An Expert Interview With Mark Gladwin, MD -- Part 2: PAH and Sickle Cell
An Expert Interview With Mark Gladwin, MD -- Part 2: PAH and Sickle Cell
Editor's Note:
In patients with sickle cell disease (SCD), the incidence of pulmonary arterial hypertension may be as high as 32%. Research suggests that intravascular hemolysis with the release of free hemoglobin, a nitric oxide (NO) scavenger, results in a relative NO deficiency state, though other pathways may be involved. In Part 2 of our interview with Mark Gladwin, MD, Chief of the Vascular Medicine Branch of the National Heart Lung and Blood Institute, we discuss these 2 conditions. In Part 1 of this interview, Dr. Gladwin discussed the interactions between PAH and HIV. Audio highlights of this interview are available.
Medscape: Studies show that 1 out of every 650 African Americans (0.15%) is homozygous for hemoglobin S, indicative of SCD of the SS variety (SCD-SS). Data suggest that for the estimated 50,000 patients with SCD-SS in the United States, there is involvement of pulmonary vasculature and resultant pulmonary hypertension (PH) in 10% to 30% of these individuals. So potentially there are between 5000 and 15,000 individuals with PH due to SCD-SS in the United States. Yet SCD-SS PH is underdiagnosed. Why is this?
Dr. Gladwin: I think this is changing right now -- that there's a paradigm change occurring in the management of adults with SCD. At least I'm hopeful that there's a paradigm change occurring. But clearly, despite a very high prevalence of PH in this population, in fact, if you look at SCD, there is only one other disease that has as high a prevalence of PH, and that's scleroderma, where anywhere from 10% to 30% of scleroderma patients develop PH.
In SCD, if you use a very rigorous cutoff of a tricuspid regurgitant jet velocity of 3 or greater, about 10% of SCD patients have PH. If you look at an abnormally high pulmonary artery systolic pressure -- that's a tricuspid regurgitant jet velocity of 2.5 or higher -- 30% of the population have abnormally high values. This high pulmonary pressure is strongly associated with risk for death. That's really unequivocal. So why aren't we recognizing and diagnosing these cases more? The major reason is that we're only now becoming aware within the sickle cell/hematology community that this is a problem. There have been a number of case series and retrospective studies over the last decade, but it really wasn't until our study and now studies by Ken Ataga at Chapel Hill and by Claudia Morris and Elliott Vichinsky at Oakland Children's Hospital that we realized how common this problem is.
Only after our observation that this mild PH is associated with a very high risk for death has it become apparent that it actually matters that we identify and screen these patients, that they're at the highest risk for death. So now that everybody knows within the academic hematology community that PH is the greatest risk factor for death in adults with SCD, people are beginning to start screening.
I think one challenge is that people had to realize that this was a real and common problem, and this knowledge -- that this is the major cause of death -- had to penetrate our collective conscience; and that if you screen with echo, you can identify patients who need intensification of their therapy and who are at the highest risk for death.
The second problem is that it appears that PH is a silent complication of SCD. What I mean by "silent" is that most patients with SCD present to emergency rooms, to their clinic doctors, to hospitals with the most overt manifestation of SCD, and that's vaso-occlusive pain crisis.
Vaso-occlusive pain crisis is probably the greatest reason for SCD patients utilizing medical resources. But it turns out that the risk factors for developing vaso-occlusive crisis are not the same risk factors as for the development of PH. Vaso-occlusive crisis is caused by hemoglobin S and by a high hemoglobin value and viscosity -- sickling of the red cells and high viscosity. PH is caused by hemolytic anemia, the actual process of hemolysis.
It turns out that patients who have the highest rates of hemolytic anemia don't necessarily come to the hospital in pain crisis all the time. So we see a lot of patients, for example, who have relatively quiet SCD. They don't get admitted in pain frequently. They have very low hemoglobin levels. They have a very high hemolytic rate. And they start presenting with progressive dyspnea, and then they are diagnosed with PH.
