Pulmonary arterial hypertension (PAH) is a fatal disease characterized by progressive narrowing of the resistance pulmonary arteries leading to right ventricular failure and ultimately death Citation[1]. PAH can be idiopathic, hereditable or associated with connective tissue disease, congenital heart disease, portal hypertension, HIV or anorexigen use Citation[1]. For years the main epidemiologic reference for the disease has been used as the gold standard to prognosticate survival. With the rapid insurgence of research, there are now nine US FDA-approved therapies (intravenous epoprostenol, intravenous, subcutaneous and inhaled treprostinil, inhaled iloprost, and oral bosentan, ambrisentan, sildenafil, and tadalafil) and this equation may no longer be valid Citation[1]. It is now time to re-evaluate the data.
The landmark registry developed in 1980, the NIH registry, evaluated patients with primary pulmonary hypertension (PPH), which represents idiopathic, familial and anorexigen-related PAH under the recent WHO classification. The NIH registry prospectively collected data on 187 patients with PPH from 32 centers in the USA between July 1981 and September 1985, and described the clinical characteristics of PPH and its natural history over a 7-year period in an era when there were no approved PAH-specific therapies Citation[2,3]. Patients had a median survival time of 2.8 years with 1-, 3- and 5-year survival rates of 68, 48 and 34%, respectively. Mortality correlated with baseline mean right atrial pressure, mean pulmonary artery pressure and cardiac index, the indices of right ventricular function Citation[2].
The NIH registry proposed an empirically derived regression equation, based on baseline hemodynamics, to predict survival in patients with PPH:
where P(t) indicates patient’s chance of survival; t = 1, 2 or 3 years; x = mean pulmonary artery pressure; y = mean right atrial pressure and z = cardiac index. The probabilities of survival at 1, 3 and 5 years, respectively are as follows: P(1) = 0.75A, P(3) = 0.55A and P(5) = 0.43ACitation[2]. This equation was subsequently validated by Sandoval et al. in a small Mexican cohort of 61 patients with PPH Citation[4]. As PAH is a highly fatal disease, for ethical reasons there have been no long-term randomized clinical trials with a placebo-control arm. This equation is the current standard to assess therapeutic benefit. Many clinical trials without a placebo-control arm have used the NIH equation to suggest improvement in survival by comparing observed survival rates on a study drug versus survival rates predicted by the NIH equation Citation[5–10].
Several contemporary registries of patients with PAH have observed improved survival in the current era compared with the NIH registry, questioning the validity of the NIH equation as an accurate predictor of survival in patients with idiopathic, familial and anorexigen-associated PAH. The French registry collected data on 674 patients with PAH in 17 university hospitals in France and reported a 1-year survival of 88% in patients newly diagnosed with PAH between October 2002 and October 2003. The 1-year survival rate of patients similar to the NIH registry was much improved (89 vs 72%) Citation[11]. Subsequently, the Pulmonary Hypertension Connection’s (PHC) registry, which collected data on 576 PAH patients referred to a single US practice from 1982 to 2006, observed similar improved survival rates. The actual 1-, 3- and 5-year survival rates of the patients with PAH were 84, 67 and 58%, respectively. Similar to the French registry, prospective 1-year survival improved versus the calculated survival by the equation, 85 versus 88%, respectively Citation[12]. The observed 1-, 3- and 5-year survival rates (92, 75 and 66%, respectively) were significantly greater than the predicted 1-, 3- and 5-year survival rates calculated using the NIH equation (65, 43 and 32%, respectively; p < 0.0001 for all comparisons)Citation[13]. In further support, the Swiss registry collected data on 252 patients referred between January 1999 and December 2004, and also reported improved survival in patients with PAH similar to the French and PHC Registries Citation[14].
The reasons for improved survival in PAH patients in the current era are unclear and are hypothesis driven. First, the number of PAH patients referred to tertiary care centers has increased when compared with the NIH registry time period, and physicians are more familiar with treating right heart failure. Second, improved survival may be a result of the greater use of anticoagulation with warfarin. PAH treatment guidelines recommend warfarin for patients with idiopathic, familial and anorexigen-associated PAH Citation[15]. Finally, the improved long-term survival in PAH patients is perhaps due to the availability of PAH-specific therapies Citation[15]. Several large observational retrospective studies showed improved long-term outcomes with intravenous epoprostenol, subcutaneous treprostinil and oral bosentan in comparison to either historical controls or in comparison to the estimated survival calculated using the NIH equation Citation[5,8,9,16,17]. Two recent meta-analyses that evaluated the effect of PAH-specific therapy on short-term survival (~13–16 weeks) suggest a reduction in mortality when all treatment strategies are pooled together, but no individual class of drug produced a statistically significant reduction in mortality Citation[18,19]. However, there are no long-term randomized, placebo-controlled treatment trials with any approved therapy for PAH; only the pivotal epoprostenol trial demonstrated survival prospectively Citation[15].
