Pulmonary Vascular Conditions

History and Physical Examination

Although no single history or physical finding is pathognomonic for PE, the history and physical examination are important diagnostic starting points. Much of the PE diagnostic algorithm is influenced by the pretest probability of PE, which is highly influenced by these clinical findings. The sudden onset of dyspnea is most associated with PE,3,4,5 and indeed is 1 of 3 syndromes in which PE may present: dyspnea, pulmonary infarct or hemorrhage, and circulatory collapse. However, dyspnea might not be present in up to 25% of patients with PE.

Many patients with PE present with some component or components of the pulmonary infarct/hemorrhage syndrome, including hemoptysis, pleuritic chest pain, lung consolidation, small pleural effusions, and/or a pleural friction rub.5 Roughly 10% to 15% of patients with acute PE present with circulatory collapse; the mortality rate with this presentation is high.5,6 Patients who die from PE typically fall into this category; most deaths attributable to PE occur within the first hour after the event.

Additional history often reported with PE includes chest pain, a sense of impending doom, syncope, or near syncope. Of importance, some patients with PE might have few symptoms, particularly in the setting of underlying cardiopulmonary disease. Other physical findings, though nonspecific, include tachycardia and tachypnea.4,7

Because PE is part of a spectrum of venous thromboembolic disease that also includes DVT, signs and symptoms of DVT also are important. Possible findings include lower extremity edema (unilateral or bilateral), Homans sign (calf pain with flexion of the knee and dorsiflexion of the ankle), or Moses sign (calf pain with compression of the calf against the tibia). DVT, especially when located in the pelvic veins, can be asymptomatic.

Electrocardiogram

Electrocardiogram (ECG) findings are nonspecific, but can be supportive of the diagnosis in the right clinical setting. The classic finding is the S₁Q₃T₃ pattern indicative of right heart strain, manifested by a large S wave in lead I, Q waves in lead III, and inverted T waves in lead III. Sinus tachycardia, atrial arrhythmia, right bundle-branch block, and even normal ECG results may be seen.8 Findings are nonspecific and PE can be neither confirmed nor excluded by ECG findings alone.

Laboratory Tests

There has been great interest in the use of serum markers for diagnosing acute thromboembolic disease. D-dimers are fibrin degradation products of thrombolysis. A highly sensitive D-dimer assay is useful in excluding PE when valid clinical scores indicate a low pretest probability. Studies have shown that in the outpatient setting, in a patient with a low (and perhaps intermediate) clinical suspicion of PE, a negative D-dimer test result effectively excludes PE; such patients can be safely discharged without further imaging or testing.9 However, the D-dimer test has not been similarly validated for inpatients or outpatients with a high clinical suspicion of PE. In those patients, a D-dimer assay should not be obtained because its value is limited. D-dimers can be nonspecifically elevated in many situations, including recent surgery, trauma, burns, pregnancy, and infection.

Echocardiography

An echocardiogram can be used in the diagnosis of PE and to stratify risk of patients with PE. A clot in the right atrium might reflect thrombus in transit, and patients with acute PE might have a dilated, hypokinetic right ventricle. This contrasts with chronic thromboembolic disease in which the right ventricle is typically hypertrophied. Central venous pressure can be elevated. Some findings, such as right ventricular hypokinesis, are associated with increased mortality risk. Use of the echocardiogram in the management of massive PE is discussed below.

Imaging

Because most PEs are the consequence of thrombi migrating from the deep venous system of the lower extremities, a relatively cost-effective, safe, and noninvasive approach to PE diagnosis is to begin with a Doppler ultrasonography of the lower extremities. A positive study result indicates the presence of venous thromboembolic disease and treatment can be initiated on this basis. In hemodynamically stable patients, further pulmonary imaging will not change management and can be avoided. However, many patients will have negative study results (or ultrasonography might be unavailable), in which case thoracic imaging is indicated.

The mainstay of imaging for PE is a multidetector helical computed tomography pulmonary angiography (CTPA) of the chest using contrast. Sensitivity and specificity of helical CTPA for PE (when adequate images are obtained) are 83% and 96%, respectively (positive likelihood ratio = 20.7, negative likelihood ratio = 0.18).10 These test result characteristics can vary by reader and available technology. The diagnostic value of the test should improve as computed tomography (CT) resolution improves (eg, 64-slice, 128-slice).

In patients who are allergic to contrast, have renal insufficiency, or are otherwise unable to undergo chest CT, ventilation-perfusion (V/Q) scanning is a reasonable alternative. The landmark Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, which was 1 of the only studies to use pulmonary angiography as the gold standard, showed V/Q scanning to be potentially useful in patients with normal (rare), low probability, and high probability V/Q scans. However, the V/Q scan is highly dependent on pretest probability, and a number of low-probability and high-probability studies might be falsely negative or positive, respectively. Intermediate-probability studies, which seem to be the most common interpretation, have wide variability in diagnostic accuracy, limiting their usefulness.4

Pulmonary angiography remains the gold standard for the diagnosis (or exclusion) of PE, though it is rarely performed anymore. It should be considered in patients who are thought to be at high risk of PE and/or high risk of complications from PE in whom other study results are negative or inconclusive.

