Percutaneous interventional cardiovascular medicine: The PCR-EAPCI Textbook

Summary

The primary focus of interventional cardiology is the coronary circulation and, recently, the aortic and mitral valves. Contemporary “adult interventionists” have paid little attention to the right heart and to the pulmonary vessels. In contrast to the systemic circulation, the pulmonary circulation is a high-flow low-resistance system. To preserve cardiac output, the right ventricle responds to an increase in resistance by augmenting right ventricular pressure. Pulmonary embolism (PE), one of the more common conditions increasing RV afterload, is a cardiovascular emergency. Depending on the clinical presentation, initial therapy is primarily aimed at life-saving restoration of flow through occluded pulmonary arteries, or at the prevention of early recurrences. Failure to resolve acute pulmonary thromboemboli is a potential explanation for chronic thromboembolic pulmonary hypertension (CTEPH). This condition appears to be one of the more common subsets of pulmonary hypertension (PH). “The end is where we start from” refers to the extensive loss of functional pulmonary vessels which has already taken place in >80% of patients with pulmonary arterial hypertension (PAH) at the point when clinical symptoms of PH occur for the first time. According to the current guidelines for the diagnosis and treatment of PH, the diagnostic classification separates pre- from post-capillary PH which originates distal to the capillaries and entails morphological changes in the pre-capillary compartment only after a significant pressure increase in the venous compartment. Currently, wedge pressure is used to distinguish between pre- and post-capillary disease. This distinction is essential because treatments are completely different for these two classes of disease. This chapter will focus on the essentials of pathology and clinical manifestations of diseases affecting the pulmonary circulation, inasmuch as they impact on interventional cardiology. In addition, it will review the role of interventions, inasmuch as they impact on pulmonary vascular disease.

Introduction

This chapter will focus on essentials of physiology, pathology and clinical manifestations of diseases affecting the pulmonary circulation, inasmuch as they impact on interventional cardiology. In addition, it will review the role of interventions, inasmuch as they impact on pulmonary vascular disease, which is a small interventional field in comparison with systemic vascular disease.

FOCUS BOX 1Incidence of thromboembolic disease and pulmonary arterial hypertensio

Yearly incidence of pulmonary embolism 69/100,000 [1]
Yearly incidence of pulmonary arterial hypertension 2.4-15/1,000,000 [2]
Yearly incidence of chronic thromboembolic pulmonary hypertension 5/1,000,000 [3]

Pulmonary embolism

SUMMARY

In contrast to the systemic circulation, the pulmonary circulation is a high-flow low-resistance system. The right ventricle responds to an increase in resistance within the pulmonary vascular bed by increasing right ventricular pressure to preserve cardiac output.

Pulmonary embolism (PE) is a relatively common cardiovascular emergency, yet it is a rare but significant complication of percutaneous coronary intervention (PCI). Data about the incidence of PE in association with PCI is limited. A small study described that PE was the reason for death in 1.7% of patients, who died during their acute hospitalisation for PTCA [4]. Venous thromboembolism (VTE) shares risk factors with atherothrombosis [5]. Prevention of arterial vascular events with rosuvastatin in the Jupiter trial [6] prevented arterial as much as venous thrombotic events [7]. Within two years, treatment with rosuvastatin prevented 99 acute myocardial infarctions, 97 strokes, but also 94 symptomatic cases of deep venous thrombosis/pulmonary embolism.

PE is a challenging diagnosis which may be missed because of variable symptoms. Early diagnosis is needed because immediate treatment is highly effective.

Depending on the clinical presentation, initial therapy is primarily aimed either at life-saving restoration of flow through occluded pulmonary arteries or at the prevention of early recurrences. Immediate risk stratification is essential ( Figure 1 ).

Both initial treatment and long-term anticoagulation must be justified in each patient by a validated diagnostic strategy.

Failure to resolve acute pulmonary thromboemboli is a potential explanation for chronic thromboembolic pulmonary hypertension (CTEPH). This condition appears to be one of the more common subsets of pulmonary hypertension [8], yet hard to diagnose. Valuable epidemiological data will be derived from the ongoing European CTEPH Registry (https://www.cteph-association.org/).

