Hemodynamics in pulmonary arterial hypertension (PAH): do they explain long-term clinical outcomes with PAH-specific therapy?
BACKGROUND
Pulmonary arterial hypertension (PAH) has witnessed dramatic treatment advances over the past decade. However, with the exception of epoprostenol, data from short-term randomized controlled trials (RCTs) have not shown a benefit of these drugs on survival. There remains a need to differentiate between available therapies and current endpoint responses which in turn, could be used to guide treatment selection and provide long-term prognostic information for patients.


METHODS
We performed a systematic literature search of MEDLINE and EMBASE databases for RCTs of PAH-specific therapy published between January 1980 and May 2009. Articles were selected if they contained a placebo comparator and described hemodynamic changes from baseline. We applied the weighted mean change in hemodynamic variables to the equation developed by the National Institutes of Health (NIH) Registry to estimate long-term survival with each therapy.


RESULTS
Ten RCTs involving 1,635 patients met the inclusion criteria. Suitable hemodynamic data were identified for bosentan, sitaxentan, sildenafil, epoprostenol, beraprost and treprostinil. 77.6% of patients were female and the mean (SD) age was 46.5 +/- 4.9 years. 55.5% of patients had idiopathic PAH (iPAH), 23.9% PAH related to connective tissue disease, and 18.2% PAH related to congenital heart disease. Based on the effects observed in short-term trials and, relative to placebo, all analyzed therapies improved survival. The estimated 1-year survival was 78.4%, 77.8%, 76.1%, 75.8%, 75.2%, and 74.1% for epoprostenol, bosentan, treprostinil, sitaxentan, sildenafil, and beraprost, respectively. These estimates are considerably lower than the 1-year observed survival reported in several open-label and registry studies with PAH-specific therapies: 88% - 97%.


CONCLUSIONS
When applied to the NIH Registry equation, hemodynamic changes from baseline appear to underestimate the survival benefits observed with long-term PAH therapy.
Steele
Peter
P
Department of Epidemiology and Preventative Medicine, Monash University, Melbourne, VIC, Australia.
Strange
Geoff
G
Wlodarczyk
John
J
Dalton
Brad
B
Stewart
Simon
S
Gabbay
Eli
E
Keogh
Anne
A
D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D015331:Cohort Studies; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology*; D007555:Isoxazoles / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use; D011687:Purines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000627:therapeutic use; D013450:Sulfones / Q000627:therapeutic use; D013876:Thiophenes / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D007555:Isoxazoles; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D013876:Thiophenes; D000068677:Sildenafil Citrate; D011464:Epoprostenol; C106276:sitaxsentan; D000077300:Bosentan; C427248:treprostinil