Prediction Rules

Most diagnostic protocols begin with a clinical assessment of the probability that the patient has experienced a PE; this information also is critical to interpretation of imaging studies. Although probability assessment can be performed on clinical grounds, many prediction rules have been developed for this purpose using readily available data. The Wells Clinical Prediction Rule is one such tool and is summarized below:11

• Clinical signs and symptoms of DVT – 3 points

• An alternative diagnosis is less likely than PE – 3 points

• Heart rate greater than 100 beats/min – 1.5 points

• Immobilization or surgery in past 4 weeks – 1.5 points

• Previous DVT or PE – 1.5 points

• Hemoptysis – 1.0 point

• Malignancy (receiving treatment, treated in past 6 months, or palliative therapy) – 1.0 point

If the patient scores less than 2 points, there is a low probability of PE. With 2 to 6 points, there is an intermediate probability; with more than 6 points, a high probability. In general, a D-dimer assay is obtained for patients with low probability of PE9; a negative D-dimer result rules out PE (no further testing or treatment indicated) and a CTPA is obtained for patients with low probability and a positive D-dimer result and for those at intermediate or high clinical probability. Negative CTPA results rule out PE; patients with positive CTPA results are treated for PE; those with intermediate CTPA results require additional testing.

Anticoagulation for Acute Pulmonary Embolism

Anticoagulation should be initiated rapidly, even empirically in patients with a moderate to high pretest probability of PE and low risk of major bleeding, while imaging studies are being performed. Heparin, discovered in the early 1900s, is the drug with which physicians have the most experience; it was the mainstay of immediate therapy for nearly a century. Of interest, despite its widespread use, only 1 randomized controlled trial involving 35 patients with acute PE has been performed.6 Outcomes are improved if therapeutic anticoagulation is achieved within 24 hours,12 and weight-based dosing protocols of unfractionated heparin (UFH) are used in many institutions to reach this goal.

Low-molecular-weight heparin (LMWH) is discussed in more detail in the following section, but many features make it appealing for anticoagulation in acute PE. Dosing is weight-based, and therapeutic levels are reached quickly. There is no routine laboratory monitoring required, though in certain circumstances (eg, pregnancy, morbid obesity) monitoring anti-Xa levels may be helpful. The incidence of heparin-induced thrombocytopenia is lower than that with UFH. Unless there are contraindications, LMWH is the preferred anticoagulant for initial use. Initial anticoagulation with UFH or LMWH should be continued for at least 5 days, and for 24 hours after the international normalized ratio is 2.0 or more.13

Massive Pulmonary Embolism

One of the more controversial topics in PE management is the patient with massive PE. The controversy begins with the definition of massive PE. This typically does not refer to anatomically massive PE with the presence of multiple emboli or large saddle emboli, but rather PE that leads to hemodynamic compromise. In addition to anticoagulation and supportive care, patients with massive PE might benefit from more aggressive interventions, such as thrombolysis to quickly decrease clot burden and reduce afterload on an acutely impaired right ventricle.

Thrombolysis results in less clot burden at 24 hours versus anticoagulation alone but has not been shown to influence mortality. Bleeding complications in some studies were increased, but a recent Cochrane review did not concur.14 Most experts agree that thrombolysis should be considered in patients without contraindications who are in shock or cardiopulmonary arrest from PE.

Another study examined the role of thrombolysis in hemodynamically stable patients with right ventricular strain on echocardiogram after a PE.15 Thrombolysis decreased the rate of secondary (or rescue) thrombolysis, but did not change mortality or other key parameters. There were fewer bleeding complications than those noted in other studies. Though there is disagreement among experts, it would seem that thrombolysis is not clearly indicated in this patient population. A Cochrane review could not determine whether thrombolytic therapy was better than heparin in submassive PE.14 However, a significant number of patients with right ventricular strain does develop hemodynamic deterioration; this suggests a need for close monitoring.

In patients who are not candidates for thrombolysis because of unacceptably high bleeding risk, specialized centers might be able to perform mechanical thrombolysis by means of interventional radiology or cardiology. Alternatively, emergent embolectomy can be performed by an experienced cardiothoracic surgeon (a procedure that often carries a high mortality risk, though admittedly with selection bias).