EPIDEMIOLOGY

Pulmonary embolism (PE) and deep venous thrombosis (DVT) are two closely related clinical presentations of venous thromboembolism (VTE). About 50% of patients with proximal DVT subsequently develop mostly asymptomatic PE [9]. Conversely, the complication of a DVT of the lower limbs accounts for approximately 70% of PEs [10, 11]. VTE is the third most common cardiovascular disease after acute ischaemic syndromes and stroke and is associated with substantial morbidity and mortality [6]. In the USA, the overall age and sex-adjusted incidence of VTE is 77.6 per 100,000 [12]. The incidence of PE among hospitalised patients is about 0.4% [13]. VTE is predominantly a disease of older age. The incidence rates increase exponentially with age in both men and women [1] [14].

The crude mortality rate for acute PE at three months is about 15%, which is higher than that for myocardial infarction [15]. One-year mortality after a VTE is 17% to 22%[16, 17] , while two-year mortality is 20% to 25% [17, 18] . Murin et al reported a 6-month fatality rate of 10.5% among patients with DVT and 14.7% among those with PE [19]. Sudden death occurs in almost 25% of patients with PE [12]. Right heart failure resulting in cardiovascular collapse is the most common reason for death [12]. It has been shown that patients diagnosed with PE during hospitalisation for another condition had a higher case-fatality rate (32.5%) than those admitted for PE. 11.6% of patients died during their initial hospitalisation, 5% of those with DVT and 23% of those with PE [18] .

Increased mortality risk in patients with PE is associated with systolic arterial hypotension, congestive heart failure, cancer, tachypnoea, poor right-ventricular function by echocardiography, chronic obstructive pulmonary disease, and age >70 years [15].

A large epidemiological study reported that 59% of incident VTE cases could be attributed to immobilisation or nursing home residence, 18% to cancer and 12% to trauma. Congestive heart failure and prior central venous catheter or pacemaker placement were responsible for 10% and 9% of VTE cases respectively. In summary, recognised clinical risk factors are responsible for ~ 75% of VTE cases, while ~ 25% are idiopathic [20].

PE has a relatively high recurrence rate. Analyses of the California Patients Discharge Data Set [19] revealed that the 6-month recurrence rate of VTE was 6.4% in the cohort of patients hospitalised for DVT and 5.8% in the cohort initially hospitalised for PE. In a prospective cohort study of 738 patients with DVT, reported recurrence rates of VTE were 7.0% at 1 year and 22.0% at 5 years [21]. Survivors of acute PE have an increased risk of CTEPH [22].

PATHOPHYSIOLOGICAL MECHANISMS OF PULMONARY EMBOLISM

The clinical manifestation of VTE can be subdivided into DVT and PE [23]. In most cases, PE is a severe complication of DVT of the legs, and ranges from asymptomatic, incidentally discovered thromboemboli to massive embolism that results in obstruction of the pulmonary vasculature. Thrombi in the leg may form at any point along the vein wall and any venous bed can be involved. The vast majority of venous thrombi are asymptomatic, and form on the valve pockets of deep veins in the calf [24]. However, these thrombi can extend into the proximal veins, including and above the popliteal veins [25], become symptomatic and prone to embolisation. In about 80% of patients with PE, signs of a DVT are documented [26]. Conversely, up to 50% of patients will develop a PE in the setting of DVT. If embolisation does not occur, the thrombus within the vein can be partially or completely resolved via recanalisation, organisation, and lysis.

PE as a complication of percutaneous coronary intervention

Percutaneous coronary intervention (PCI) is associated with various in-hospital complications including death, myocardial infarction, emergency coronary artery bypass grafting, stroke, contrast-induced nephropathy, and vascular access-site complications [27]. PE is a relatively common cardiovascular emergency, yet it is a rare but significant complication of PCI, occurring in 1.7% of cases [4]. The mortality related to PE in this PCI population is 0.016% [4]. No data exists regarding more recent experience after introduction of femoral vascular closure devices, which have reduced the time to ambulation.

Under dual antiplatelet therapy with aspirin and clopidogrel, PE was observed in only 0.026% of patients within 6 months [28]. Data from the PEP study and from the Anti-Platelet Trialists’ systematic review shows that aspirin significantly reduces the risk of VTE in surgical patients. However, there is no general evidence that aspirin is a drug that is useful for the prevention of VTE in any patient group [29, 30].

