GASTROENTEROLOGY 2006;130:120 –126
Deleterious Effects of -Blockers on Exercise Capacity and Hemodynamics in Patients With Portopulmonary Hypertension STEEVE PROVENCHER,* PHILIPPE HERVE,‡ XAVIER JAIS,* DIDIER LEBREC,§ MARC HUMBERT,* GERALD SIMONNEAU,* and OLIVIER SITBON* *Centre des Maladies Vasculaires Pulmonaires (UPRES EA 2705), Service de Pneumologie, Hôpital Antoine Béclère, Clamart; ‡Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson; and §Laboratoire d’Hemodynamique Splanchnique et de Biologie Vasculaire, INSERM Unité 481, Hôpital Beaujon, Clichy, France
Background & Aims: It has been suggested that -blockers might be harmful in pulmonary arterial hypertension. However, no study has evaluated the effect of -blockers in these patients. The aim of this study was to investigate the effect of -blockers on exercise capacity and pulmonary hemodynamics in patients with portopulmonary hypertension receiving -blockers for the prophylaxis of variceal bleeding. Methods: Ten consecutive patients with moderate to severe portopulmonary hypertension (mean pulmonary artery pressure of 52 [10] mm Hg) underwent a 6-minute walk test and a right heart catheterization at baseline and 2 (1) months after -blocker withdrawal. Results: Following -blocker withdrawal, 9 of 10 patients increased their 6-minute walked distance with a mean increase in the whole group of 79 (78) meters (P ⴝ .01). Cardiac output increased by 28% (P < .01) with no change in mean pulmonary artery pressure, resulting in a 19% decrease in pulmonary vascular resistance (P < .01). Increases in cardiac output were related to a 25% increase in heart rate (P < .01), whereas stroke volume was unchanged (P ⴝ .65). The improvements in exercise tolerance were associated with increases in chronotropic response (maximal heart rate minus resting heart rate) from 18 (9) to 34 (12) beats/min (P < .01) during the 6-minute walk test. Conclusions: In patients with moderate to severe portopulmonary hypertension, -blockers are associated with significant worsening in exercise capacity and pulmonary hemodynamics. These deleterious effects support the contraindication of -blockers in patients with portopulmonary hypertension.
ortal hypertension is a known predisposing factor for the development of pulmonary arterial hypertension (portopulmonary hypertension),1 occurring in 0.6%– 2.0% of biopsy-proven cirrhotic patients.2 As compared with cirrhotic patients with increased pulmonary artery pressure related to increases in cardiac output and/or blood volume, patients with portopulmonary hypertension display extensive pulmonary vascular remodeling
P
(increased pulmonary vascular resistance) leading to right heart failure.2 Many of them receive -blockers for the prophylaxis of variceal bleeding.3 Although it has been suggested that -blockers might be harmful for patients with pulmonary arterial hypertension, no study has been performed to investigate the effect of -blocker withdrawal on exercise capacity and pulmonary hemodynamics in patients with portopulmonary hypertension. The aim of the present study was to document the short-term and long-term effects of -blocker withdrawal on pulmonary hemodynamics, exercise capacity, and course of hepatic disease in a cohort of patients with portopulmonary hypertension.
Patients and Methods Study Population Ten consecutive patients referred to our institution for the evaluation of suspected portopulmonary hypertension while receiving -blockers were prospectively evaluated. Pulmonary arterial hypertension was defined as mean pulmonary artery pressure ⬎25 mm Hg and pulmonary vascular resistance ⬎240 dyn · s · cm⫺5 with a pulmonary artery occlusion pressure ⬍15 mm Hg.2 Portal hypertension was defined as the presence of esophageal varices at esophagogastroscopy or hepatic venous pressure gradient ⬎4 mm Hg during right heart catheterization4 with a definite cause of liver disease. One patient was included following liver transplantation performed more than 1 year before the first evaluation at our center. She already had mild portopulmonary hypertension at the time of transplantation. Other causes of pulmonary hypertension were excluded according to our routine investigation, including echocardiography, pulmonary function tests, computed tomography of the chest, ventilation-perfusion scintigraphy, human immunodeficiency virus serology, and autoimmune Abbreviation used in this paper: NYHA, New York Heart Association. © 2006 by the American Gastroenterological Association 0016-5085/06/$32.00 doi:10.1053/j.gastro.2005.10.013
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screening. None of the patients had obstructive or restrictive lung disease, left heart dysfunction on echocardiography, hemoglobin level ⬍110 g/L, or a musculoskeletal abnormality precluding exercise capacity assessment. The study was approved by the ethics board of our institution, and patients gave written consent.