Risk Stratification

Risk stratification of the patient with acute PE is necessary to identify those at high risk of adverse outcomes during hospitalization. In addition to hemodynamic instability and right ventricular dysfunction, laboratory evidence of myocardial injury portends a poor prognosis. At least 2 meta-analyses have suggested a substantial increased risk of mortality from PE and short-term risk of all-cause mortality in these patients.16,17 Likewise, another study demonstrated that increased levels of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide were associated with an increase in adverse events.18

Inferior Vena Cava Filters

Inferior vena cava filter placement typically is indicated in patients who have not benefited from anticoagulation or have a contraindication to anticoagulation.19 Controversial indications include patients with large pulmonary clot burden who still have residual lower extremity clot and patients with severe cardiac or pulmonary disease who have no reserve to tolerate another event.

Complications include vein perforation and filter migration or obstruction with clot, though all are rare. The incidence of recurrent PE is decreased with inferior vena cava filter placement, but at the cost of an increased DVT rate at 1 year.20 If the filter becomes occluded, collateral vessels may form around the filter, allowing a thrombus to bypass the filter and PE to occur. The long-term effects of these filters are unknown and caution should be taken when placing them in young patients who may have them for a lifetime. Newer filters, designed to be removed within weeks or months of placement, are a possible alternative in these patients.

Long-Term Anticoagulation

The only option for long-term oral outpatient anticoagulation is warfarin, which antagonizes vitamin K-dependent clotting factors II, VII, IX, and X. Warfarin can be started on the first day of anticoagulation concurrently with UFH or LMWH. UFH or LMWH should be continued for a total of at least 5 days and for 24 hours after achieving a therapeutic international normalized ratio.13 Warfarin should not be started without concurrent heparin, because there is a paradoxical initial procoagulant period before the anticoagulant effects of warfarin.

Duration of anticoagulation depends on the setting of the PE, whether it was provoked or not, and the presence or absence of hypercoagulable states, including malignancy (Table 1). Patients with a PE in the setting of malignancy, for example, should receive 3 to 6 months of anticoagulation with LMWH, followed by warfarin indefinitely or until the cancer is in remission.13

Case 1, cont’d. You are asked if you want to obtain a D-dimer test for June. You think she has a very high clinical probability of pulmonary embolism (PE), and explain that this test is not useful in this setting. After checking renal function, a therapeutic dose (1 mg/kg) of low-molecular-weight heparin (LMWH) is administered subcutaneously, and a helical computed tomography pulmonary angiography is obtained, the findings of which demonstrate several large PEs. June is hemodynamically stable, with no indication for thrombolysis. Despite the radiographic appearance of the clot, an emergent echocardiogram in the emergency department reveals no right ventricular strain. She is admitted to the hospital and continued on LMWH. She improves over several days and is discharged home receiving LMWH.

Limitations of Current Anticoagulants

Unfractionated heparin and VKAs have 3 general limitations. Both have a narrow therapeutic window of effective anticoagulation without the risk of bleeding or recurrent thrombosis. Laboratory monitoring is required to ensure dosing within this therapeutic window. Finally, the therapeutic dose of these drugs is highly variable among patients, depending on genetics and multiple other factors.21

For example, UFH inadvertently binds endothelial cells and a variety of serum proteins that negatively influence its bioavailability and anticoagulant effect. Some of these proteins are platelet-derived, and can potentially lead to a life-threatening immune response called heparin-induced thrombocytopenia (HIT). In addition, heparin cannot effectively inactivate fibrin-bound thrombin within a thrombus, and a clot may continue to propagate despite a presumed therapeutic dose.21,22 As a result, newer anticoagulants have been developed with improved bioavailability that enhance efficacy and frequently are easier to administer without the need for monitoring.

Low-Molecular-Weight Heparin

Low-molecular-weight heparins (LMWHs) were the first drugs to improve on heparin’s limitations. LMWHs are one-third the molecular weight of UFH, making their bioavailability and dosing effect more predictable. The improved pharmacokinetics of LMWH over UFH typically negates the need for routine monitoring.23 In addition, the reduced binding of LMWH by platelet-derived proteins significantly decreases the incidence of HIT compared with UFH.23,24

Heparin is an indirect thrombin inhibitor and asserts its anticoagulant effects through binding antithrombin (AT). The heparin-AT complex results in a 4,000-fold increase in antithrombin activity that primarily inhibits thrombin and factor Xa from propagating coagulation (Figure 1).21,25 LMWH readily binds AT but is too small to promote inhibition of thrombin. Therefore, the anticoagulant effect of LMWH primarily is manifested via inhibition of factor Xa.

Figure 1

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Figure 1

Abbreviated Coagulation Cascade and Site of Action of Anticoagulants

^aAntithrombin inhibits factor Xa and thrombin to abate coagulation.

There currently are 3 LMWHs approved for use in the United States. Enoxaparin, dalteparin (Fragmin), and tinzaparin (Innohep) are all manufactured differently; therefore, dosing, clinical use, and anticoagulant effect are not interchangeable (Table 2).23 Each of the LMWHs listed is approved to treat acute deep venous thrombosis (DVT) with or without pulmonary embolism (PE), and to prevent DVT. There are no superiority trials; therefore, no drug can be recommended over another. Choice of a LMWH depends on local prescribing practice, physician comfort, and clinical situation.