The other problem is that patients with SCD are dying before their pulmonary pressures rise very high. So oftentimes, they're still New York Heart class II, and they're dying. We think this is because they have mild PH, but then they get an intermittent illness, a vaso-occlusive crisis, a chest syndrome, an episode of anemia, perhaps exercise with severe anemia; these things trigger an acute rise in PH on top of their chronic PH, and they're dying suddenly. So we think they die before they get to the point where they develop overt exercise impairment and dyspnea.
The last problem is socioeconomic, and this is a big problem. Unfortunately, in this country, we do not have universal healthcare, [not] even for our most at-risk citizens, including those people with genetic diseases. The SCD population is at great risk for not working, or for not working in the highest-paying jobs because recurrent illness essentially takes them off of the track for advancement. [Because of this] many of these patients become partially or incompletely insured. That makes it very hard to start providing universal screening with Doppler echocardiogram.
So, to summarize these issues, there's a problem with appreciating that PH is a major risk; there's a problem with patients dying before they have obvious PH; and there's a problem, a socioeconomic problem, in terms of insurability that's leading to a failure to perform Doppler echocardiogram in every patient.
Medscape: PH of SCD is associated with hemolysis, impaired NO bioavailability, chronic hypoxemia, thromboembolism, and parenchymal and vascular injury because of sequestration of sickle erythrocytes, chronic liver disease, and asplenia. Can you explain these interactions?
Dr. Gladwin: Well, let me start with hemolysis. Beyond SCD, there's an emerging syndrome of hemolysis-associated PH. Virtually every disease associated with chronic hemolysis is now being linked to a high prevalence of PH.
So in SCD, 10% to 30% of patients develop PH. In thalassemia intermedia and thalassemia major -- another hemolytic anemia -- 10% to 30% develop PH. In hereditary spherocytosis and stomatocytosis (red cell membrane defects associated with intravascular hemolysis), there are now many case series and case reports of PH. In pyruvate kinase deficiency, which leads to oxidative stress-induced hemolysis, there are reports of PH. There are now reports of PH in alloimmunization-associated hemolysis and in microangiopathic hemolytic diseases, like thrombotic thrombocytopenic purpura and hemolytic uremic syndrome -- the latter disease is [in the news] now, due to the contaminated spinach in the last week.
So PH is virtually epidemic among the hemolytic anemias, and this made us start thinking more about what was a common feature of these diseases. One major feature of these diseases is anemia, although patients with iron-deficiency anemia, the most common cause of nonhemolytic anemia in the world, do not develop PH.
The second common feature of these diseases is hemolysis. We've studied very intensively the biochemical and physiologic effects of hemolysis in patients with SCD. What happens is that when you hemolyze, hemoglobin bursts out of the red blood cell into the plasma. We all know that hemoglobin's job is to maintain oxygenation of our tissues. But hemoglobin does another thing, and that is to react with, and destroy, the gas molecule NO, which is a critical regulator of vessel health. NO is made by the endothelial cells that line our blood vessels. It dilates our blood vessels, inhibits clotting, and inhibits the expression of endothelin, a vasoconstrictor molecule. It also reacts with, and inactivates, superoxide. So essentially NO is what I like to call the "WD-40 of our blood vessels," because it maintains our blood vessels to be open, flowing, and lubricated. As the hemoglobin spills out of red cells, it instantaneously destroys the NO. This promotes vasoconstriction and thrombosis or clotting; activates adhesion molecules; activates endothelin; and essentially leads to all the processes that we know ultimately drive the development of PH.
We have now found in animal models, studies with patients with SCD, and in epidemiologic studies looking at large cohorts like the Cooperative Study of Sickle Cell Disease, that the hemolytic rate predicts a number of vascular complications, which include PH, cutaneous leg ulcers, priapism, and an increased risk for death. It looks like there exists a clinical subphenotype of SCD which includes PH, leg ulcers, and priapism; these clinical manifestations can occur in other hemolytic diseases as well.
In addition to hemolysis releasing hemoglobin into plasma, which destroys the NO, the red cell also contains high concentrations of an important enzyme called arginase-1. Arginase-1 degrades arginine, which is the amino acid that makes NO. So if you release arginase into plasma during hemolysis, you mop up all the arginine, and that further reduces NO levels.