Clinical and Hemodynamic Assessment Patients underwent a clinical and hemodynamic evaluation at baseline (on -blockers) and after -blocker discontinuation. The evaluation included a medical history, modified New York Heart Association (NYHA) functional class assessment (graded from I to IV, the higher value meaning more severe exercise limitation), physical examination, routine blood tests, and a nonencouraged 6-minute walk test according to the American Thoracic Society recommendations.5 All patients had a practice test. A second test performed 24 hours later was used for analysis. Heart rate and peripheral oxygen saturation were measured at rest and at the end of the 6-minute walk test by a pulse oximeter (Nonin 2500; Nonin Medical, Plymouth, MN). Postwalk dyspnea was assessed using the Borg scale (graded from 1 to 10, the higher value meaning more dyspnea during the test).6 Hemodynamic evaluation was performed during the same week according to our routine protocol.7,8 None of the patients responded to acute vasodilator testing.8,9 All patients underwent endoscopic evaluation. Variceal band ligation was performed in patients with varices. Following band ligation, -blocker therapy was progressively tapered over 1 week and clinical and hemodynamic evaluation was repeated 2 (1) months after -blocker discontinuation. During that period, patients remained free of prostacyclin derivatives, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, calcium channel blockers, digoxin, -blockers, or nitrate derivatives. None of the patients were anticoagulated. To better investigate the effect of -blockers on hemodynamics and exercise capacity, the last 2 patients underwent hemodynamic evaluation during submaximal exercise according to our routine protocol.10 Exercise was performed in the supine position with an ergometer fixed to the catheterization table (Cycline 100; Tecmachine, Andrezieux-Boutheon, France). In addition to hemodynamic variables at rest, measurements were repeated after the patients’ legs were positioned on the pedals. Patients were then instructed to pedal at a rate of 60 rpm, the workload being increased stepwise by 10 W every 3 minutes from 0 up to a maximum of 40 W. Hemodynamic parameters were measured during the last minute of each workload step. Patients subsequently treated with vasodilator therapy underwent clinical and hemodynamic evaluation after 6 months of treatment and once a year thereafter, according to our routine protocol. Patients who remained untreated (no vasodilator therapy) were assessed once a year. Periodic endoscopic evaluations were performed with variceal band ligation if
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necessary. The date -blockers were withdrawn was used as the start point to determine duration of follow-up. The cutoff date was February 1, 2005.
Statistical Analysis Results are expressed as means (SD). Comparisons between clinical and resting hemodynamic parameters on -blockers and after -blocker discontinuation were performed using analysis of variance. Comparisons between the modified NYHA functional class on -blockers and after -blocker discontinuation were performed using the Fisher exact test. For patients undergoing exercise hemodynamics, linear regression analysis of data points (mean pulmonary artery pressure and cardiac output at different exercise stages) was performed to determine the slope and the intercept of the pressure-flow relationship of each exercise testing. Comparisons of the pressure-flow slopes were performed using analysis of covariance. P ⬍ .05 was considered statistically significant. Data were analyzed using Statview 5.0 (SAS Institute, Inc, Cary, NC).