Since the NIH equation appears to underestimates survival, we developed a new regression equation, the PHC equation, to predict survival in patients with idiopathic, familial, and anorexigen-associated PAH in the current era:
where P(t) = probability of survival; t = number of years after diagnosis; x = mean pulmonary artery pressure; y = mean right atrial pressure; and z = cardiac index Citation[13]. The PHC equation was derived using exponential regression in 249 patients with idiopathic, familial and anorexigen-associated PAH referred to a single US center from 1991 to 2007. Patients diagnosed with PAH before 2004 were included retrospectively, and those who were diagnosed after 2004 were studied prospectively. After extensive modeling, suprisingly the PHC equation uses the same three baseline hemodynamics (mean right atrial pressure, mean pulmonary artery pressure and cardiac index) as the NIH equation, albeit with different coefficients. Since patients with positive acute vasodilatory response have a much better survival compared with nonresponders Citation[20], a separate equation for responders was developed. When applied to other published PAH cohorts, the predicted survival calculated using the PHC’s equations was comparable to the actual observed survival Citation[13].
Admittedly, the PHC equation needs to be validated prospectively in another idiopathic, familial and anorexigen-associated PAH cohort. Once prospectively validated, this equation could be used to estimate contemporary survival in patients with idiopathic, familial and anorexigen-associated PAH. In addition, the PHC’s equations could potentially be used in clinical and research settings to determine response to therapy and changes in prognosis that occur with changes in invasive hemodynamic profile. Survival in WHO category I PAH patients as a whole should not be evaluated using these equations, since congenital heart disease-associated PAH carries a better prognosis, and connective tissue disease-associated PAH carries a worse prognosis than other forms of PAH Citation[21,22]. The PHC equation was developed based on a heterogeneous patient collection on a variety of PAH-specific therapies. Thus, it may not be useful for demonstrating improved survival with a new drug in clinical trials, but may be helpful for clinical prognostication. The equation needs to be let out of the gate. The test will be in the hands of the pulmonary hypertension physicians.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- McLaughlin VV, Archer SL, Badesch DB et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J. Am. Coll. Cardiol.53(17), 1573–1619 (2009).
- D’Alonzo GE, Barst RJ, Ayres SM et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann. Intern. Med.115(5), 343–349 (1991).
- Rich S, Dantzker R, Ayres S et al. Primary pulmonary hypertension: a national prospective study. Ann. Intern. Med.107, 216–223 (1987).
- Sandoval J, Bauerle O, Palomar A et al. Survival in primary pulmonary hypertension. Validation of a prognostic equation. Circulation89, 1733–1744 (1994).
- Barst RJ, Galie N, Naeije R et al. Long-term outcome in pulmonary arterial hypertension patients treated with treprostinil. Eur. Respir. J.28(6), 1195–1203 (2006).
- Kuhn KP, Byrne DW, Arbogast PG et al. Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am. J. Respir. Crit. Care Med.167(4), 580–586 (2003).
- McLaughlin VV. Survival in patients with pulmonary arterial hypertension treated with first-line bosentan. Eur. J. Clin. Invest.36(Suppl. 3), 10–15 (2006).
- McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation106(12), 1477–1482 (2002).
- McLaughlin VV, Sitbon O, Badesch DB et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur. Respir. J.25(2), 244–249 (2005).
- Provencher S, Sitbon O, Humbert M, Cabrol S, Jais X, Simonneau G. Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension. Eur. Heart J.27(5), 589–595 (2006).
- Humbert M, Sitbon O, Chaouat A et al. Pulmonary arterial hypertension in France: results from a national registry. Am. J. Respir. Crit. Care Med.173(9), 1023–1030 (2006).
- Thenappan T, Shah SJ, Rich S et al. A USA-based registry for pulmonary arterial hypertension: 1982–2006. Eur. Respir. J.30(6), 1103–1110 (2007).
- Thenappan T, Shah SJ, Rich S, Tian L, Archer SL, Gomberg-Maitland M. Contemporary survival in patients with pulmonary arterial hypertension: a reappraisal of the National Institutes of Health risk stratification equation. Eur. Respir. J.35(5), 1079–1087 (2009).
- Fischler M, Speich R, Dorschner L et al. Pulmonary hypertension in Switzerland: treatment and clinical course. Swiss Med. Wkly138(25–26), 371–378 (2008).
- Badesch DB, Abman SH, Simonneau G, Rubin LJ, McLaughlin VV. Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest131(6), 1917–1928 (2007).
- Sitbon O, Humbert M, Nunes H et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J. Am. Coll. Cardiol.40(4), 780–788 (2002).
- Sitbon O, McLaughlin VV, Badesch DB et al. Survival in patients with class III idiopathic pulmonary arterial hypertension treated with first line oral bosentan compared with an historical cohort of patients started on intravenous epoprostenol. Thorax60(12), 1025–1030 (2005).
- Galie N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur. Heart J.30(4), 394–403 (2009).
- Macchia A, Marchioli R, Tognoni G et al. Systematic review of trials using vasodilators in pulmonary arterial hypertension: why a new approach is needed. Am. Heart J.159(2), 245–257 (2010).
- Sitbon O, Humbert M, Jais X et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation111(23), 3105–3111 (2005).
- Kawut SM, Taichman DB, Archer-Chicko CL, Palevsky HI, Kimmel SE. Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest123(2), 344–350 (2003).
- Fisher MR, Mathai SC, Champion HC et al. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum.54(9), 3043–3050 (2006).