Patients with SCD have other things that appear to lead to PH in addition to hemolysis, and this includes iron overload. They're at risk for iron overload because they've received a lot of transfusions. We don't yet understand why iron overload contributes to the development of PH, but epidemiologic data suggest that it does. They also often don't have a spleen, because they've sickled in their spleen in childhood and destroyed the organ. Patients with other forms of hemolytic anemia often have their spleens removed, so their hemoglobin level increases. Again, we don't know why taking out the spleen, or losing your spleen, increases the risk for PH. We suspect that it's because the spleen serves an important job of clearing the old, damaged red blood cells. And if you take the spleen out, we suspect that those old, damaged red cells now could become entrapped in the lung and hemolyze in the lung, and that could further magnify the pathology of PH.
Medscape: Can you briefly discuss the role of endothelins in SCD and how this affects PH?
Dr. Gladwin: Well, the endothelins are sort of the yin and NO is the yang in that they oppose and complement each other in terms of blood flow regulation. So endothelin-1 is one of the most potent vasoconstrictors ever discovered. So it constricts blood vessels, and NO is one of the most potent dilators ever discovered. They work together in concert; so as NO goes up, endothelin goes down, and as endothelin goes up, NO goes down. In PH, what we see is that NO is low and endothelin is very high.
That is also exactly what is seen in SCD. Patients with SCD have high endothelin-1 levels in steady state. During chest syndrome or crisis, these levels rise higher. NO does the opposite; in steady state there is NO bioavailability; and in chest syndrome or crisis, the NO collapses to zero. So the endothelin system, like in other forms of PH, appears to be elevated and increased in patients with SCD.
Presumably, similar to other forms of PH, where there's a low NO bioavailability but high vasoconstrictor availability, specifically high endothelin-1, this leads to chronic constriction and smooth muscle hypertrophy of the pulmonary artery. Ultimately this causes a proliferative pathological remodeling of the pulmonary vessels, which occludes the pulmonary blood vessels.
Medscape: Even when diagnosed, many physicians elect not to treat SCD-SS PH. Why?
Dr. Gladwin: I think the major reason is that up until this time, people did not know that PH conferred an increased risk for death. Now they do know. So more and more, we're getting patients referred to us who sometimes are already on therapy. Many of my colleagues are now beginning to treat patients with SCD with bosentan or with sildenafil, because now there are available pills. So I think that the medical community didn't realize how bad it was to have PH in SCD. Also, they didn't have treatments such as orally available drugs like bosentan or sildenafil.
I also think that we didn't have data specific to SCD showing that these medications work. And that's absolutely vital right now -- that when we identify these patients, we need to refer them to treatment centers where research studies are taking place, centers looking at these available drugs for the treatment for PH.
Dr. Medscape: What are the current studies?
Dr. Gladwin: Right now, there are 2 major trials that are in process. There is "A Study of Patients Having Pulmonary Hypertension Associated With Sickle Cell Disease and Completing an ASSET Study" (http://www.clinicaltrials.gov/ct/show/NCT00360087?order=1) which we are running at the National Institutes of Health. This study is supported by the NIH and the makers of the drug bosentan. The second study, "Bosentan to Treat Pulmonary Arterial Hypertension in Sickle Cell Disease (Asset 1 Study)" (http://www.clinicaltrials.gov/ct/show/NCT00307359?order=3), is also being run in 27 centers around the world. This study is currently recruiting patients. I think it's vital that we refer patients to study sites for treatment studies aimed at determining whether these medications help patients with SCD. Patients will get treated; we'll find out whether the drugs work; and we also have open-label treatment at the end of study, so patients are guaranteed to receive active treatment when they enroll in these studies. There is also a large National Heart, Lung, and Blood Institute (NHLBI) study that's going to be launching very soon; it's a placebo-controlled trial of sildenafil. The study centers have now been selected by the NHLBI and enrollment will start in the spring. It is important that we get patients into both of these trials. Many physicians are starting therapy for their patients, and I think at this point we really need to focus on getting the patients in the trial so that we can prove definitively that these drugs work, so that the knowledge will then spread and people will begin using these drugs appropriately.
