End points in pulmonary arterial hypertension: the way forward

Abstract

Pulmonary arterial hypertension is a rare disease of poor prognosis. Despite its rarity w1,000 patients have been randomised in placebo-controlled trials using novel therapies, including prostacyclin analogues, endothelin receptor antagonists and, most recently, phosphodiesterase 5 inhibitors. Nearly all of these trials have used exercise capacity, measured by the unencouraged 6-min walking distance, as the primary end point and a variety of other measurements as secondary end points. This approach has been productive, leading to the licensing of a number of effective treatments. Future clinical trials, however, will probably assess drug combinations, make comparisons between drugs and include less severely ill patients. It is, therefore, timely to examine the end points used.The authors discussed the various end points that have been used in the past and possible end points that might be used in the future. End points considered included measurements of: exercise capacity, haemodynamics, quality of life, imaging of the right heart and circulation, and chemical markers of pulmonary hypertension.Many of these show promise but will have to be used in parallel and compared with conventional end points such as the 6-min walking distance before their value can be demonstrated convincingly to the regulatory authorities. Pulmonary arterial hypertension (PAH) is a disease of the peripheral pulmonary arteries of varying patho-aetiology. Interestingly, whatever the aetiology, the histology of the vessels is similar, prompting a unified approach to treatment. Initial success was achieved with anticoagulants and calcium channel blockers [1], but calcium channel blockers are effective in v10% of patients. Later, it was found that continuous intravenous epoprostenol was effective even in those who could not use the calcium channel blockers [2]. In 2001 and 2002, w1,000 patients with PAH were entered into placebocontrolled trials [3][4][5][6][7]. Nearly all of these trials have used the unencouraged 6-min walking distance and resting haemodynamics as end points. Results were significant, but not dramatic in physiological terms, with mean increases in 6-min walking distance ranging 17-72 m, and decreases in mean pulmonary artery pressure (Ppa) never exceeding a few millimetres of mercury. Although patients reported improvement, survival remains limited, and none of the newly introduced therapies has yet been shown to reverse the pathological process.Some physicians monitoring clinical trials consider that the end points used may not best adequately represent the effectiveness of therapy. It is likely that placebo-controlled trials will become unacceptable and, in the future, more backto-back comparisons of different therapies and also comparisons of different combinations of therapy will be introduced. In order to convince patients, physicians, funding agencies and regulatory bodies of the value of treatments which are often expensive, it is worth considering whether other end points should be examined that more adequ...

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