Enoxaparin is the most extensively studied LMWH. LMWHs are cleared by the kidneys, and they must be used with caution in elderly patients, patients with diabetes, or those with a creatinine clearance (CrCl) less than 30 mL/min/173 m² and a high risk of bleeding.13,23,26 In addition, obesity alters the pharmacokinetics of LMWH and special prophylactic and therapeutic dosing is recommended for obese patients.23

Fondaparinux

Fondaparinux is a synthetic anticoagulant composed of a high-affinity pentasaccharide to AT. As with LMWH, the fondaparinux-AT complex is too small to inhibit thrombin activity and produces its anticoagulant effect by inhibiting factor Xa. Fondaparinux is rapidly absorbed after subcutaneous injection and is renally excreted.22,23 Its extended half-life (17 hours in young patients and 21 hours in elderly patients) allows for once-daily injections. Caution is needed for patients with risk of or impaired renal function; fondaparinux is contraindicated in patients with a CrCl less than 30 mL/min/1.73 m² (Table 2). Treatment doses are weight-based, and monitoring standards have not been established.23 Fondaparinux is approved for DVT prevention and treatment of acute symptomatic DVT with or without PE.

Unlike LMWH and UFH, fondaparinux does not bind platelet-derived proteins or cross-react with HIT antibodies. Therefore, HIT should not develop from fondaparinux exposure, and these properties might make it an ideal drug to treat HIT. However, there is 1 case report potentially linking fondaparinux to HIT with thrombosis, and further studies are needed before this can be recommended.27,28

Direct Thrombin Inhibitors

Direct thrombin inhibitors (DTIs) bind thrombin and block its enzymatic activity, producing an anticoagulant effect. There are 3 approved DTIs in the United States: lepirudin (Refludan), bivalirudin (Angiomax), and argatroban (Argatroban) (Table 2). These drugs are not intended for general anticoagulation as they carry increased risk of bleeding complications. They are approved for treatment of HIT or for anticoagulation associated with percutaneous coronary intervention in patients with HIT.23

Lepirudin is cleared by the kidneys and is contraindicated in patients with CrCl less than 30 mL/min/1.73 m². In addition, 40% of patients exposed to lepirudin will develop antilepirudin antibodies, and drug reexposure can induce anaphylaxis. Therefore, patients with HIT and previous exposure to lepirudin or desirudin (Iprivask) should be treated with an alternative drug.23,28

Argatroban and bivalirudin are safe to use in patients with renal failure; however, dose adjustments are needed for argatroban in the setting of severe hepatic impairment or for the critically ill. Therapeutic dosing is weight-based and delivered via continuous intravenous (IV) infusion.

Oral Direct Factor Xa and Thrombin Inhibitors

There currently are no oral direct factor Xa and thrombin inhibitors approved for clinical use for PE treatment. Because of the importance of identifying oral drugs to replace VKAs, these drugs are being developed for prophylaxis and treatment of thromboembolic disease with a goal of fixed-dose regimens that do not require monitoring. The DTI ximelagatran was briefly approved in Europe but removed from the world market secondary to hepatic toxicity.

Whether this was directly related to the drug or a class effect is undetermined.22 A new oral DTI, dabigatran (Pradaxa), recently was approved by the Food and Drug Administration as an alternative to warfarin for stroke and systemic thromboembolism prevention in patients with paroxysmal and permanent atrial fibrillation with risk factors for stroke or systemic thromboembolism who do not have a prosthetic heart valve or hemodynamically significant valve disease, renal failure, or advanced liver disease.29

Venous Thromboembolism Treatment

For the treatment of acute upper or lower extremity DVT, the ACCP recommends LMWH 1 to 2 times/day over UFH. No difference in safety or treatment efficacy has been demonstrated between the LMWH preparations, and in a single study, fondaparinux was judged to be noninferior to enoxaparin.13 However, in patients with acute DVT and renal failure, UFH is recommended over LMWH and fondaparinux. Monitoring of the anti-Xa level is not necessary unless LMWH is used in pregnancy.13

Low-molecular-weight heparin also is recommended as the initial drug treatment in acute submassive or asymptomatic PE; fondaparinux in a single study was demonstrated to be noninferior to LMWH.13 The ACCP recommends UFH as the first-line drug in patients with massive PE, or in patients who may require thrombolytic therapy. Again, UFH is recommended over LMWH or fondaparinux in patients with acute PE and renal failure.