Venous thromboembolism and atherothrombosis

Atherothrombosis and VTE are associated [31], and share risk factors such as obesity, hypertension, dyslipidaemia, diabetes, and smoking [32, 33, 34]. Inflammation, systemic and local hypercoagulability, and endothelial injury play crucial roles in the development of both atherothrombosis and VTE [33, 35]]. Patients with acute coronary syndromes or stroke have an increased susceptibility of VTE [36, 37]. Additionally, an association between atherosclerotic disease and spontaneous venous thrombosis has been demonstrated [38]. Subsequent studies detected a drastically increased cardiovascular risk in patients with a prior history of VTE compared with those without such a history [39, 40, 41, 42].

The prognostic value of C-reactive protein, a sensitive systemic marker of inflammation for cardiovascular events [43, 44] and VTE [45], has been investigated. Rosuvastatin prevented arterial events in a population with elevated high-sensitivity C-reactive protein levels [46] in the Jupiter trial (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) [6], and simultaneously prevented symptomatic venous thrombotic events [7].

Hypercoagulability plays an important role in the development of VTE as well as in atherothrombosis. An increased risk of both conditions has been described in women on oestrogen and progesterone therapy and in patients with lupus anticoagulant [47]. Endothelial injury as a trigger for atherothrombosis and DVT has been well established [48, 49, 50].

RISK FACTORS FOR PE

Although PE can occur in patients without any known risk factor, certain predisposing factors are associated with an increased risk of VTE. The International Cooperative Pulmonary Embolism Registry (ICOPER) showed that less than a quarter of PE were idiopathic or unprovoked [15]. In 1856, Virchow first proposed a triad of factors leading to intravascular coagulation, including stasis of blood flow, vascular endothelial damage, and hypercoagulability of blood [51]. Risk factors for VTE are outlined Table 1. [52, 53]. The incidence of VTE correlates with increasing age for both idiopathic and secondary PE [54]. Approximately 65% of patients with PE are aged 60 years or older. The incidence of PE is eight times higher in patients over 80 compared with those under 50 years of age [55]. Total risk depends on the number of predisposing factors [56].

Two large meta-analyses have investigated vascular access-related complications in patients undergoing percutaneous transfemoral coronary procedures [57, 58]. In both studies, venous thromboembolic events were not included in the reporting of vascular access-related complications. Whether the condition is under-reported, or VTE as a complication of coronary angiography has in fact decreased since the general implementation of arterial puncture site closing devices shortening bed rest after coronary angiography, is unknown. In addition, the improvement of patient care and the implementation of dual antiplatelet therapy and continued anticoagulation might be responsible for the apparent reduction of VTE after PCI.

RISK STRATIFICATION

PE is a potentially life-threatening disorder. The rate of recurrent and potentially fatal events may be significantly reduced by treatment with either unfractionated heparin (UFH), low-molecular weight heparin (LMWH), or fondaparinux [23]. Risk stratification of patients with PE helps to distinguish between those candidates at low risk who are appropriate for a therapy outside the hospital setting and those individuals at higher risk who require hospitalisation.

According to the ESC guidelines, the severity of PE is stratified into high (>15%), intermediate (3% to 15%) and low risk (<1%) of PE-related early death (in-hospital or 30-day mortality) as depicted in Figure 1A [52]. The presence of hypotension or shock at the time of PE diagnosis is the most powerful predictor of early death, independent of further risk markers [15, 59]. Consequently, haemodynamically unstable individuals with suspected PE should immediately be classified as high-risk patients and require an emergency diagnostics and treatment. All other patients are thus automatically identified as non-high-risk patients and should be further stratified into intermediate and low risk patients after PE has been confirmed. This stratification may critically influence treatment and the duration of hospitalisation and should be based on the Pulmonary Embolism Severity Index (PESI) [60] or simplified PESI (sPESI) [61] ( Figure 1 [B] ). The PESI, comprising 11 routinely available clinical parameters, represents a well-established approach to estimate 30-day mortality for patients with acute PE. This model can be used to give clinicians a beside risk assessment tool for patients with PE, without any need for imaging studies such as echocardiography or laboratory tests. To reduce the technical complexity of the original prediction rule, a simplified version of the PESI score has been developed, which is easily calculated at bedside ( Figure 1 [B] ) [61]. Recent data suggest that both PESI and the sPESI predict 30-day mortality after acute symptomatic PE.

