Registries and randomised controlled trials in pulmonary arterial hypertension: are they revealing?

Authors


Mardi Gomberg-Maitland, Pulmonary Hypertension Center, 5841 S Maryland Ave MC5403, Chicago, IL 60637, USA
Tel./Fax: + 773 702 5589
Email: mgomberg@medicine.bsd.uchicago.edu

In the 1960s, a rare disease became briefly more common with the introduction of the diet pill, aminorex. Increased cases of pulmonary hypertension were noted and mirrored the increase in prescriptions for the drug. This prompted the first WHO symposium on primary pulmonary hypertension (PPH) in Geneva in 1973. The leaders initiated the meeting to “shed some light” on this poorly understood orphan disease and to chart the direction for further research and understanding. This ultimately led to the NIH registry in the United States conducted from 1981 to 1988. This was the first national registry and remains the benchmark study to which all subsequent comparisons of survival outcomes in pulmonary hypertension is compared. The NIH registry enrolled 194 patients, focused explicitly on PPH and included both incident and prevalent cases. It demonstrated a female predominance that has been consistently seen in subsequent registries. The mean age at diagnosis was 35 years and the median survival was 2.8 years. It indicated that patients present late with 75% experiencing NYHA FC III or IV type symptoms at diagnosis. Despite advances in our understanding and enhanced availability of screening technologies such as echocardiography, subsequent registries have also confirmed this late presentation. One finding from the NIH registry that appears to have definitively changed over the past two decades is that patients appear to be older, with the mean age moving from the mid 30s to late 40s.

Subsequent to the NIH registry, a number of other registries emerged including the anorexigen-focused IPPHS study in Europe and SOPHIA in North America. More recently, national registries from France, China, Scotland as well as the United States have confirmed that it is an uncommon disease, but not as rare as previously thought. Curious discrepancies have emerged across the Atlantic with significantly more women registered in the US REVEAL database in US than in the French national registry.

Clinical trials do provide, however, a source of information on demographics and outcomes in pulmonary hypertension. The second WHO symposium in 1998 held in Evian, France, brought the PH community together for a historical reclassification of the disease. By redefining the classification along clinical grounds, the former PPH was grouped under the new heading pulmonary arterial hypertension (PAH) along with other histologically similar causes of pulmonary vascular disease including PAH associated with connective tissue disease and congenital head disease. This prompted the beginning of multiple randomised controlled trials (RCTs) and resulted in the discovery and approval of therapies in three distinct pathways. However, although each trial has been relative small and patients carefully selected, a recent meta-analysis allowed for the pooling of data from these trials. This has led to very useful epidemiological data that are surprisingly perhaps, closely concordant with the information emerging from registries. The argument against the validity of clinical trial information is that the patients are carefully selected, more stable than and not as sick as real-life patients and therefore that the clinical trials predominately include prevalent cases. On the other hand, patients with good walk tests (> 400 m) are generally excluded, thereby counteracting in part the more positive selection bias that is assumed.

The meta-analysis reviewed all trials over an 18-year period (1990–2008) and included 23 trials with a total of 3199 patients, for an average duration 14.3 weeks. Women made up 79% of study participants, which would be considered a positive bias (65% women in French registry). Interestingly, 75% of the trial participants had NYHA FC III-IV symptoms, which compares favourably with 75% in the French Registry, 80% in the Chicago Pulmonary Hypertension Connection registry and 75% in the NIH Registry. Despite the relatively short study period in these trials, the all-cause mortality rate in the control group was 3.8% suggesting that the patients selected in RCT’s are indeed very sick. Extension studies from a number of these RCT’s have demonstrated improved outcomes over historical controls of 71–88% survival at 2–3 years [BREATH-1 Long-term (3 years), SUPER-2 Long-term (3 years), AIRES-E Long-term (2 years), SC Treprostinol (3 years)]. These results are in keeping with the French national registry data, the Chicago registry and the REVEAL registry regarding prevalent cases.

Survival has improved in current registry data; the cause for improvement unfortunately is unclear and is hypothesis driven. For example, similar to the French Registry prospective 1 year survival improved in the PH Connection registry (85% and 88%) compared to the calculated survival by the NIH equation. However, there are no long-term randomised, placebo-controlled treatment trials with any approved therapy for PAH; only the pivotal epoprostenol trial demonstrated survival prospectively. New equations and risk assessment tools are emerging that not only have potential to provide prognostic information to the patient and their physicians, but if validated may be used as markers for therapeutic response and tools to stratify patients in clinical trials.

The need for a large global database is critical for the future of our understanding and management of this disease. As this is an orphan disease, to gain the data needed to determine the intrapatient and interpatient genetic and environmental susceptibilities and differences between PAH aetiologies, a global initiative is the best method to acquiring sufficient numbers of patients for valid associations, trends and biomarker determination.

Conclusion

Evidence from clinical trial and registry data generated from the PH community is significant, but our knowledge is still at an early stage. Incident vs. prevalent is important distinction when analyzing registry data. Survival is improved, but the mechanisms are likely multifactorial and perhaps epigenetic. A global initiative is warranted to increase our understanding of this orphan disease.

Disclosure

The authors have no disclosures directly related to this editorial. Dr. Gomberg-Maitland has received research grant support from Acteloin, Gilead, Lilly/Icos, Novartis, Pfizer, and United Therapeutics and has served as a consultant/steering committee member for Gilead, Medtronic, Pfizer, and United Therapeutics. She has received money for organizing education from AB Comm Inc. for CME symposia. She has a patent filed entitled, “Compositions and Methods for Treating Pulmonary Hypertension” for the use of sorafenib in pulmonary hypertension. Dr. Sean Gaine has received research grant support from Actelion and Pfizer and has received speaker and advisory honoraria from Novartis, United Therapeutics, Actelion, GSK, Pfizer, and United Therapeutics. WO/2007/087575