Venous Thromboembolism Prevention

The majority of hospitalized medical and surgical patients have increased risk of venous thromboembolic disease and benefit from thromboprophylaxis. The enhanced pharmacokinetics and bioavailability that make LMWH and fondaparinux preferred drugs for treatment of acute DVT and PE also make them the preferred drugs for thromboprophylaxis.26,32,33 In addition, LMWHs are preferred over UFH for ease of dosing and the reduced incidence of HIT. It should be noted that fondaparinux was superior to enoxaparin in preventing DVT in orthopedic patients undergoing hip fracture surgery and total knee arthroplasty.34 Caution should be taken when using these drugs in elderly patients or patients with renal disease.

Case 2, cont’d. Seven days later, Joan presents to your office with reports of increased edema and pain in the right lower extremity. She states symptoms are similar to those with the prior DVT. Ultrasound confirms the presence of a DVT. Joan asks you how she could possibly develop a DVT because she was receiving heparin prophylaxis during the hospitalization.

Diagnosis

Heparin-induced thrombocytopenia is a syndrome, and the diagnosis is based on clinical suspicion followed by laboratory confirmation. For patients receiving heparin or who have received heparin within the previous 2 weeks, a diagnosis of HIT should be investigated if the platelet count decreases by 50% or more and/or a thrombotic event occurs between days 5 and 14 after heparin initiation, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia develops.

The first indication of developing HIT is a decrease in platelet count. Patients typically present with a platelet count less than 150,000 cells/mm3 or a relative decrease of 50% or more from baseline, although the decrease might be less in some patients.28 It is important to determine the pretest probability of HIT before obtaining confirmatory serologic tests because up to 50% of patients, particularly after cardiac surgery, can test positive for heparin-platelet antibodies but never develop clinical HIT.28

Using the 4Ts scoring system allows the physician to estimate the pretest probability of HIT and determine whether there is high, intermediate, or low clinical suspicion.36 Four factors (thrombocytopenia [percentage of decrease or platelet nadir], timing of platelet decrease with respect to heparin exposure, thrombosis or other sequelae, and evidence of other causes for thrombocytopenia) are scored from 0 to 2. Laboratory tests are only performed in patients with a high (score of 6 to 8) or intermediate (score of 4 to 5) risk of HIT. An explanation of scoring pretest probability of HIT can be found online (available at http://scalpel.stanford.edu/2007-2008/articles/Pretest%204%20Ts%20in%20dx%20HIT,%20%20J%20thrombosis%20and%20hemostasis,%202006.pdf).

There are quantitative and functional assays available to detect heparin-platelet antibodies. The quantitative immunoassays are more readily available and less labor-intensive but are more prone to false-positive results in patients with an intermediate risk of HIT. Functional assays, such as the serotonin release assay, serve as secondary tests to the immunoassays in these situations, and have very high positive and negative predictive values.37 They are somewhat impractical because few US clinicians are skilled in performing these tests. A diagnostic and treatment algorithm is provided in Figure 2.

Figure 2

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Figure 2

A Diagnostic and Treatment Algorithm for HIT

^aDTI: lepirudin, argatroban, or bivalirudin should be chosen based on drug availability, physician comfort, patient hepatic and renal function, and patient history of exposure to lepirudin.

^bIf no alternative diagnosis explains the thrombocytopenia or other HIT-associated symptoms, continued DTI therapy should be considered; consider hematology subspecialist consultation.

DTI = direct thrombin inhibitor; HIT = heparin-induced thrombocytopenia; LMWH = low-molecular-weight heparin.

Information from Warkentin TE, Greinacher A, Koster A, et al. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest. 2008;133(6 Suppl):340S-380S; Keeling D, Davidson S, Watson H. The management of heparin-induced thrombocytopenia. Br J Haematol. 2006;133(3):259-269. Erratum in Br J Haematol. 2006;134(3):351.

Treatment

If the clinical suspicion of HIT is high or intermediate, all heparin, including LMWH and heparin flushes to manage central lines, should be discontinued and an alternative nonheparin anticoagulant initiated.28 If the patient is undergoing anticoagulation with a VKA, it should be discontinued and vitamin K administered in doses of 10 mg orally or 5 to 10 mg IV.28 The DTIs lepirudin, argatroban, and bivalirudin are the recommended anticoagulants in HIT (Table 2).21,28 The DTI should be chosen based on drug availability, physician comfort, patient hepatic and renal function, and patient history of prior exposure to lepirudin.

Anticoagulation with the DTI should be continued until the platelet count has returned to at least 150,000 cells/mm3 before starting a VKA. Therapy with the DTI and VKA should overlap by at least 5 days and until the appropriate INR is maintained for at least 48 hours before DTI discontinuation.28 The INR should be maintained at 2.0 to 3.0 for at least 4 weeks in cases of HIT without thrombosis and up to 6 months in cases of HIT with thrombosis. Further study is needed to determine optimal duration of oral therapy. In general, patients with HIT should avoid further exposure to heparin products. Fondaparinux is an appropriate alternative for future anticoagulation in this patient population.28

Case 2, cont’d. Concerned about thrombosis associated with heparin-induced thrombocytopenia (HIT), you obtain a complete blood count. The results reveal a platelet count of 90,000 cells/mm³. Joan is admitted to the hospital and confirmatory laboratory test results are positive for HIT. On admission, she is given an argatroban infusion and warfarin is added after the platelet count is higher than 150,000 cells/mm³. You counsel Joan on the causes of HIT, and heparin is listed as an allergy in her chart.

