Prostacyclin and Primary Pulmonary Hypertension

Fortunately, primary pulmonary hypertension is uncommon. Most physicians only know of it from reading in medical school that it is a fatal disease that typically affects young women in the prime of their life and for which no therapy exists. Those who have had to care for affected patients can testify to how it erodes the quality of a patient's life by making the most menial task limited by dyspnea, syncope, and fatigue and how it progresses unabated until the patient succumbs. In the past, experts would feel a profound sense of ambivalence when a patient with the disorder was referred. Although they could provide a correct diagnosis and expert care, they knew that they could do little to alter the clinical course.

In 1982, heart and lung transplantation was reported as a definitive therapy [1]. Although it did provide a glimmer of hope, the few centers experienced in heart and lung transplantation, the long waiting time to receive donor organs, and the high postoperative morbidity and mortality rates painted heart and lung transplantation as a less than ideal therapeutic triumph. Despite this, many physicians felt that a patient should receive heart and lung transplantation at the earliest opportunity after the diagnosis was made.

The medical management has come a long way since those days. In 1987, the use of high doses of calcium channel blockers was reported to reverse the progression of the disease and restore a normal quality of life in approximately 25% of patients [2]. Subsequently, this regimen was also shown to improve survival dramatically [3].

In 1990, prostacyclin used in short-term treatment trials for patients refractory to other therapy yielded positive results [4]. These experiences led to multicenter clinical trials and ultimately the study that Barst and colleagues report in this issue [5].

Prostacyclin provides a great advance in our ability to treat patients with primary pulmonary hypertension. Importantly, it represents a successful strategy to treat an illness characterized by reduced levels of an endothelial cell byproduct [6] with a parenterally administered formulation of that compound. Although the medication is associated with considerable side effects, it is rare for a patient who receives it not to gain a sense of well-being and better exercise tolerance. Although prostacyclin treatment was originally developed to sustain a patient long enough to have transplantation [7], some patients feel so well that they decide to forego transplantation for the time being. Many of the patients receiving therapy return to active work in their vocations.

Prostacyclin is not, however, without shortcomings. Because prostacyclin can only be given as a continuous intravenous infusion, a permanent central venous catheter must be put in place. The infection rate in this current series was substantial, with seven episodes of sepsis in three patients and one fatal episode. The risk for serious infections is not unique to these patients and has been reported in other series of medical therapies for which the placement of long-term central venous catheters is needed [8]; the risk appears to be unavoidable. Barst and colleagues also report nine episodes of catheter thrombosis in five patients. Although these were readily treated with intracatheter thrombolytic agents, this complication does predispose the patient to a risk for subsequent embolization. In patients with a patent foramen ovale and right-to-left shunting, cerebral embolism and stroke could result. The authors also saw eight episodes of “system failures” of some sort related to either the pump device or catheter connections; one episode was fatal.

Barst and colleagues did not address the cost-effectiveness of this therapy. Although the cost of prostacyclin in the United States (currently under Food and Drug Administration review) is unknown, it is likely to be several thousand dollars per patient per month in view of its cost in Europe. This cost is in addition to the expense of an ambulatory pump device and all the necessary intravenous cartridges, lines, and supplies. In this time of scrutinized health care resources, one can no longer assume that third-party insurers will automatically provide coverage for every established treatment if the expense is seen as excessive. Yet, judging from the reported use of prostacyclin in primary pulmonary hypertension, it is clear that prostacyclin improves the quality of life and the survival of affected patients. Although the cost of prostacyclin therapy is high, it may still be less than the cost of hospitalizations for recurrent failure of the right side of the heart for patients not given prostacyclin and the cost of receiving lung transplantation, which would be the only alternative therapy for these patients.

We need to look at less expensive formulations of prostacyclin for clinical use and alternative delivery systems that will be safer, simpler, and less expensive. Until those are developed, it would be difficult to consider prostacyclin as a first-line therapy for all patients or for patients who have minimal or no symptoms. Nonetheless, physicians who care for patients with this disease consider prostacyclin a breakthrough in their ability to treat these patients with a therapy that restores vitality to their daily lives and provides a hope of a better tomorrow.

• Copyright ©2004 by the American College of Physicians