Patients at intermediate risk are further classified into intermediate-high and intermediate-low risk patients according to signs of right ventricular (RV) dysfunction based on imaging and/or biomarkers. Defined markers of RV dysfunction are RV dilatation, hypokinesis or pressure overload on echocardiography, RV dilatation on spiral computed tomography, and elevated right heart pressures at right-heart catheterisation. N-terminal (NT)-proBNP represents the best validated biomarker for severity of haemodynamic compromise and RV dysfunction in the setting of PE [62]. NT-proBNP plasma levels of 600 pg/mL were found as the optimal cut-off value for identifying patients at increased risk [63]. Troponin T or I testing can detect myocardial injury and positive results identify patients at higher risk. The development of high-sensitive assays has further improved the prognostic value of troponin T [64].

The presence of concomitant DVT in patients with acute symptomatic PE is an independent predictor of death in the three months following the diagnosis [61]. Therefore, bilateral lower extremity compression ultrasonography should assist with risk stratification of patients with acute PE. Venous ultrasound imaging of the entire deep vein system is highly specific (about 95%) and sensitive (over 90%) for the diagnosis of DVT [65, 66, 67].

DIAGNOSTIC STRATEGIES

Due to the large variety and low specificity of symptoms, the diagnosis of PE is challenging. Chest computed tomography (CT) is regarded as highly sensitive and specific test for PE [68]. The key to the diagnosis of PE is a high index of clinical suspicion. In order to avoid unnecessary exposure to radiation and contrast agent, without overlooking the condition, a sophisticated diagnostic algorithm has been established [52].

Clinical signs and symptoms

The clinical presentation of patients with PE is highly variable. Frequently reported symptoms include dyspnoea, pleuritic and substernal chest pain, palpitations, cough, seizures, faints and haemoptysis. Patients with high thrombus burden can present with circulatory collapse, mental status changes, syncope and arrhythmias [69, 70] . Clinical signs include tachypnoea, tachycardia, signs of DVT (leg pain, warmth, or swelling), fever and cyanosis.

Differential diagnosis of chest pain

Acute chest pain represents one of the most common diagnostic challenges in emergency medicine, accounting for approximately 8% to 10% of the 119 million emergency department visits yearly in the USA [71]. The differential diagnosis ranges from non-serious musculoskeletal aetiologies to life-threatening cardiac disease. In one large study [72] of patients attending the emergency department with chest pain, 8% were diagnosed with AMI, 9% with unstable angina, 6% with stable angina, 21% had non-ischaemic cardiac problems, and at least 2% of patients with AMI were discharged in error. However, more than 50% of patients with acute chest pain had non-cardiac problems, such as aortic dissection or PE, which may mimic coronary syndromes [73]. Approximately 0.5% of patients who attend emergency departments with suspicion of acute coronary syndrome have a PE [73]. The underlying cause of chest pain varies depending on whether a patient is seen by a general practitioner or at the emergency department. In general practices nearly 50% of patients with chest pain have musculoskeletal pain, whereas in the emergency department 45% have cardiac problems [73, 74, 75, 76] . However, even in general practices, PE was identified in 3% of patients with thoracic pain [76]. About 3% of patients admitted to a coronary care unit with acute chest pain suffered from PE [76]. The enhancement of patient care by rapid diagnoses is an important health care issue.

Physical examination

The diagnosis for PE begins with a careful clinical examination and determination of risk factors. Decreased breath sounds, wheezing, respiratory crackles, accessory muscle use, increased jugular venous pressure, and a right ventricular heave may be detected by physical examination.

Electrocardiogram

An electrocardiogram (ECG) is routinely performed in patients with chest pain attending the emergency department. The ECG is, however, a poor diagnostic tool for PE. Though the ECG is often abnormal, the findings are neither sensitive nor specific. The greatest use of the ECG in patients with suspected PE is to rule out other potential life-threatening diagnoses that can be more readily diagnosed such as myocardial infarction.

The S1Q3T3 pattern is a typical ECG manifestation of acute right ventricular pressure and volume overload. An S wave in lead I indicates a complete or more often incomplete right bundle-branch block. A Q-wave, mild ST-elevation and an inverted T wave in lead III are repolarisation abnormalities possibly triggered by subendocardial ischaemia of the right ventricle.

