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(Circulation. 1996;93:484-488.)
© 1996 American Heart Association, Inc.

Articles

Clinical Significance of the Pulmonary Vasodilator Response During Short-term Infusion of Prostacyclin in Primary Pulmonary Hypertension

Olivier Raffy, MD; Réza Azarian, MD; François Brenot, MD; Florence Parent, MD ; Olivier Sitbon, MD; Patrick Petitpretz, MD; Philippe Hervé, MD; Pierre Duroux, MD ; A. Tuan Dinh-Xuan, MD; Gérald Simonneau, MD

From the Service de Pneumologie et Réanimation Respiratoire, Université Paris-Sud, Hôpital Antoine Béclère, Clamart, France.

Correspondence to François Brenot, MD, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine Béclère, 157 Rue de la Porte de Trivaux, Clamart 92141, France.

	Abstract

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Background The short-term vasodilator response to prostacyclin (PGI₂) in patients with primary pulmonary hypertension (PPH) is not only unpredictable but also extremely variable in magnitude. In this retrospective study, we attempted to evaluate in a nonselected population of patients with PPH the degree of vasodilatation achieved during short-term infusion of PGI₂ and to investigate whether patients with PPH differed in terms of baseline characteristics and prognoses, according to the level of vasodilatation achieved during initial testing with PGI₂.

Methods and Results Between 1984 and 1992, 91 consecutive patients with PPH underwent catheterization of the right side of the heart with a short-term vasodilator trial with PGI₂ (5 to 10 ng·kg^-1·min^-1). According to the level of vasodilatation achieved during PGI₂ infusion, patients were divided into three groups: nonresponding (NR, n=40), moderately responding (MR, n=42), and highly responding (HR, n=9) patients. All three groups were defined by a decrease in total pulmonary resistance index (TPRi) of <20%, between 20% and 50%, and >50%, respectively, relative to control values. Prolonged oral vasodilator therapy was subsequently started only in MR and HR patients. All patients had long-term oral anticoagulant therapy. The survival rate at 2 years (transplant recipients excluded) was significantly higher in HR patients compared with NR and MR patients (62% versus 38% and 47% survivors, respectively; P<.05). Comparisons between groups showed no significant differences in baseline hemodynamics or clinical characteristics except for a longer time between onset of symptoms and diagnosis (ie, first catheterization) of PPH in HR patients than in NR and MR patients (71±61 versus 35±34 and 21±21 months, respectively; P<.05).

Conclusions In this study, patients with PPH exhibiting a decrease in TPRi >50% during short-term PGI₂ challenge at the time of diagnosis had longer disease evolutions and better prognoses than patients with a lower vasodilator response.

Key Words: hemodynamics • epoprostenol • survival

	Introduction

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PPH is a rare but in most cases rapidly fatal disease. More than 40 years after the first hemodynamic description,¹ medical treatment of PPH (including oxygen supplementation, anticoagulation, and treatment of heart failure) remains mainly palliative, and only heart-lung or lung transplantation seems capable of improving long-term prognosis.² Although vasodilators have raised considerable hope, it appears that only a few patients actually benefit from long-term oral vasodilator therapy. To date, no prospective and controlled study has demonstrated the benefit of long-term oral vasodilator therapy in terms of survival.³ Unfortunately, the hemodynamic response to vasodilators in patients with PPH is inconstant.⁴ Because there is no reliable clinical or hemodynamic characteristic at baseline that can predict the hemodynamic response, it is now commonly accepted that long-term oral vasodilator therapy should be started only in patients who exhibit a significant pulmonary vasodilator response during short-term trials, so the threshold of this significant response remains controversial.^{5 6 7} Epoprostenol, a stable derivative of PGI₂, has been shown to be safe during short-term testing^{6 8} and reliable in predicting the hemodynamic response to other vasodilators.^{9 10} PGI₂ is therefore currently regarded as a drug of choice for the detection of a reversible component in patients with PPH.

The aims of our study were to evaluate in a nonselected population of patients with PPH the degree of vasodilating effect of a short-term infusion of PGI₂, to determine whether there was any relation between the degree of this response and patient clinical or hemodynamic baseline characteristics, and to evaluate the influence of this response on prognosis.