Results During this period, no patient referred to our institution for portopulmonary hypertension and receiving -blockers was excluded. Characteristics of Patients Clinical characteristics of patients are shown in Table 1. -blockers were prescribed for primary (n ⫽ 9) or secondary (n ⫽ 1) prophylaxis of variceal bleeding, including 1 patient who received -blockers for primary prophylaxis before liver transplantation. -blockers were continued for unknown reasons following the procedure. Eight patients received propranolol, and 2 patients received atenolol. The mean duration of treatment before the first evaluation was 50 (25) months. Overall, patients had been treated with -blockers for 38 (27) months before the first reported symptom suggestive of pulmonary hypertension. Exercise capacity and hemodynamic characteristics of the patients are shown in Tables 2 and 3. All patients displayed moderate to severe pulmonary arterial hypertension with major impairment in exercise capacity. Clinical and Hemodynamic Evaluation After -Blocker Discontinuation Following -blocker discontinuation, 70% of patients (7/10) improved to (n ⫽ 6) or remained (n ⫽ 1) in modified NYHA functional class II (Table 2). Similarly, the 6-minute walked distance increased in 9 of 10 patients from 338 (79) to 417 (54) meters (P ⫽
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Table 1. Clinical Characteristics of Patients at Baseline (n ⫽ 10) -blockers prescribed Patient no.
Age (y)
Cause of portal hypertension
Child–Pugh classa
Esophageal varices
Drug
Dose (mg)
Prophylaxis
1 2 3 4 5 6 7 8 9 10
44 60 34 70 48 49 36 52 52 52
Alcoholic cirrhosis Alcoholic cirrhosis Hepatitis C cirrhosis Alcoholic cirrhosis Alcoholic cirrhosis Portal vein thrombosis Alcoholic cirrhosis Budd–Chiari syndrome Hepatitis C cirrhosisb Alcoholic cirrhosis
B B A B B N/A A N/A N/A B
Large Small Small Small Large Large Large Large None Large
Propranolol Atenolol Propranolol Propranolol Propranolol Propranolol Propranolol Propranolol Atenolol Propranolol
160 100 160 160 160 160 160 320 100 320
Primary Primary Primary Primary Secondary Primary Primary Primary Primary Primary
N/A, not applicable. (range) values for liver function tests were as follows: aspartate aminotransferase (normal, ⬍50 IU/L), 63 IU/L (39 –111 IU/L); alanine aminotransferase (normal, ⬍60 IU/L), 60 IU/L (26 –142 IU/L); total bilirubin (normal, ⬍17 mol/L), 31 mol/L (11–73 mol/L); alkaline phosphatase (normal, ⬍110 IU/L), 110 IU/L (65–182 IU/L); ␥-glutamyl transferase (normal, ⬍50 IU/L), 153 IU/L (52–320 IU/L); international normalized ratio, (normal, ⬍1.1), 1.5 (1.0 –2.1). bThis patient underwent liver transplantation 17 months before the first evaluation at our center. At the time of transplantation, she had mild portopulmonary hypertension (mean pulmonary artery pressure, 28 mm Hg: cardiac output, 7.21 L · min⫺1; pulmonary vascular resistance, 255 dyn · s · cm⫺5). She subsequently deteriorated in the first few months following the procedure (4 months after transplantation; mean pulmonary artery pressure, 37 mm Hg; cardiac output, 4.19 L · min⫺1; pulmonary vascular resistance, 516 dyn · s · cm⫺5). She received -blockers for primary prophylaxis of variceal bleeding before liver transplantation. -blockers were continued for unknown reasons following the procedure. aMean
Hemodynamic evaluation after -blocker discontinuation revealed a 28% increase in cardiac output (P ⬍ .01) with no change in mean pulmonary artery pressure, resulting in a 19% decrease in pulmonary vascular resistance (P ⬍ .01) (Table 3). Increases in cardiac output were mainly mediated through increases in heart rate (P
.01). Resting heart rate, maximal heart rate reached during the 6-minute walk test, and chronotropic response during the test (maximal heart rate minus resting heart rate) also increased significantly. These improvements were associated with a decrease in Borg dyspnea scale.
Table 2. Functional Evaluation of Patients on -Blockers and 2 ⫾ 1 Months After Cessation of -Blocker Therapy Modified functional NYHA class
Distance (m)
HRbaseline (beats/min)
HRpeak (beats/min)
⌬HR (beats/min)
Patient no.