Further ECG signs of RV strain are T-wave inversion in leads V1–V4, a QR pattern in lead V1, and incomplete or complete right bundle-branch block [77, 78]. These findings may be helpful, particularly when of new onset. Nevertheless, such changes are generally associated with the more severe forms of PE and may be found in right ventricular strain of any cause such as acute bronchospasm, pneumothorax and other acute lung disorders.

Implicit and explicit (prediction) rules

Clinical signs, symptoms and routine laboratory tests do not allow the exclusion or confirmation of acute PE but help to estimate a likelihood of PE [52]. The assessment of clinical probability of PE is based on a combination of individual symptoms, signs and common tests, either implicitly by the clinician or by the use of prediction rules. Implicit clinical judgement combines the knowledge and experience of the clinician to estimate the likelihood of PE. The value of this assessment has been shown in several large series [79, 80]. The main limitations of implicit judgement are lack of standardisation and the challenge of acquiring sufficient experience.

Therefore, prediction rules have been developed for calculating the probability of clinically suspected PE which are independent of physicians’ implicit judgement and which have demonstrated similar accuracy [81]. Prediction rules calculate the probability of suspected PE from a combination of symptoms and clinical signs. The revised Geneva score [82] and Wells score [83] represent two established and well validated prediction rules that were further simplified to increase their usefulness in clinical practice ( Table 2 and Table 3 [84, 85]).

D-dimer

Plasma D-dimer, a degradation product of cross-linked fibrin, is a very sensitive but non-specific marker for VTE. A negative test result is valid to rule out PE in patients with a low or moderate clinical probability [67]. However, positive D-dimer tests should be considered with caution because this parameter is susceptible to false positive results. Levels of D-dimer are elevated in many other clinical conditions, such as cancer, inflammation, infection, necrosis, bleeding, dissection of the aorta, pregnancy and hospitalisation per se [86]. For this reason, D-dimer is not a useful parameter for confirming PE. The number of patients with suspected PE in whom D-dimer needs to be determined to exclude one PE is between three in the emergency department and ten or above in other conditions [52]. Physical examination should be performed as the first diagnostic step, prior to considering D-dimer [52]. It has become evident that the specificity of D-dimer in individuals with suspected PE declines with age [87]. Therefore, an age-adjusted cut-off (patient's age in years × 10 µg/L) has been developed to improve the specificity of D-dimer testing for excluding PE [88]. The combination of pretest clinical probability assessment with an age-adjusted D-dimer cutoff increased the specificity of D-dimer as diagnostic biomarker significantly without any loss in sensitivity [89].

Echocardiography

Echocardiography is non-invasive, can immediately be performed at the bedside, provides rapid results, and circumvents radiographic contrast and radiation exposure. Tricuspid insufficiency jet velocity, RV dimensions, disturbed RV ejection pattern or depressed contractility of the RV free wall are accepted as indirect signs of PE. Due to the reportedly low sensitivity of around 60% to70%, echocardiography cannot exclude PE [90, 91, 92]. Hence, echocardiographic examination is reserved for haemodynamically unstable, hypotensive patients. Direct visualisation of right heart enlargement and of right heart thrombi, as in 4% to18% of patients with acute PE, justifies the initiation of specific treatment [93, 94].

Transoesophageal echocardiography for searching emboli in main pulmonary arteries may be considered for immediate decision-making in patients with severe haemodynamic compromise [93, 94], visualising thrombus in the proximal pulmonary arteries [95, 96], and in systemic veins and the right heart. However, the proximal part of the left pulmonary artery can be assessed in only 47% of patients [97].

Computed tomography

CT angiography has replaced pulmonary angiography as the method of choice for imaging the pulmonary vasculature for suspected PE, particularly since the implementation of multidetector CT [52]. Conventional pulmonary angiography leads to an increased bleeding risk during thrombolysis [98, 99], and is associated with higher mortality in unstable patients [100] . Multidetector CT is at least as accurate as invasive pulmonary angiography [101, 102] and allows the adequate visualisation of the pulmonary arteries up to at least the segmental level [103, 104] .

A positive CT has a high positive predictive value (92% to 96%) in patients with intermediate or high clinical probability of PE [105]. Large clinical trials have established Multidetector CT as a reliable method to exclude PE [106, 107]. However, whether patients with a negative CT should be further examined by compression ultrasonography (CUS) and/or ventilation-perfusion scintigraphy (V/Q scan) or pulmonary angiography is still controversial [52].