	Methods

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Patients
We retrospectively studied the medical records of patients hospitalized in our institution (Hôpital Antoine Béclère, Clamart, France) from 1984 through 1992 with a diagnosis of PPH. PPH was defined by a mean resting PAP >25 mm Hg during catheterization of the right side of the heart, with a mean PWP <12 mm Hg, and exclusion of potential causes of secondary pulmonary hypertension on the basis of previously defined criteria (Table 1).¹¹ Patients with PPH associated with portal hypertension or HIV infection also were excluded from the study. For each patient, a complete clinical and functional evaluation—including clinical symptoms and signs, degree of disability assessed by NYHA functional classification, time between onset of symptoms (dyspnea or syncope on exertion) and first catheterization, and pulmonary function variables—was obtained at the time of diagnosis. Attention was also paid to the other clinical conditions commonly recognized to be associated with PPH (Raynaud's phenomenon, antinuclear antibody titer >1/80).

View this table: [in this window] [in a new window]   Table 1. Secondary Causes for PPH

Hemodynamic Measurements
All patients underwent catheterization of the right side of the heart by means of a 7F triple-lumen flow-directed thermodilution catheter (Swan-Ganz, Baxter-Edwards). Baseline hemodynamics were recorded with patients in the supine position, at rest, and breathing room air and included mean RAP, mean PAP, and mean PWP. CO was measured by the thermodilution technique; CI was calculated as CO divided by body surface area in square meters. Because PWP was previously shown not to change acutely during vasodilator challenge in patients with PPH¹² and could not be recorded during the entire hemodynamic study in many of our patients, only the TPRi, calculated as PAP divided by CI, was considered. Mean systemic arterial pressure was monitored continuously with an external automated blood pressure cuff (Dynamap, Critikon). Mixed SO₂ was measured in baseline conditions and in some cases during PGI₂ infusion.

Short-term Trial With PGI₂
Hemodynamic parameters also were obtained for each patient during short-term infusion of PGI₂ (Flolan, Wellcome). The infusion was started through a peripheral vein at an initial dose of 5 ng·kg^-1·min^-1 and was increased in a stepwise manner to 10 ng·kg^-1·min^-1 over 30 to 45 minutes, depending on each patient's tolerance (flush, headache, nausea, or a fall in systemic arterial pressure). On the basis of the level of the decrease in TPRi during PGI₂ infusion, three groups of patients were individualized as follows: NR patients, those with a decrease in TPRi of <20%; MR patients, those with a decrease between 20% and 50%; and HR patients, those with a decrease of >50%. Subsequently, only in significant short-term responders to PGI₂ (ie, MR and HR patients) could other vasodilators (isoproterenol, nitroglycerin, phentolamine, diltiazem, and hydralazine) be tested intravenously to select the best agent available for long-term oral treatment. Only the results of the short-term testing with PGI₂ are detailed further.

Therapy
Long-term oral vasodilator therapy was started in all HR patients and in only 36 MR patients. For the remaining 6 MR patients, only PGI₂ was found to be effective during short-term testing. Long-term oral vasodilator therapy consisted of diltiazem (4 HR and 14 MR patients), isosorbide dinitrate (1 HR and 8 MR patients), prazosin (3 HR and 12 MR patients), and isoproterenol (4 HR and 6 MR patients). Only 3 HR and 4 MR patients received a combination of two medications (isoproterenol with diltiazem or prazosin). All patients received anticoagulant therapy with acenocoumarol to maintain an international normalized ratio between 1.5 and 2.¹³ None of the patients was treated with long-term continuous infusion of PGI₂. The selection criteria for lung or heart-lung transplantation were (1) age 55 years; (2) patients in NYHA functional class III or IV; (3) RAP >8 mm Hg, CI <2.2 L·min^-1·m^-2 , and TPRi >20 U/m²; (4) the absence of general contraindication for transplantation; and (5) the absence of short-term vasodilator response to PGI₂ or other vasodilators or failure during follow-up to respond to long-term oral vasodilator therapy (which was discontinued in such a case).¹⁴

Follow-up and Survival
No patient was lost during follow-up. All were followed every 3 months for at least 6 months. Survival was estimated between the date of first catheterization and July 1, 1992, or the date of death, which was related to PPH in all patients (sudden death or heart failure). A separate survival analysis was done for lung and heart-lung transplant recipients.

Statistical Analysis
Values are expressed as mean±SD unless stated otherwise. Between-group comparisons of quantitative data were made by one-way ANOVA. When the F value was significant (P<.05), we performed a post hoc analysis with the Scheffé test to examine the differences between means. Comparison of qualitative data required a ² test with Yates' correction. Within groups, the effect of short-term PGI₂ infusion was analyzed with Student's t test for paired values. The Kaplan-Meier product-limit method was used for survival analysis, and survival rates were compared between groups with the log-rank test. A value of P<.05 was considered statistically significant.

