Abstract
After half a century of clinical experience and research, management of pulmonary arterial hypertension remains a challenge. Currently, data to support the use of standard therapies for pulmonary arterial hypertension (oxygen supplementation, diuretics, digoxin, anticoagulation, and calcium channel blockers) are mostly retrospective, uncontrolled prospective, or derived from other diseases with similar but not identical manifestations. In the absence of any further prospective, controlled studies, it is reasonable to use these therapies when they are tolerated. When these therapies are poorly tolerated, however, the threshold for discontinuation should be low.
Pulmonary arterial hypertension (PAH) was first described in 1891 in a case report by Romberg [1]. The term “primary pulmonary hypertension” (PPH) was first used in 1951 when Dresdale and colleagues [2] reported clinical features and hemodynamics of 39 patients. Until approximately two decades ago, before the development of specific PAH therapies, such as prostacyclin analogs, endothelial receptor antagonists, and phosphodiestrase-5 inhibitors, PAH (especially idiopathic [IPAH] or PPH form of PAH) was considered a disease that was universally fatal with a median survival of 2.8 years [3]. An explosion of research and drug development has resulted in the development of several specific PAH therapies (see other articles elsewhere in this issue) [4–21]. Therapies such as oxygen supplementation, calcium channel blockers (CCBs), anticoagulation, digoxin, and diuretics have been in use since long before the development of the newer specific PAH agents. These therapies have been referred to as “standard PAH therapies” or “conventional PAH therapies” [22]. The concept of these standard therapies originated from the experience with other pulmonary and cardiac diseases with similar'but not identical'manifestations in terms of symptoms (eg, edema in congestive left heart failure and use of diuretics) or physiologic observations (eg, hypoxemia in emphysema and use of oxygen supplementation therapy, low cardiac output in left ventricular [LV] systolic dysfunction and use of digoxin, high blood pressure in essential systemic hypertension and use of vasodilators, prothrombotic tendency in venous thromboembolism and use of anticoagulation). These practices were subsequently adopted in the treatment of PAH and right heart dysfunction and failure. None of these therapies is supported by well-designed placebo-controlled trials. Some of these practices are based on marked symptomatic relief or improvement with short-term use (eg, diuretics for edema) or by observations based on acute testing in the laboratory setting (eg, improvement in cardiac output by single administration of digoxin) [23] or from autopsy findings [24–26] (eg, in situ microthrombi in lungs of patients who have PAH and use anticoagulation). Therapies such as anticoagulation have been supported by a few retrospective studies [27,28] and an uncontrolled, single-center prospective study [29] , especially in IPAH [30]. This raises the ethical question of the appropriateness of performing a placebo-controlled trial in these patients. On the other hand, the short-term benefits from diuretics are so obvious that it virtually obviates the need for a clinical trial to validate such benefit. For these reasons it seems unlikely that any large, prospective, clinical trials will examine the role of the standard therapies used in PAH in the near future. Such trials are needed, however. Especially lacking are data about use of standard therapies in PAH other than IPAH (associated [APAH]). It may be possible that in specific populations, these therapies may not be helpful, that they may be less helpful than they are currently considered, or that they may be even harmful.
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