History and Physical Examination

Symptoms associated with PAH often are nonspecific. Dyspnea and fatigue are common but not universal. Chest pain, syncope, and near syncope may occur.44 The history should focus on risk factors for PAH, such as associated diseases (Table 3), drugs, toxins, and family history.

Physical findings of PAH are variable. Initially, there might be only a pronounced pulmonic component of the second heart sound (with or without an associated tricuspid regurgitation murmur). As the disease progresses, evidence of RV failure, such as jugular venous distension, edema, ascites, or hepatomegaly, can ensue.

Ancillary Testing

Ancillary testing will not make the diagnosis of PAH, but can identify or exclude etiologies or suggest alternative diagnoses. Chest x-ray can show enlarged pulmonary arteries and right atrial or ventricular enlargement. The electrocardiogram can likewise show right atrial enlargement or evidence of RV strain. Pulmonary function test results often are normal in PAH or might show an isolated diffusion defect; this testing is useful in evaluating restrictive or obstructive lung disease.45 Ventilation-perfusion scanning is the best available imaging modality to screen for chronic thromboembolic disease and should be performed in most patients.46 Computed tomography (CT) scan, though the mainstay diagnostic test for acute embolus, might not detect all cases.

Echocardiography

Echocardiography serves as a screen for PAH and provides valuable information about right and left ventricular size and function, valvular disease, and congenital heart disease. Echocardiography also estimates the pulmonary artery systolic pressure.47 This is an estimate only and can be misleading. It also can be difficult to assess contributions of pulmonary venous pressure by echocardiography. For these reasons, PAH therapy should never be started on the basis of echocardiography findings alone.

Right Heart Catheterization

Right heart catheterization is the gold standard for PAH diagnosis.48 All patients with suspected PAH should undergo this procedure before treatment with PAH-specific therapy. Direct measurement of pulmonary hemodynamics, contributions of left atrial pressures, and assessment of shunt are fundamental in guiding therapeutic decision making. Right heart catheterization should be carried out at centers experienced in the evaluation of patients with PAH.

Case 3, cont’d. You suspect William is at risk of pulmonary arterial hypertension and obtain a screening echocardiogram. The echocardiogram shows a hypertrophied and dysfunctional right ventricle, with an estimated pulmonary artery systolic pressure of 65 mm Hg.

Calcium Channel Blockers

In a small percentage of patients with idiopathic PAH, and in a negligible percentage of patients with PAH associated with other conditions, the disease might be more predominantly one of vasoconstriction rather than proliferation. Pulmonary artery pressures can be lowered rapidly in these patients with a short-acting vasodilator, such as nitric oxide, epoprostenol, or adenosine. For patients with a reduction of mean pulmonary artery pressure by more than 10 mm Hg to a mean of less than 40 mm Hg with a normalized or increased cardiac output, high-dose calcium channel blockers can be beneficial. Several uncontrolled studies have shown benefit in this patient population.50,51 However, less than 10% of patients with idiopathic PAH (and few patients with PAH associated with other conditions) experience such a reduction with vasodilator treatment.52 The empiric use of calcium channel blockers in patients who do not experience this reduction can have dangerous, even fatal, consequences and should be avoided.

Prostacyclin

Prostacyclin has positive benefits on the RV and pulmonary vasculature; prostacyclin expression is decreased in patients with PAH.53 The synthetic prostacyclin epoprostenol was introduced in 1995 and was the first drug available that was specific for PAH treatment. Randomized controlled trials with epoprostenol have been performed in patients with idiopathic PAH, heritable PAH, and scleroderma, demonstrating improved exercise capacity, pulmonary hemodynamics, and survival in patients diagnosed with primary PH (now referred to as idiopathic PAH).54,55,56 Epoprostenol has a short half-life (approximately 6 minutes), and must be administered via continuous infusion through a dedicated Hickman catheter. Adverse effects include nausea, vomiting, jaw pain, headaches, and diarrhea. Catheter-related infections are a serious and potentially life-threatening complication. A potentially fatal rebound phenomenon occurs if epoprostenol is interrupted; in case of interruption, peripheral intravenous (IV) epoprostenol should be administered immediately until new central access is obtained.