-b
F-up
-b
F-up
-b
F-up
-b
F-up
-b
F-up
1 2 3 4 5 6 7 8 9 10 Mean (SD)
3 3 2 3 3 3 3 3 3 3
3 2 2 2 2 3 2 3 2 2
315 309 440 310 280 515 252 331 325 307 338 (79)
325 400 450 406 415 485 493 394 450 352 417b (54)
70 66 65 62 67 67 64 65 64 68 66 (2)
78 78 67 90 82 77 74 102 86 76 81c (10)
92 84 91 90 81 69 80 85 70 95 84 (9)
119 122 90 135 122 96 121 122 103 120 115c (14)
24 20 26 28 14 2 16 20 6 27 18 (9)
41 44 23 45 40 19 47 20 17 44 34c (12)
a
NOTE. Baseline SpO2 (95% [2%] vs 95% [1%]; P ⫽ .879), minimal SpO2 (90% [4%] vs 90% [6%]; P ⫽ .671), and desaturation during the 6-minute walk test (⫺6% [3%] vs ⫺5% [5%]; P ⫽ .714) remained unchanged following -blocker withdrawal. Conversely, mean Borg dyspnea scale score decreased from 3.3 (1.4) to 2.5 (1.3) (P ⫽ .037) following -blocker withdrawal. Distance, 6-minute walked distance; HRbaseline, heart rate measured at rest; HRpeak, peak heart rate measured during the 6-minute walk test; ⌬ HR, HRpeak ⫺ HRbaseline; -b, initial evaluation while patients were on -blockers; F-up, evaluation performed 2 (1) months after cessation of -blocker therapy. aP ⫽ .02 using the Fisher exact test. bP ⬍ .01 as compared with value at baseline. cP ⬍ .01 as compared with value at baseline. Only statistically significant differences are figured.
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Table 3. Resting Hemodynamics of Patients on -Blockers and 2 ⫾ 1 Months After Cessation of -Blocker Therapy Main pulmonary arterial pressure (mm Hg)
Cardiac output (L · min⫺1)
Stroke volume (mL)
Heart rate (beats/ min)
Calculated pulmonary vascular resistance (dyn · s · cm⫺5)
Patient no.
-b
F-up
-b
F-up
-b
F-up
-b
F-up
-b
F-up
1 2 3 4 5 6 7 8 9 10 Mean (SD)
62 60 42 51 54 53 67 53 40 37 52 (10)
64 68 43 59 47 62 60 66 28 40 54 (12)
3.94 3.19 5.21 3.36 4.08 5.17 4.66 4.58 5.63 5.24 4.51 (0.84)
4.18 3.91 6.50 4.97 6.65 6.89 6.06 6.60 6.25 5.89 5.79a (1.07)
58 50 77 57 56 85 73 66 88 87 70 (14)
56 48 98 60 75 77 67 66 88 77 71 (15)
68 64 68 59 73 61 64 69 64 60 65 (4)
74 81 66 83 89 89 81 100 71 77 81a (10)
1076 1204 614 1024 941 665 996 838 483 473 832 (258)
1091 1146 455 789 493 627 673 691 371 407 668a (278)
NOTE. Mixed venous oxygen saturation increased from 62 (9)% to 65 (10)% (P ⫽ .018) following -blocker withdrawal. Hemoglobin concentration remained stable during follow-up (134 [17] vs 133 [19] g/L; P ⫽ .762). -b, initial evaluation while patients were on -blockers; F-up, evaluation performed 2 (1) months after cessation of -blocker therapy. aP ⬍ .01 as compared with value at baseline. Only statistically significant differences are figured.