	Results

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Between 1984 and 1992, 155 consecutive patients with PPH were referred to our center for diagnostic and therapeutic evaluation. Sixty-four patients were excluded from the present study because of associated portal hypertension (n=21) or HIV infection (n=15) and because short-term testing with vasodilators was judged hazardous in 28 patients whose conditions were too critical. Subsequently, hemodynamics after short-term testing with PGI₂ were available for analysis in 91 patients (61 women, 30 men) with a mean age of 42±13 years (range, 17 to 68 years). As previously defined, we had 40 NR patients (44%), 42 MR patients (46%), and 9 HR patients (10%), with a mean prostacyclin-induced decrease in TPRi of 6±10%, 33±8%, and 54±6%, respectively. As Fig 1 shows, the vasodilator response in MR and HR patients was probably not related to a mathematical artifact in the calculation of TPRi resulting from a predominant increase in CI because it also was associated with a decrease in PAP. Table 2 lists the clinical features and pulmonary function variables of the three groups at the time of diagnosis. Table 3 gives the hemodynamic status under control conditions and during short-term PGI₂ infusion.

View larger version (13K): [in this window] [in a new window]   Figure 1. Plot showing the effects of short-term PGI2 infusion on mean PAP and CI in the three groups of patients. Mean PAP decreased, whereas CI increased only in MR and HR patients. Error bars are SEM.

View this table: [in this window] [in a new window]   Table 2. Clinical Characteristics and Functional Status of Patients at the Time of Diagnosis

View this table: [in this window] [in a new window]   Table 3. Hemodynamic Status Under Control Conditions and During Short-term Infusion of PGI2

We did not find any clinical or hemodynamic baseline characteristics predictive of the short-term response to PGI₂ and its magnitude, except for a longer time between onset of symptoms and first catheterization (duration of symptoms), which was 71±61 versus 35±34 and 21±21 months in the NR and MR groups (P<.05). There was no relation between the presence or absence of Raynaud's phenomenon and the short-term pulmonary vasodilator responsiveness to prostacyclin or survival. The women-to-men ratio was higher in the HR group than in the other two groups (Table 2), but this difference did not reach statistical significance (P>.3).

The survival rate (transplanted patients excluded) was significantly higher in HR than in NR and MR patients, with 62%, 38%, and 47% of patients surviving at 2 years, respectively (Fig 2); the survival rate between NR and MR patients was not significantly different.

View larger version (11K): [in this window] [in a new window]   Figure 2. Plot showing survival curves of the three groups of patients (transplant recipients excluded; Kaplan-Meier life table analysis). Survival rates between groups were compared with the log-rank test. No MR patient was followed for >50 months at the time of the study.

Fourteen patients (6 NR and 8 MR) had received transplants at the time of the study. They did not differ from patients who did not receive transplants in baseline clinical findings and functional variables and in baseline hemodynamics (RAP, 8±4 mm Hg; PAP, 69±20 mm Hg; CI, 2.3±0.3 L·min^-1·m^-2; TPRi, 34±14 U/m²; P>.1). The 2-year survival rate in patients who received transplants was 76% and was not significantly different from that in HR patients.

	Discussion

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PPH generally is regarded as a progressive and rapidly fatal condition, with death occurring 2 to 3 years after the onset of symptoms.^{15 16 17} Nevertheless, after anecdotal reports of individual spontaneous survivals exceeding 10 or even 15 years,^{18 19} larger recent series have reported that the prognosis of PPH is much more heterogeneous than previously thought. In a selected population of patients with PPH referred for heart-lung transplantation, Glanville et al¹⁵ found that 30% of patients were alive 5 years after diagnosis. More recently, the NIH Registry for the Characterization of Primary Pulmonary Hypertension reported a similar survival rate.²⁰ In keeping with such findings, Robin³ hypothesized that survival in PPH fits a bimodal distribution, with one form of the disease, sometimes called "malignant," characterized by an accelerated course leading to death within a few months; the other form is characterized by a clinical and hemodynamic stability over years after diagnosis and finally a better spontaneous prognosis.³ This apparent heterogeneity of the clinical course in PPH notwithstanding, individual prognostic features remain poorly known.^{21 22} Several clinical or hemodynamic parameters have been associated with a poor prognosis, including NYHA functional class,²⁰ elevated RAP,^{17 20 23} elevated pulmonary vascular resistance and PAP,²⁰ decreased CO (or systolic stroke index),^{15 17 20 23} and low systemic arterial and mixed venous oxygen saturations.^{13 23} However, these parameters reflect only the state of impairment of the right ventricular systolic function characterizing the advanced stages of the disease, and it has been emphasized that they provide only an instantaneous and static view of the patient's hemodynamic status but not a precise idea of the dynamic of the disease, which is highly individual.²⁴

