Do we need controlled clinical trials in pulmonary arterial hypertension?

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Abstract
Phase III controlled clinical trials (CCT) are required by both the scientific community and Regulatory Agencies as definitive proof of the safety and efficacy of new modalities of treatment. Uncontrolled, small phase II studies are performed at the very beginning of the development of new treatments to confirm the expected effects (proof of concept) and to assess the effective dose (dose finding). A well−designed phase III CCT incorporates elements such as prospective randomization, placebo-control and double-blindness, that ensure the reliability of the results. To increase the chance of success, a pivotal CCT needs an appropriate sample size based on the foreseeable changes of predefined primary end-points. Small, pilot phase III studies are usually required to gauge those changes and to test the appropriateness of the study design. A multicentre cooperation ensures a fast enrolment rate and reproducibility of results. The development of the current treatments of patients with pulmonary arterial hypertension (PAH), defined after the World Health Organization classification 3, have not followed all the golden rules of CCT. In fact, the favourable effect of oral anticoagulant therapy in patients with PPH or pulmonary hypertension associated with anorexigens, is based on the retrospective analysis of single centre studies 4–6. These experiences showed an improvement of survival in the group treated with oral anticoagulant therapy, in comparison to a concurrent nonrandomized, untreated control group. The retrospective design has left some important unanswered questions, such as the optimal level of anticoagulation, that are currently left to the judgment of the physician. On the other hand, the demonstration of the presence of thrombophylic predisposition 7–9 and of thrombotic changes in the microcirculation 10 and the elastic pulmonary arteries 11 of PPH patients, represent a strong rationale for the use of oral anticoagulant therapy in these subjects. In addition, the demonstration of the positive prognostic effect of calcium channel−blocking drugs (CCBs) in vasoreactive PPH patients (15–20% of all PPH patients) has been shown in a single centre, nonrandomized, uncontrolled study 5. In this case, the control group was represented by nonvasoreactive patients that had a worse spontaneous prognosis than vasoreactive patients 12. Therefore, the favourable prognostic effect of CCB treatment shown in the study could have been exaggerated by an inappropriate comparison. The randomization of vasoreactive patients in treated and untreated groups would have given a more reliable demonstration of the positive effect of CCB. On the other hand, the demonstration of a consistent reduction in pulmonary arterial pressure by pharmacological test, as observed in vasoreactive patients, poses ethical questions about giving a placebo instead of CCB in these subjects. Unfortunately, the results of this study have occasionally been extended in clinical practice to nonvasoreactive patients or to patients not acutely tested. In fact, it is common experience that ∼50% of the PPH population is treated with CCB, whereas only 15–20% of PPH patients are vasoreactive 13. This may reduce the global beneficial impact of CCB treatment in PPH patients, due to the frequent and sometimes severe side-effects of these drugs when administered in nonvasoreactive subjects 13.

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