Ventilation–perfusion scintigraphy

Ventilation–perfusion scintigraphy (V/Q scan) is a validated option for patients with contraindications to CT, such as allergy to iodine contrast dye or renal failure, despite a high proportion of inconclusive results [108].

Lung scan results usually indicate the level of probability of PE according to criteria established in the North American PIOPED trial [108]. In general, V/Q scan results have to be verified by further tests. Only high-probability V/Q scan results in patients with high degree of probability are accepted as diagnosis without further clarification [52].

Diagnostic algorithm

According to the ESC guidelines [52], the diagnostic algorithm differs substantially between suspected high-risk and non-high-risk PE. Therefore, prompt and accurate risk stratification to guide appropriate diagnostic steps is of major importance. Both diagnostic algorithms are illustrated in Figure 2 .

Suspected high-risk PE

High-risk PE, characterised by the presence of shock or arterial hypotension, accounts for 5% of all cases of PE and has a short-term mortality of at least 15% [109]. This underlines the potential life-threatening nature of high-risk PE, and the need for emergency treatment. Therefore, a simple and rapid diagnostic algorithm for the diagnosis of PE is of great practical benefit. Crucially, emergency CT or bedside echocardiography is recommended for diagnostic purposes.

Due to its availability in most emergency rooms, bedside transthoracic echocardiography is the most useful initial examination for the diagnosis of right ventricular dysfunction. In the absence of echocardiographic signs of RV overload or dysfunction, massive PE is excluded and the search for other causes is indicated. In the case of positive echocardiographic findings, CT should confirm the diagnosis of PE. In highly unstable patients, or if other tests are not available, echocardiography alone is sufficient to justify rapid treatment. If the patient is stabilised and CT is available, a CT should be performed immediately. After confirming the diagnosis, PE-specific treatment is justified.

Suspected non-high-risk pulmonary embolism

In the majority of patients admitted to the emergency department with suspected PE, the diagnosis can be excluded by careful evaluation. The assessment of clinical probability by the revised Geneva score [82] and the Wells score [83] is recommended as a first step ( Table 2 and Table 3 ). If the likelihood of PE is low or intermediate, D-dimer measurements as the next diagnostic step that should be performed for ruling out PE. D-dimer determination combined with clinical probability assessment allows PE to be ruled out in around 30% of this patient group [107, 110, 111, 112, 113]. In patients with high clinical probability of PE, the measurement of D-Dimer is frequently unhelpful due to its low negative predictive value [114].

If the likelihood of PE is high, or if the D-dimer is elevated, then CT angiography is indicated. This has become the main thoracic imaging modality for suspected PE [115, 116]. Hence, Multidetector CT is the second-line test in patients with an elevated D-dimer level and the first-line test in patients with a high clinical probability [52].

THERAPEUTIC STRATEGIES

The treatment of choice depends on the calculated risk of PE-related early mortality. Therefore, accurate risk stratification is crucial for the selection of treatment. The initial risk stratification of suspected and/or confirmed PE based on the presence of shock and hypotension is needed to differentiate between high-risk and non-high-risk patients for selecting appropriate therapeutic strategies.

In non-high-risk PE patients, further stratification to intermediate or low-risk PE patients on the presence of imaging or biochemical markers of RV dysfunction and myocardial injury is recommended. However, anticoagulation with unfractionated heparin should be initiated without delay in high-risk as well as non-high-risk PE patients [52]. A therapeutic algorithm in accordance with the ESC guidelines is depicted in Figure 3 .

New oral anticoagulants (NOACs)

Rivaroxaban, abixaban and edoxaban are oral factor Xa inhibitors. Dabigatran is an orally administered direct thrombin inhibitor. NOACs do not require laboratory monitoring and have no food interactions and only a few drug interactions [117, 118]. Over the last decades physicians were well trained in the use of conventional anticoagulant treatments with heparin and vitamin K antagonists. Since the new oral anticoagulants (NOACs) received regulatory approval for the acute and continued treatment of PE, physicians are challenged to optimally implement their use in clinical practice. Table 4 helps identify patients that are suitable for treatment with a NOACs. The use of NOACs is not recommended in patients with severe renal impairment. Table 5 gives an overview about dosing of NOACs. A recently published review [119] summarises in more detail NOACs for the treatment and prevention of thromboembolic diseases.