The other thing that I want to point out is that we still don't know whether PH in SCD is a marker of death or a direct cause of death. I think our data suggest that it's both. So in addition to treating or referring patients for the treatment of PH, it's also very important that we intensify their SCD therapy. If they're not on hydroxyurea, we treat them with hydroxyurea. If they need transfusions, we give them transfusions. If they have iron overload, we chelate the iron. If they have nocturnal or exercise desaturations, then we give them oxygen. There's a lot that we can do to treat SCD. When you identify a patient with SCD and PH, we have to intensify their SCD-specific therapy, and we have to enroll them in trials for the direct treatment of PH.
Medscape: Are there new data on the effects of treatment modalities for PH in patients with SCD?
Dr. Gladwin: There are still very few data. We have an open-label, phase 2 study, in which we treated 12 patients with SCD with sildenafil for more than 3 months. And we now have 22 patients on sildenafil for almost 3 years. In that study, we reported that it dropped pulmonary pressure; it increased 6-minute walk distance; and it lowered the blood levels of N-terminal brain natriuretic peptide, which is a marker released from the stressed or pressure-overloaded heart. So all of those things suggest a benefit.
We have unpublished data now with 5 patients on bosentan, where we've added bosentan to sildenafil, and it appears to be improving those patients' hemodynamics and exercise performance as well. There have been small series of patients reported by Oswaldo Castro describing the effects of epoprostenol sodium, or prostacyclin, in patients with SCD and PH, where it's been shown to lower the pulmonary vascular resistance.
But we really don't yet have sufficient phase 2/3 data for these treatments in SCD. And that's why these 2 studies that I've mentioned -- the ASSET trial with bosentan, a placebo-controlled, international trial, and the upcoming sildenafil trial at NHLBI -- are absolutely vital studies. We have to begin screening patients around the country and referring patients to these study sites.
Medscape: Part 1 of this 2-part series includes an in-depth discussion on the interactions between PAH and HIV.
Editor's Note:
In patients with sickle cell disease (SCD), the incidence of pulmonary arterial hypertension may be as high as 32%. Research suggests that intravascular hemolysis with the release of free hemoglobin, a nitric oxide (NO) scavenger, results in a relative NO deficiency state, though other pathways may be involved. In Part 2 of our interview with Mark Gladwin, MD, Chief of the Vascular Medicine Branch of the National Heart Lung and Blood Institute, we discuss these 2 conditions. In Part 1 of this interview, Dr. Gladwin discussed the interactions between PAH and HIV. Audio highlights of this interview are available.
Medscape: Studies show that 1 out of every 650 African Americans (0.15%) is homozygous for hemoglobin S, indicative of SCD of the SS variety (SCD-SS). Data suggest that for the estimated 50,000 patients with SCD-SS in the United States, there is involvement of pulmonary vasculature and resultant pulmonary hypertension (PH) in 10% to 30% of these individuals. So potentially there are between 5000 and 15,000 individuals with PH due to SCD-SS in the United States. Yet SCD-SS PH is underdiagnosed. Why is this?
Dr. Gladwin: I think this is changing right now -- that there's a paradigm change occurring in the management of adults with SCD. At least I'm hopeful that there's a paradigm change occurring. But clearly, despite a very high prevalence of PH in this population, in fact, if you look at SCD, there is only one other disease that has as high a prevalence of PH, and that's scleroderma, where anywhere from 10% to 30% of scleroderma patients develop PH.
In SCD, if you use a very rigorous cutoff of a tricuspid regurgitant jet velocity of 3 or greater, about 10% of SCD patients have PH. If you look at an abnormally high pulmonary artery systolic pressure -- that's a tricuspid regurgitant jet velocity of 2.5 or higher -- 30% of the population have abnormally high values. This high pulmonary pressure is strongly associated with risk for death. That's really unequivocal. So why aren't we recognizing and diagnosing these cases more? The major reason is that we're only now becoming aware within the sickle cell/hematology community that this is a problem. There have been a number of case series and retrospective studies over the last decade, but it really wasn't until our study and now studies by Ken Ataga at Chapel Hill and by Claudia Morris and Elliott Vichinsky at Oakland Children's Hospital that we realized how common this problem is.