⬍ .01), whereas stroke volume remained unchanged (P ⫽ .65). Pulmonary hemodynamics during submaximal exercise was also assessed before and after -blocker cessation in 2 patients. Five to 7 pulmonary artery pressure and cardiac output data points were recorded during each exercise. The relationship between pressure and flow (as measured by cardiac output) was linear for each exercise with significant correlation coefficients (all R2 ⬎ 0.80; all P ⬍ .01) (Figure 1). Compared with baseline, the slope of the pressure-flow relationship (indicating the level of pulmonary vascular resistance) decreased from 8.5 to 5.5 mm Hg · L⫺1 · min⫺1 (P ⫽ .26) and from 18.0 to 10.3 mm Hg · L⫺1 · min⫺1 (P ⫽ .01) after -blocker cessation for patients 1 and 2, respectively. In both patients, cardiac output was higher at rest and at each workload level during exercise. This increase in cardiac output was related to an increased heart rate at rest and during exercise, while the stroke volume remained unchanged (data not shown). Long-term Follow-up Mean duration of follow-up after -blocker discontinuation was 23 (18) months (median, 19 months), during which none of the patients had variceal hemorrhage. In addition to furosemide (n ⫽ 8) and aldactone (n ⫽ 9), 4 patients received specific therapy for pulmonary arterial hypertension. Among them, 1 patient has been treated with intravenous epoprostenol, leading to clinical and hemodynamic improvement initially. The treatment was complicated by 1 episode of catheter-related sepsis and worsening of ascites, necessitating repetitive paracentesis. The patient finally died 18 months after initi-
ation of epoprostenol therapy from progressive right heart failure. Three patients have been treated with bosentan without elevation of liver enzyme levels. The first of them remains stable after 3 years of therapy, with a 6-minute walked distance of 525 meters as compared with 485 meters before initiation of therapy. The second patient improved his 6-minute walked distance from 325 to 465 meters after 6 months of treatment. The third patient has been treated for ⬍6 months. The remaining 6 patients received no specific vasodilator during follow-up. Among them, 5 patients were classified as modified NYHA functional class II at last follow-up. Their 6-minute walked distance improved from 321 (72) meters at baseline to 443 (34) meters after -blocker withdrawal and remained stable (432 [40] meters; P ⫽ .34) after 21 (13) months of follow-up. Conversely, 1 patient displayed a significant worsening after 12 months with a 174-meter decrease in 6-minute walked distance (from 352 to 178 meters), being classified as modified NYHA functional class III.
Discussion The present study shows that in the context of moderate to severe portopulmonary hypertension, withdrawing -blockers improves exercise capacity and resting pulmonary hemodynamics. These improvements appear to be mostly related to removal of the negative chronotropic effect of -blockers and less importantly to a decrease in pulmonary vascular resistance. Significant improvements in modified NYHA functional class distribution and 6-minute walked distance
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Figure 1. Pressure-flow relationship evaluated during exercise hemodynamics on -blockers (black square) and after cessation of -blocker therapy (gray circles) for (A) patient 1 and (B) patient 2. mPAP, mean pulmonary artery pressure; CO, cardiac output.
were observed in most patients after discontinuation of -blockers. Furthermore, 5 patients displayed persistent clinical improvement without any vasodilator therapy. Discontinuation of -blockers also led to significant increases in resting cardiac output and heart rate and to a 19% decrease in pulmonary vascular resistance, while stroke volume remained unchanged. These improvements in exercise tolerance were comparable to those observed in recent randomized placebo-controlled trials evaluating prostanoid derivatives, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors in the context of idiopathic pulmonary arterial hypertension.11 Very similar results were also reported in a recent series of 11 patients with portopulmonary hypertension treated with bosentan in which the 6-minute walked distance increased by 78 meters as compared with 79 meters in our study.12 The interpretation of these latter results is, however, problematic because whether or not -blockers were prescribed or withdrawn for these patients remains unknown. Given the major influence
