[Pulmonary hypertension treatment: future prospects].

characterized by an increase in pulmonary vascular resistance that leads to a progressive decline in exercise capacity and, with time, to failure of the right ventricle and death. Without treatment, life expectancy is less than 3 years from diagnosis. None of the treatments initially tested (calcium channel blockers, anticoagulants) were able to effect an increase in survival in controlled trials, and only in patients with a positive response to vasodilator tests (who account for no more than a quarter of the total) were there indications of the possibility of improvement. The only option in many cases was lung transplantation, which had less than brilliant success rates even in the best health care facilities. In 1976, while studying thromboxane A2, Moncada et al 4 discovered a molecule that would make a notable change in the course of pulmonary hypertension: prostacyclin. The results of the first randomized trial of this molecule in a small number of patients were published in 1990. The molecule had been renamed epoprostenol, and it was shown to induce a rapid improvement in hemodynamic parameters compared to conventional treatment. It was also associated with an increase in exercise capacity that was maintained at 18 months. Perhaps most noteworthy was that this improvement was independent of the result of vasodilator testing. Six years later came the most important study, in 81 functional class III and IV patients entered into a national registry. In that study D’Alonzo et al followed the patients for 12 weeks and detected a significant improvement in the 2 parameters most clearly associated with a poor prognosis: functional class and exercise capacity as measured by the 6-minute walk test. Thus, we had a treatment that clearly improved the clinical picture of patients affected by this devastating disease. However, the most important question remained: Was it possible to increase survival with epoprostenol? Certain findings from the previous trial—specifically that 8 patients in the control group died compared to none in the group treated with epoprostenol—seemed to suggest that it was. Then came a period in which some small studies were published, but the next important one came in 2002. A total of 162 consecutive patients followed for 36 months were compared with those of the aforementioned historical registry from the 1980s. The comparison was very much in favor of epoprostenol. We thus had a drug that improved quality of life, increased survival, and allowed patients initially placed on waiting lists for lung transplantation to leave those lists. But the news was not all good. Epoprostenol is a difficult-to-manage drug with an extremely short half life that requires continuous intravenous infusion and increasing doses due to a tolerance effect. Its high pH (10.2 to 10.8) after reconstitution, together with the above-mentioned characteristics, requires the use of a central venous catheter, with the risks that entails. More drugs were needed. Prostanoids were a promising direction to go in, and this encouraged research into more stable molecules with a longer half life that would make another route of administration possible. In 1996 a study was published in which iloprost, a derivative of prostacyclin, was used for the first time. During nebulization of the drug a fall in pulmonary resistances occurs together with an increase in cardiac output, with no appreciable changes in systemic blood pressure. This made iloprost the treatment of choice in Germany by the end of the 1990s. Subsequently, the first long-term controlled trials were published. Then, in 2002, the placebo-controlled Aerosolized Iloprost Randomized (AIR) trial was finally published. This trial in a large sample demonstrated the efficacy of nebulized iloprost in improving the quality of life and exercise capacity of patients with pulmonary hypertension. Although its half life is longer than that of epoprostenol and it can be administered in aerosol form, iloprost has several important drawbacks. Perhaps the most important of these is the number of doses and the dosing intervals needed—between 6 and 9 per day—or 1 inhalation every 2 to3 hours, with interruption during the night. For many patients, this represents a considerable disruption to their daily lives. Moreover, in some cases an increase in pulmonary resistances between doses has been observed, leading to right ventricular overload with a decrease in exercise tolerance. Nighttime doses are required by slightly less than 10% of patients. A small ultrasonic nebulizer that is easier to handle than the HaloLite (Profile Therapeutics, Bognor Regis, UK) device initially used is now available. A form of the drug specifically designed for inhalation of the exact dose has now been put on the market, and this has decreased the time needed to administer the drug considerably.