Palevsky et al²⁵ recently rationalized the prognostic value of short-term vasodilator testing in PPH by showing a positive correlation between short-term response to various vasodilators, clinical outcome, and the degree of medial hypertrophy. Despite this report, very few data are available in the literature about the relation between the initial short-term response to vasodilators in PPH and survival, and surprisingly no data are available on PGI₂, although many researchers regard this potent vasodilator as the gold standard for detecting a reversible component in PPH.^{4 6 10} Rich and Levy,¹⁷ studying 12 patients defined as survivors (alive 2 years after first catheterization) or nonsurvivors (deceased <6 months after the first catheterization), found no correlation between the short-term response to conventional doses of nifedipine and survival. From a larger group of patients, the same authors²⁶ reported that survival was positively correlated with the existence of a short-term response to nifedipine and hydralazine (defined as a fall in total pulmonary resistance 20%) but not with the magnitude of this response or long-term oral vasodilator therapy.

In the present study, the clinical and baseline hemodynamic characteristics of patients were similar to those of patients in the NIH registry.¹¹ Considering a 20% decrease in baseline TPRi as a positive response, 56% of our patients (51 of 91) were short-term responders to PGI₂. Although the choice of this threshold is questionable,^{6 7 24 26} it has been adopted by many authors and in >50% of the patients evaluated with short-term infusion of vasodilators in the NIH registry.¹² According to this definition of a vasodilator response, our 56% responder ratio is consistent with data from the literature regarding other vasodilators.^{6 12} An important finding was that a small proportion of our patients (10%) exhibited a dramatic decrease in their baseline TPRi (>50%) with an increase in CO and a significant fall in mean PAP (Table 3); this hemodynamic response currently is considered the optimal vasodilator response.^{7 24} These HR and MR patients but not NR patients also had a significant increase in SO₂ during PGI₂ challenge. This increase in SO₂ probably was a result of the increased CO (Table 3). We found no difference in the initial clinical and hemodynamic characteristics between these HR patients and the remaining patients, except for a significantly longer duration of symptoms in the former. This is not consistent with the hypothesis that a favorable short-term response to vasodilators is related to a less advanced stage of the disease⁴ but might indicate a spontaneously slower evolution.

One of the most interesting findings was that HR patients had a significantly longer survival rate compared with MR and NR patients. The lack of a control group for long-term vasodilator treatment does not allow us to say that there are actually two distinct clinical outcomes in PPH. Nevertheless, the fact that HR patients had longer clinical evolutions at the time of diagnosis and the lack of a difference in survival between NR (untreated) and MR (treated with oral vasodilators) patients suggest that the acute response to PGI₂ may identify a particular subgroup in the PPH population that is characterized by a spontaneously slower evolution and hence a better prognosis. Rich et al²⁷ recently reported a 5-year survival rate of 94% in 16 patients with PPH treated with high doses of oral calcium channel blockers (nifedipine or diltiazem). It is of interest that none of these patients exhibited <50% decrease in TPRi during short-term vasodilator testing at the time of diagnosis. Because extensive clinical data regarding these patients were not available, we cannot rule out that their high survival rate, instead of being related only to vasodilator therapy, reflects a spontaneously better evolution that might have been identified by their high response to vasodilators at the time of initial short-term testing.

In conclusion, the magnitude of the short-term response to a potent and safe (short-acting) vasodilator like PGI₂ at the time of diagnosis may be of primary interest in identifying patients with the best spontaneous prognosis. Patients with a decrease in baseline TPRi of 50%, usually associated with a significant decrease in mean PAP, seem to have better survival rates. Because the issue of whether this better prognosis is related to a different natural course of the disease or to the effects of long-term treatment remains unresolved, long-term vasodilator therapy, particularly with high-dose calcium channel blockers, seems to be indicated in such patients. In our opinion, however, they should not be selected initially for lung transplantation.

	Selected Abbreviations and Acronyms

 

CI = cardiac index CO = cardiac output HR = highly responding MR = moderately responding NR = nonresponding NYHA = New York Heart Association PAP = pulmonary artery pressure PGI2 = prostacyclin PPH = primary pulmonary hypertension PWP = pulmonary wedge pressure RAP = right atrial pressure TPRi = total pulmonary resistance index

	Acknowledgments

 
We thank all the nurses of the department and all respiratory physicians and cardiologists for referring patients.

Received February 7, 1995; revision received August 10, 1995; accepted September 14, 1995.

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