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of -blockers on exercise capacity and hemodynamics, evaluation of new therapies for portopulmonary hypertension should only be performed after withdrawal of -blockers. Because exercise capacity appears to be more related to exercise hemodynamics than resting pulmonary hemodynamics,10 we investigated exercise pulmonary hemodynamics in 2 patients. The decrease in the slope of the pressure-flow relationships during exercise confirmed that the improvement in the resistive properties of pulmonary vessels after -blocker withdrawal was also present during exercise. The decrease in pulmonary vascular resistance may have resulted from decreased vascular tone related to -adrenoreceptor–mediated vasodilatation,13,14 changes in autonomic nervous system drive, and decreased hypoxic vasoconstriction related to improved cardiac output and mixed venous oxygen saturation. In addition to disproportionate increases in mean pulmonary artery pressure during exercise, pulmonary hypertensive patients are characterized by a limited increase in stroke volume15–17 and the inability to increase heart rate during exercise (chronotropic incompetence).18,19 Thus, increases in cardiac output are mainly achieved through increases in heart rate. For a given stroke volume, a higher maximal heart rate reached during exercise should therefore result in a higher maximal cardiac output. Indeed, both resting stroke volume and chronotropic response (maximal heart rate minus resting heart rate during exercise) have recently been shown to be the only 2 hemodynamic variables independently related to the 6-minute walked distance in patients with pulmonary arterial hypertension.20 Further blunting of the chronotropic response during exercise with -blockers may worsen the limited cardiac reserve and the exercise capacity of these patients. In the present study, heterogeneous responses in stroke volume were observed following -blocker withdrawal. However, changes in stroke volume were ⬍10% in 7 of 10 patients, and the low number of patients precludes any subgroup analysis. Conversely, withdrawal of -blockers was associated not only with increases in resting heart rate but also in maximal heart rate and chronotropic response achieved during the 6-minute walk test. Together with the decrease in pulmonary vascular resistance, these changes in heart rate reserve are likely to explain the improvement in exercise tolerance observed in these patients. This finding emphasizes for the first time the potential role of pharmacologic manipulation of heart
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rate response in the context of pulmonary arterial hypertension. Reducing portal blood flow with -blockers has been shown to be effective in preventing both initial and recurrent variceal bleeding.3,21 However, none of the patients experienced variceal bleeding during follow-up. This might be related to prophylactic varix ligation in 6 patients, periodic endoscopic evaluation, the potential role of the vasodilator treatment used during follow-up in some patients, and the relatively low cardiac output secondary to pulmonary hypertension. It is important to note that although anticoagulation is part of the conventional treatment for idiopathic pulmonary arterial hypertension, none of the patients received such therapy. Thus, our findings indicate that, because of their major negative influence on exercise capacity and pulmonary hemodynamics, -blockers are not recommended in patients with moderate to severe portopulmonary hypertension and suggest that other forms of prophylaxis such as variceal band ligation are clearly recommended for patients at risk of bleeding. Whether or not -blockers are well tolerated in patients with mild (mean pulmonary artery pressure ⬍35 mm Hg) portopulmonary hypertension remains unknown. As a matter of fact, the 2 less severely impaired patients at baseline (despite moderate to severe portopulmonary hypertension) did not significantly improve their exercise capacity following -blocker withdrawal. Many patients with other forms of pulmonary arterial hypertension who report palpitations and chest pain or who have concomitant diseases requiring -blocker therapy may receive such therapy. Moreover, because there is evidence that excessive adrenergic stimulation exists in both chronic left and right heart failure,22 it has been suggested that -blockade might have a potential therapeutic role in pulmonary arterial hypertension,23 as demonstrated in patients with chronic left heart failure.24 Although a beneficial effect of long-term low-dose -blockers cannot be excluded in a subset of patients, our study clearly supports the current contraindication of -blockers in all forms (type) of pulmonary arterial hypertension. In conclusion, withdrawal of -blocker therapy was associated with an increase in exercise capacity and cardiac output in patients with moderate to severe portopulmonary hypertension in association with the removal of the negative chronotropic and the vasoconstrictive effects of -blockers. Given these deleterious effects, -blockers are not recommended for patients with portopulmonary hypertension.
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Received March 31, 2005. Accepted October 5, 2005. Address requests for reprints to: Steeve Provencher, MD, Hôpital Antoine Béclère, 157 rue de la Porte de Trivaux, 92140 Clamart, France. e-mail: steeveprovencher@hotmail.com; fax: (33) 1-46-30-3824. Supported by a fellowship grant from Université Laval, Québec, Canada (to S.P.).