Only after our observation that this mild PH is associated with a very high risk for death has it become apparent that it actually matters that we identify and screen these patients, that they're at the highest risk for death. So now that everybody knows within the academic hematology community that PH is the greatest risk factor for death in adults with SCD, people are beginning to start screening.
I think one challenge is that people had to realize that this was a real and common problem, and this knowledge -- that this is the major cause of death -- had to penetrate our collective conscience; and that if you screen with echo, you can identify patients who need intensification of their therapy and who are at the highest risk for death.
The second problem is that it appears that PH is a silent complication of SCD. What I mean by "silent" is that most patients with SCD present to emergency rooms, to their clinic doctors, to hospitals with the most overt manifestation of SCD, and that's vaso-occlusive pain crisis.
Vaso-occlusive pain crisis is probably the greatest reason for SCD patients utilizing medical resources. But it turns out that the risk factors for developing vaso-occlusive crisis are not the same risk factors as for the development of PH. Vaso-occlusive crisis is caused by hemoglobin S and by a high hemoglobin value and viscosity -- sickling of the red cells and high viscosity. PH is caused by hemolytic anemia, the actual process of hemolysis.
It turns out that patients who have the highest rates of hemolytic anemia don't necessarily come to the hospital in pain crisis all the time. So we see a lot of patients, for example, who have relatively quiet SCD. They don't get admitted in pain frequently. They have very low hemoglobin levels. They have a very high hemolytic rate. And they start presenting with progressive dyspnea, and then they are diagnosed with PH.
The other problem is that patients with SCD are dying before their pulmonary pressures rise very high. So oftentimes, they're still New York Heart class II, and they're dying. We think this is because they have mild PH, but then they get an intermittent illness, a vaso-occlusive crisis, a chest syndrome, an episode of anemia, perhaps exercise with severe anemia; these things trigger an acute rise in PH on top of their chronic PH, and they're dying suddenly. So we think they die before they get to the point where they develop overt exercise impairment and dyspnea.
The last problem is socioeconomic, and this is a big problem. Unfortunately, in this country, we do not have universal healthcare, [not] even for our most at-risk citizens, including those people with genetic diseases. The SCD population is at great risk for not working, or for not working in the highest-paying jobs because recurrent illness essentially takes them off of the track for advancement. [Because of this] many of these patients become partially or incompletely insured. That makes it very hard to start providing universal screening with Doppler echocardiogram.
So, to summarize these issues, there's a problem with appreciating that PH is a major risk; there's a problem with patients dying before they have obvious PH; and there's a problem, a socioeconomic problem, in terms of insurability that's leading to a failure to perform Doppler echocardiogram in every patient.
Medscape: PH of SCD is associated with hemolysis, impaired NO bioavailability, chronic hypoxemia, thromboembolism, and parenchymal and vascular injury because of sequestration of sickle erythrocytes, chronic liver disease, and asplenia. Can you explain these interactions?
Dr. Gladwin: Well, let me start with hemolysis. Beyond SCD, there's an emerging syndrome of hemolysis-associated PH. Virtually every disease associated with chronic hemolysis is now being linked to a high prevalence of PH.
So in SCD, 10% to 30% of patients develop PH. In thalassemia intermedia and thalassemia major -- another hemolytic anemia -- 10% to 30% develop PH. In hereditary spherocytosis and stomatocytosis (red cell membrane defects associated with intravascular hemolysis), there are now many case series and case reports of PH. In pyruvate kinase deficiency, which leads to oxidative stress-induced hemolysis, there are reports of PH. There are now reports of PH in alloimmunization-associated hemolysis and in microangiopathic hemolytic diseases, like thrombotic thrombocytopenic purpura and hemolytic uremic syndrome -- the latter disease is [in the news] now, due to the contaminated spinach in the last week.
