Standard Therapies For Pulmon... Health Article

Anticoagulation

Currently no prospective, randomized, placebo-controlled trials are available to provide evidence for or against the use of anticoagulation in patients who have PAH. Currently, it is a widely accepted practice to use anticoagulation in patients who have PAH (WHO group I [35]) unless there is a contraindication.

Patients who have significant PAH may have a sedentary lifestyle. Venous engorgement and stasis (as a result of elevated right atrial pressures) and poor flow through pulmonary and systemic circulations as a consequence of low cardiac output place them at increased risk for developing venous thromboembolism. The pulmonary vascular bed is already significantly compromised in patients who have PAH by the time they become symptomatic and the diagnosis is made. As a consequence, even a relatively minor pulmonary embolic event has more significant hemodynamic and gas exchange consequences and may be life threatening.

Substantial evidence from human studies of biochemical and serologic markers suggests presence of a prothrombotic state in patients who have PAH. Three key elements that influence existence of a prothrombotic state are endothelial function, platelet activation, and plasma proteins related to coagulation and fibrinolysis. Certain components of these three elements have been shown to have aberrant behavior favoring a prothrombotic state in several human studies involving patients with idiopathic and associated forms of PAH ( Table 4) [85–93]. The evidence of these prothrombotic abnormalities is more robust in IPAH and chronic thromboembolic pulmonary hypertension (CTE-PHT) than most other forms of PAH. Some of these abnormalities have been shown to reverse with specific PAH therapies, such as intravenous prostacyclin [94–97] or bosentan [98].

Theoretical concerns about importance of thromboembolism are supported by various early observations ( Table 5) [24–26,99,100].

Retrospective [27,28,101] clinical studies and a small prospective [29] , noncontrolled, nonrandomized clinical study of PPH patients has shown that use of anticoagulation with warfarin seems to confer a survival advantage in patients who have PPH ( Table 6) [27–29,101–103]. In PAH, other than IPAH, the evidence—either basic science or clinical—for or against the use of anticoagulation is even scarcer (with the exception of CTE-PHT, in which the need for chronic anticoagulation is well established). Because there are many similarities in the clinical course, hemodynamics, and histopathology of these and IPAH patients, the practice of anticoagulation has been extended to other forms of PAH. It should be noted, however, that the risk of bleeding complication ( Table 7) and need for anticoagulation ( Box 2) may differ in other causes of APAH [104].

There are no data from human studies as to whether there is any difference in terms of efficacy among various anticoagulation agents such as warfarin, unfractionated heparin, or low molecular weight heparins. Warfarin is the most commonly used agent for anticoagulation in patients who have PAH. Substantial data from animal studies suggest that heparin may have some additional therapeutic advantage in subjects with PAH. Human studies, however, have not been performed to support this theoretical superiority. Heparin has been shown to prevent development of PAH and RV hypertrophy in animal models (hypoxic mice or guinea pig model of PAH) [105,106]. The mechanism of action of heparin on pulmonary vasculature is not completely understood. Proposed mechanisms include inhibition of platelet-derived growth factor [105] and inhibition of pulmonary artery smooth muscle cell growth, probably by upregulation of expression of cell cycle regulation of gene p27, which influences the level of cyclin-dependent kinase inhibitor [107]. Cyclin-dependent kinase and cyclin-dependent kinase inhibitor play key roles in the balance between cell proliferation and cell quiescence. Research also has shown in animal models that anticoagulation with warfarin does not have the same effect as that of heparin to protect animals from developing PAH upon prolonged exposure to hypoxia [108]. O-hexanoyl low-molecular-weight heparin derivatives have been shown to be more effective in growth inhibition of bovine pulmonary artery smooth muscle cells in culture than heparin [109]. Because of such observations, the authors concluded that heparin derivatives may be envisioned as potential future PAH therapy. Currently, there are no human clinical data to support the use of heparin or heparin derivatives instead of warfarin in patients who have PAH.

In clinical practices, warfarin has been the agent most frequently used. Target international normalized ratio (INR) in most US centers is between 1.5 and 2.5 and in many European centers it is 2.0 to 3.0. Both approaches are based on expert opinions, weighing potential benefits of therapy versus risk of bleeding complications with higher target INR [110]. It may be appropriate to keep INR > 2.0 in the following situations:

1. In any patient in whom there exists a clinical indication for anticoagulation (eg, atrial fibrillation, CTE-PHT, acute recent venous thromboembolism, or prosthetic valve)

2. In patients with remote history of idiopathic venous thromboembolism

3. In patients in whom ventilation-perfusion (V/Q) scans or PA angiograms are not consistent with chronic pulmonary thromboembolic disease (CPTED) but who have at least one subsegmental mismatched defect or diffusely decreased tracer uptake in certain subsegments or in whom PA angiograms are unequivocal for the absence of CPTED

4. In patients with history of ischemic stroke or transient ischemic attack with known right-to-left shunt

The role of antiplatelet agents such as aspirin and clopidogrel has not been thoroughly evaluated. A recent preliminary randomized, double-blind, placebo-controlled, crossover study of 19 patients who have IPAH explored the biochemical effects of clopidogrel and aspirin on inhibition of platelet aggregation eicosanoid metabolism [111]. The study represents the first well-structured, placebo-controlled trial to evaluate biochemical effects of antiplatelet agents in patients who have IPAH. The study showed that both drugs inhibit platelet aggregation in patients who have IPAH. Arachidonic acid–induced platelet inhibition was more completely blocked by aspirin, whereas ADP-induced platelet aggregation was more effectively blocked by clopidogrel. Only aspirin inhibited thromboxane metabolite production without affecting prostaglandin I2 metabolite synthesis, thus restoring normal eicosanoid balance.

Empiric anticoagulation may be considered if clinical suspicion of PAH is moderate to high and an echocardiogram shows an estimated pulmonary artery pressure >60 while the patient is undergoing evaluation [112]. When an interruption in anticoagulation therapy is required, such as before a surgical procedure, in the absence of any other indication for anticoagulation warfarin may be stopped 5 to 7 days before the procedure and restarted after the procedure when the increased risk of bleeding has resolved, without any overlap with intravenous heparin or subcutaneous low molecular weight heparin. When the INR is <1.5, appropriate deep venous thrombosis prophylaxis should be instituted when patients are hospitalized or as appropriate for the patient's clinical status [113].