groups and
among investigators to promote more collaborative efforts
in the evaluation of end points in PAH.
Acknowledgements
The following physicians and their Expert Groups at the
Scotland conference contributed information adapted for
this article. Their contribution is gratefully acknowledged.
Regulatory: Nazzareno Galie (Chair), Paul
Corris, Maurizio Rainisio
Imaging: Adam Torbicki (Chair), Richard Coulden,
Andrew Peacock, Michael Sproule
Hemodynamics: Robert Naeije (Chair), Philippe
Herve, Marco Maggiorini, Gerald Simonneau
Exercise Capacity: Lewis Rubin (Chair), Marius
Hoeper, Ronald Oudiz, Joan Barbera
Quality of Life: Sean P. Gaine (Chair), Joanna
Pepke-Zaba, Stephen P. McKenna
Hormonal and Blood Studies: Marc Humbert (Chair),
Marion Delcroix, David Langleben, Horst Olschewski
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