So PH is virtually epidemic among the hemolytic anemias, and this made us start thinking more about what was a common feature of these diseases. One major feature of these diseases is anemia, although patients with iron-deficiency anemia, the most common cause of nonhemolytic anemia in the world, do not develop PH.
The second common feature of these diseases is hemolysis. We've studied very intensively the biochemical and physiologic effects of hemolysis in patients with SCD. What happens is that when you hemolyze, hemoglobin bursts out of the red blood cell into the plasma. We all know that hemoglobin's job is to maintain oxygenation of our tissues. But hemoglobin does another thing, and that is to react with, and destroy, the gas molecule NO, which is a critical regulator of vessel health. NO is made by the endothelial cells that line our blood vessels. It dilates our blood vessels, inhibits clotting, and inhibits the expression of endothelin, a vasoconstrictor molecule. It also reacts with, and inactivates, superoxide. So essentially NO is what I like to call the "WD-40 of our blood vessels," because it maintains our blood vessels to be open, flowing, and lubricated. As the hemoglobin spills out of red cells, it instantaneously destroys the NO. This promotes vasoconstriction and thrombosis or clotting; activates adhesion molecules; activates endothelin; and essentially leads to all the processes that we know ultimately drive the development of PH.
We have now found in animal models, studies with patients with SCD, and in epidemiologic studies looking at large cohorts like the Cooperative Study of Sickle Cell Disease, that the hemolytic rate predicts a number of vascular complications, which include PH, cutaneous leg ulcers, priapism, and an increased risk for death. It looks like there exists a clinical subphenotype of SCD which includes PH, leg ulcers, and priapism; these clinical manifestations can occur in other hemolytic diseases as well.
In addition to hemolysis releasing hemoglobin into plasma, which destroys the NO, the red cell also contains high concentrations of an important enzyme called arginase-1. Arginase-1 degrades arginine, which is the amino acid that makes NO. So if you release arginase into plasma during hemolysis, you mop up all the arginine, and that further reduces NO levels.
Patients with SCD have other things that appear to lead to PH in addition to hemolysis, and this includes iron overload. They're at risk for iron overload because they've received a lot of transfusions. We don't yet understand why iron overload contributes to the development of PH, but epidemiologic data suggest that it does. They also often don't have a spleen, because they've sickled in their spleen in childhood and destroyed the organ. Patients with other forms of hemolytic anemia often have their spleens removed, so their hemoglobin level increases. Again, we don't know why taking out the spleen, or losing your spleen, increases the risk for PH. We suspect that it's because the spleen serves an important job of clearing the old, damaged red blood cells. And if you take the spleen out, we suspect that those old, damaged red cells now could become entrapped in the lung and hemolyze in the lung, and that could further magnify the pathology of PH.
Medscape: Can you briefly discuss the role of endothelins in SCD and how this affects PH?
Dr. Gladwin: Well, the endothelins are sort of the yin and NO is the yang in that they oppose and complement each other in terms of blood flow regulation. So endothelin-1 is one of the most potent vasoconstrictors ever discovered. So it constricts blood vessels, and NO is one of the most potent dilators ever discovered. They work together in concert; so as NO goes up, endothelin goes down, and as endothelin goes up, NO goes down. In PH, what we see is that NO is low and endothelin is very high.
That is also exactly what is seen in SCD. Patients with SCD have high endothelin-1 levels in steady state. During chest syndrome or crisis, these levels rise higher. NO does the opposite; in steady state there is NO bioavailability; and in chest syndrome or crisis, the NO collapses to zero. So the endothelin system, like in other forms of PH, appears to be elevated and increased in patients with SCD.
Presumably, similar to other forms of PH, where there's a low NO bioavailability but high vasoconstrictor availability, specifically high endothelin-1, this leads to chronic constriction and smooth muscle hypertrophy of the pulmonary artery. Ultimately this causes a proliferative pathological remodeling of the pulmonary vessels, which occludes the pulmonary blood vessels.
Medscape: Even when diagnosed, many physicians elect not to treat SCD-SS PH. Why?