Treprostinil (Remodulin, Tyvaso) is a prostacyclin analogue that can be administered continuously subcutaneously (Remodulin), continuously IV (Remodulin), or by intermittent inhalation (Tyvaso). Adverse effects for the parenteral routes typically are similar to those of epoprostenol, although treprostinil has a half-life of approximately 4 hours, which provides an additional margin of safety for establishing new IV access should the drug become interrupted. Subcutaneous treprostinil is administered in a manner similar to an insulin pump and carries the additional adverse effect of insertion site pain. In studies, subcutaneous treprostinil improved symptoms, exercise capacity, and hemodynamic status.57,58 Based on 2 limited uncontrolled studies, IV treprostinil was found to be safe and effective in patients with PAH.59

Inhaled prostacyclin analogues include iloprost (Ventavis) and treprostinil. Iloprost was approved based on a European randomized controlled trial in patients with PAH and chronic thromboembolic disease that demonstrated improvement in exercise capacity, symptoms, and decreased pulmonary vascular resistance and clinical events.60 Iloprost is approved for dosing 6 to 9 times/day, which likely limits compliance as treatment time takes on average 3 to 5 min/treatment. Inhaled treprostinil is delivered 4 times/day, with treatment times averaging 1 to 2 min/treatment. In addition to the adverse effects seen with other prostacylins, cough, sore throat, and chest pain can be seen with the inhaled drugs.

Endothelin Receptor Antagonists

Endothelin has multiple negative effects on pulmonary hemodynamics and the right ventricle. Endothelin is active at 2 receptors, endothelin A and B. Bosentan (Tracleer) is a nonselective endothelin receptor antagonist of both receptors shown in many trials of PH of various etiologies to improve exercise capacity, functional class, hemodynamic status, echocardiographic variables, and time to clinical worsening.61,62,63,64 It is an oral drug with twice-daily dosing. Bosentan may elevate liver transaminases; liver function test (LFT) results should be monitored monthly while the patient is taking the drug.

Ambrisentan (Letairis) is an oral endothelin receptor antagonist with once-daily dosing whose pivotal study also showed improvement in exercise capacity and clinical events.65 LFT abnormalities, though less than with bosentan, should be evaluated monthly.

Endothelin receptor antagonists are contraindicated in pregnancy. Women of childbearing age taking an endothelin receptor antagonist should be counseled to use 2 forms of birth control, including a barrier method, and should undergo monthly pregnancy testing in addition to LFTs.

Phosphodiesterase Type 5 Inhibitors

Phosphodiesterase type 5 (PDE5) inhibition leads to cyclic guanosine monophosphate-mediated positive effects on the pulmonary vasculature. Two PDE5 inhibitors are Food and Drug Administration-approved for PAH in the United States. Sildenafil and tadalafil have demonstrated improvements in exercise capacity and hemodynamic status when used as monotherapy.66,67 Sildenafil is administered 3 times/day; tadalafil is approved for once-daily dosing. Adverse effects of both drugs include headaches, epistaxis, and potential for visual disturbances. Given the potential for severe and life-threatening hypotension with coadministration with nitrates or alpha blockers, these drugs should be avoided in patients taking PDE5 inhibitors.

Combination Therapy

Several studies have shown benefit when a second drug was added for patients already receiving another PH-specific drug.68,69,70 The evidence supports the addition of a second drug for patients who are still symptomatic while taking 1 drug, although which drugs, what order, which combination, and what timeline for adding therapies remain unclear. Though many of the initial PAH trials involved monotherapy versus placebo, nearly all current and future trials likely will involve a control arm of PH-specific monotherapy because use of placebo in this disease when approved drugs are available has ethical implications.

Novel/Future Approaches

Current therapies in PAH focus on the previously discussed pathways. Therapies are being explored that approach these pathways in new fashions, use novel delivery of current therapies, manipulate additional pathways (eg, platelet-derived growth factor, serotonin, vasoactive intestinal peptide), or focus on improving RV adaptation. Many multicenter clinical trials are ongoing and are in need of enrollment of patients with this rare disease.

Risk Factors and Diagnosis

Risk factors for diastolic dysfunction include advanced age, female sex, systemic hypertension, coronary artery disease, obstructive sleep apnea, and diabetes.73 The diagnosis often is difficult to make on the basis of noninvasive testing, but can be suggested by a careful history and physical examination, focusing on risk factor identification. For example, the presence of longstanding systemic hypertension, obesity, and a history of daytime somnolence would all be consistent with possible diastolic dysfunction.

Echocardiography may be nondiagnostic, but findings of left atrial enlargement and a delayed relaxation pattern on Doppler evaluation suggest the diagnosis. Differentiating pulmonary hypertension due to diastolic dysfunction from PAH can be difficult and might require hemodynamic evaluation through right and/or left heart catheterization; this invasive testing is important for obtaining the correct diagnosis and initiating an effective treatment regimen. Right heart catheterization will diagnose this disorder by measurement of not only PAP, but also the pulmonary capillary wedge pressure (which approximates left atrial pressure). Left heart catheterization can demonstrate an elevated left ventricular end-diastolic pressure.

