Normal Limits

"Chance is the very guide of life"

"In practical medicine the facts are far too few for them to enter into the calculus of probabilities... in applied medicine we are always concerned with the individual" -- S. D. Poisson

November 19, 2005

NEJM - Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension (Galie et al 2005)

Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monophosphate, thereby enhancing the cyclic guanosine monophosphate�mediated relaxation and growth inhibition of vascular smooth-muscle cells, including those in the lung.

In this double-blind, placebo-controlled study, we randomly assigned 278 patients with symptomatic pulmonary arterial hypertension (either idiopathic or associated with connective-tissue disease or with repaired congenital systemic-to-pulmonary shunts) to placebo or sildenafil (20, 40, or 80 mg) orally three times daily for 12 weeks. The primary end point was the change from baseline to week 12 in the distance walked in six minutes.

This was an impressive international collaboration involving 53 centers in the United States, Mexico, South America, Europe, Asia, Australia, South Africa, and Israel. "Local institutional review boards or independent ethics committees approved the protocol, and written informed consent was obtained from all patients." One may raise the issue that with so many different investigators at different medical centers in different countries using different equipments, are the measurements really comparable? Perhaps there are some systematic differences in their measurements that are not seen because each center on average contributed only 5 patients? I believe that in this case since both the primary outcome (baseline walking distance) and the major baseline characteristic (WHO functional class) are so straightforward to implement, systematic differences, if any, should not be severe (sorry no data to back this one up). The same may not be said of the many secondary hemodynamic outcomes (e.g., mean pulmonary arterial pressure) that are also presented in the paper.

As a trial designed to evaluate the efficacy and tolerability of 3 different doses of sildenafil, the question of multiple comparisons invariably arises--that is, given all the possible statistical tests we could make between the outcomes of patients receiving 0, 20, 40, or 80 mg of sildenafil, how do we control for alpha, the chance that whatever trend is discovered is attributable to chance alone? The statistical solution is to control for the experiment-wise error rate using sequential step-down, closed testing procedure.

A stratified central-randomization scheme was used to assign patients to four treatment groups � those receiving 20, 40, or 80 mg of sildenafil or placebo three times daily � in a 1:1:1:1 ratio. The randomization was stratified with respect to the baseline walking distance (<325 m or >=325 m) and cause of pulmonary arterial hypertension.

Missing data for assessments at week 12 were imputed with the use of the last-observation-carried-forward method.

The change in mean pulmonary-artery pressure and World Health Organization (WHO) functional class and the incidence of clinical worsening were also assessed, but the study was not powered to assess mortality. Patients completing the 12-week randomized study could enter a long-term extension study.

The distance walked in six minutes increased from baseline in all sildenafil groups; the mean placebo-corrected treatment effects were 45 m (+13.0 percent), 46 m (+13.3 percent), and 50 m (+14.7 percent) for 20, 40, and 80 mg of sildenafil, respectively (P<0.001 for all comparisons). All sildenafil doses reduced the mean pulmonary-artery pressure (P=0.04, P=0.01, and P<0.001, respectively), improved the WHO functional class (P=0.003, P<0.001, and P<0.001, respectively), and were associated with side effects such as flushing, dyspepsia, and diarrhea. The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo. Among the 222 patients completing one year of treatment with sildenafil monotherapy, the improvement from baseline at one year in the distance walked in six minutes was 51 m.

As Dr. Hayward et al proposed in Health Affairs, RCTs should present the effects of treatment stratified with respect to multivariate risk models. This allows decision-makers to evaluate the usefulness of the treatment in the common currency of risks and benefits.

In this case, while no multivariate risk prediction model exists for pulmonary arterial hypertension, baseline 6-minute-walk distance and WHO class are of prognostic value. A stratified analysis shows:

Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension.

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