Dr. Gladwin: I think the major reason is that up until this time, people did not know that PH conferred an increased risk for death. Now they do know. So more and more, we're getting patients referred to us who sometimes are already on therapy. Many of my colleagues are now beginning to treat patients with SCD with bosentan or with sildenafil, because now there are available pills. So I think that the medical community didn't realize how bad it was to have PH in SCD. Also, they didn't have treatments such as orally available drugs like bosentan or sildenafil.
I also think that we didn't have data specific to SCD showing that these medications work. And that's absolutely vital right now -- that when we identify these patients, we need to refer them to treatment centers where research studies are taking place, centers looking at these available drugs for the treatment for PH.
Dr. Medscape: What are the current studies?
Dr. Gladwin: Right now, there are 2 major trials that are in process. There is "A Study of Patients Having Pulmonary Hypertension Associated With Sickle Cell Disease and Completing an ASSET Study" (http://www.clinicaltrials.gov/ct/show/NCT00360087?order=1) which we are running at the National Institutes of Health. This study is supported by the NIH and the makers of the drug bosentan. The second study, "Bosentan to Treat Pulmonary Arterial Hypertension in Sickle Cell Disease (Asset 1 Study)" (http://www.clinicaltrials.gov/ct/show/NCT00307359?order=3), is also being run in 27 centers around the world. This study is currently recruiting patients. I think it's vital that we refer patients to study sites for treatment studies aimed at determining whether these medications help patients with SCD. Patients will get treated; we'll find out whether the drugs work; and we also have open-label treatment at the end of study, so patients are guaranteed to receive active treatment when they enroll in these studies. There is also a large National Heart, Lung, and Blood Institute (NHLBI) study that's going to be launching very soon; it's a placebo-controlled trial of sildenafil. The study centers have now been selected by the NHLBI and enrollment will start in the spring. It is important that we get patients into both of these trials. Many physicians are starting therapy for their patients, and I think at this point we really need to focus on getting the patients in the trial so that we can prove definitively that these drugs work, so that the knowledge will then spread and people will begin using these drugs appropriately.
The other thing that I want to point out is that we still don't know whether PH in SCD is a marker of death or a direct cause of death. I think our data suggest that it's both. So in addition to treating or referring patients for the treatment of PH, it's also very important that we intensify their SCD therapy. If they're not on hydroxyurea, we treat them with hydroxyurea. If they need transfusions, we give them transfusions. If they have iron overload, we chelate the iron. If they have nocturnal or exercise desaturations, then we give them oxygen. There's a lot that we can do to treat SCD. When you identify a patient with SCD and PH, we have to intensify their SCD-specific therapy, and we have to enroll them in trials for the direct treatment of PH.
Medscape: Are there new data on the effects of treatment modalities for PH in patients with SCD?
Dr. Gladwin: There are still very few data. We have an open-label, phase 2 study, in which we treated 12 patients with SCD with sildenafil for more than 3 months. And we now have 22 patients on sildenafil for almost 3 years. In that study, we reported that it dropped pulmonary pressure; it increased 6-minute walk distance; and it lowered the blood levels of N-terminal brain natriuretic peptide, which is a marker released from the stressed or pressure-overloaded heart. So all of those things suggest a benefit.
We have unpublished data now with 5 patients on bosentan, where we've added bosentan to sildenafil, and it appears to be improving those patients' hemodynamics and exercise performance as well. There have been small series of patients reported by Oswaldo Castro describing the effects of epoprostenol sodium, or prostacyclin, in patients with SCD and PH, where it's been shown to lower the pulmonary vascular resistance.
But we really don't yet have sufficient phase 2/3 data for these treatments in SCD. And that's why these 2 studies that I've mentioned -- the ASSET trial with bosentan, a placebo-controlled, international trial, and the upcoming sildenafil trial at NHLBI -- are absolutely vital studies. We have to begin screening patients around the country and referring patients to these study sites.
Medscape: Part 1 of this 2-part series includes an in-depth discussion on the interactions between PAH and HIV.