Case 4, cont’d. Because of John’s poor exercise tolerance, dyspnea, and abnormal echocardiogram results, you pursue additional evaluation. Full pulmonary function testing reveals a mildly decreased diffusing capacity for carbon monoxide but no obstruction or restriction. Chest x-ray shows small bilateral pleural effusions. Overnight oximetry (while he wears a continuous positive airway pressure device, which he wears regularly) reveals no hypoxic events. Ventilation-perfusion scanning shows no wedge-shaped perfusion defects. You begin furosemide 20 mg 2 times/day and refer him for right heart catheterization.

Treatment

The treatment approach to patients with diastolic dysfunction focuses on maximizing diastolic filling through aggressive blood pressure control, heart rate control, and diuresis. The correct diagnosis for this group of patients is imperative, because treating empirically with pulmonary vasodilators can decrease pulmonary vascular resistance and venous return to the noncompliant LV, thereby worsening pulmonary edema. An early study using epoprostenol in patients with LV dysfunction reported increased mortality, and studies involving other drugs currently are ongoing.74

Chronic Obstructive Pulmonary Disease

Epidemiologic studies in severe COPD indicate that the majority of patients exhibit PH.75 This PH is predominantly in the mild to moderate range and is a strong predictor of early mortality.76,77 Treatment is focused on the correction of hypoxemia and management of the obstructive lung disease with an appropriate inhaler regimen. There is no evidence that specific treatment for PH is safe or effective in this group of patients. Pulmonary vasodilators have the potential to worsen gas exchange in this group by eliminating the compensatory hypoxic vasoconstriction in diseased areas of lung. A short-term study with the endothelin antagonist bosentan revealed no appreciable improvement in exercise capacity or quality of life.78 A small trial of sildenafil in COPD-related PH revealed small improvements in PAP, but worsened hypoxemia.79 Larger clinical trials in this population are ongoing that will help define the safety and efficacy of specific PH treatment.

Within this group of patients with COPD is a much smaller subset with severe PH that is out of proportion to the underlying pulmonary parenchymal disease. These patients have moderate airway obstruction but severe hypoxemia and a severely reduced diffusing capacity of carbon monoxide on pulmonary function testing. Hemodynamic evaluation reveals elevated PAPs (ie, mean PAP more than 40 mm Hg). These patients have a markedly reduced lifespan compared with other patients with COPD.80 Referral of these patients to a PH center should be considered, because clinical trials are ongoing to determine whether PH drugs are safe and effective.

Interstitial Lung Disease

Interstitial lung disease is a term that encompasses a group of disorders that affects the pulmonary interstitium rather than the small airways. Within this group of disorders, the most commonly encountered diagnosis is idiopathic pulmonary fibrosis (IPF). The incidence of PH in IPF is unknown, because much of the data are collected from lung transplantation centers, creating a selection bias. Similar to patients with COPD, patients with IPF and PH experience early mortality, which increases linearly with PAP.81

Small, short-term trials of sildenafil, bosentan, and inhaled prostacyclin showed no detrimental effects of oxygenation in these patients, although the potential exists.82,83,84 Long-term trials of specific PH treatments in this population are ongoing, but there currently is not enough evidence for treatment recommendations. Therefore, treatment should focus on the underlying disease and maintaining oxygenation.

Obstructive Sleep Apnea

The repeated apneic episodes characteristic of obstructive sleep apnea (OSA) can also elevate PAP in a sustained fashion.85 Similar to patients with pulmonary parenchymal disease, the elevation in PAP seen with OSA is most often mild to moderate.86 Treatment is focused on correction of the sleep-disordered breathing, management of comorbidities, and weight loss. Severe elevations of PAP are uncommon in OSA and should prompt a more thorough evaluation at a PH center.

Diagnostic Evaluation

The diagnosis of PH in patients with lung disease and hypoxia can be difficult, as both conditions present with dyspnea and fatigue. A thorough diagnostic evaluation is warranted when the patient’s dyspnea is out of proportion to the reduction in pulmonary function test results, or when there are signs and symptoms of right heart failure.

A basic evaluation includes full pulmonary function testing, polysomnography if the history suggests sleep-disordered breathing, chest x-ray, and complete echocardiography with Doppler interrogation (Figure 4). Patients with elevated estimated systolic PAP on echocardiogram, enlargement or hypertrophy of right heart chambers, and/or depressed right ventricle function out of proportion to other test results may benefit from right heart catheterization. Referral to a PH center is appropriate in this setting.

Figure 4

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Figure 4

Approach to the Patient With Pulmonary Disease and Suspected Pulmonary Hypertension

CXR = chest x-ray; PFT = pulmonary function test; PASP = pulmonary artery systolic pressure.

Information from Galie N, Hoeper M, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2009;30(20):2493-2537.