High-risk pulmonary embolism

High-risk PE patients have a high mortality rate and complication risk [59, 109, 120]. Acute RV failure with resulting low systemic output is the leading cause of death in patients with high-risk PE. The first few hours after admission to the emergency department are associated with an increased risk of in-hospital death[120]. Therefore, rapid haemodynamic and respiratory support is of vital importance. The infusion of saline solution is useful to maintain adequate systemic pressure. If the systemic arterial pressure remains below 90 mmHg or if tissue perfusion is not sufficient, the administration of vasopressors or catecholamines is recommended [59, 109]. Immediate pharmacological or mechanical reopening of the occluded pulmonary arteries is indicated.

Anticoagulation

A parenteral anticoagulation should be administered without delay in haemodynamically unstable patients with suspected PE. Intravenous weight-adjusted unfractionated heparin is the treatment of choice. Subcutaneous LMWH or fondaparinux have not been tested in the setting of hypotension and shock. The anticoagulant effect of unfractionated heparin can be easily monitored and if necessary reversed rapidly by protamine. High-risk PE patients should not receive NOACs in the acute phase as these drugs have not been evaluated in conjunction with primary reperfusion therapies.

Thrombolytic therapy

Systemic thrombolysis improves RV function and haemodynamic status in patients with acute PE [121]. Therefore, thrombolytic therapy is the first-line treatment that should be immediately administrated in high-risk patients as soon as PE is confirmed. However, the beneficial effects of thrombolysis are limited to the first few days; in survivors, differences disappear one week after administration [122, 123].

Because direct local infusion of the thrombolytic agent has not been shown to be advantageous [124], systemic intravenous administration is recommended. Approved thrombolytic agents, regimens, and contraindications are summarised in Table 6 [125]. Accelerated thrombolytic regimens are preferable to prolonged infusions of thrombolytic drugs over 12-24 hours [52].

In high-risk PE patients, thrombolysis is associated with a critical reduction of mortality of approximately 22% compared to heparin alone. Despite these impressive outcome data, thrombolysis is withheld in more than two-thirds of patients with high-risk PE according to real world registry data [126, 127]. The reasons for underuse of systemic thrombolysis is unclear and cannot be completely explained by rising catheter-based or surgical revascularisation rates [127]. Challenging the validity of relative contraindications to thrombolysis may help to increase the use of thrombolysis in unstable patients with life-threatening PE.

The main complication of thrombolytic therapy is bleeding. The Pulmonary Embolism Thrombolysis (PEITHO) trial revealed a 2% incidence of haemorrhagic stroke and 6.3% incidence of major non-intracranial bleeding in patients treated with tenecteplase [128], which has led to the recommendation that routine thrombolysis is not recommended in patients who are not in shock.

Interventional treatment

In patients with absolute contraindications and in those whose unstable conditions do not allow sufficient time for systemic thrombolysis to be effective, surgical embolectomy or catheter-directed intervention are alternative reperfusion therapies if appropriate expertise is available [129]. Approximately one third of patients with an acute major PE are not eligible for thrombolysis because of contraindications such as recent surgery, trauma, stroke, advanced cancer or concomitant active bleeding [109]. Furthermore, interventional management should be considered as adjunctive therapy when thrombolysis has failed. Critical clinical conditions which warrant interventional strategies have not been clearly defined. However, several criteria, such as shock with large thrombus burden, severe RV failure with large saddle embolism or moderate RV failure with proximal embolism, justify an interventional approach in a patient with acute PE.

Surgical embolectomy

Historically, surgical embolectomy was restricted to clinically futile circumstances in moribund patients who required cardiopulmonary resuscitation. Over recent years, however, pulmonary embolectomy has become a routine operation with significantly reduced operative risk in centres with established cardiac surgery programmes [129, 130]. This operation requires rapid induction of anaesthesia, a median sternotomy, incision of the main pulmonary artery, and institution of cardiopulmonary bypass. Emboli can be removed from both pulmonary arteries using forceps under direct vision. Generally, this procedure is performed under normothermia without cardioplegic cardiac arrest [130]. The first successful surgical pulmonary embolectomy, called Trendelenburg’s operation, was performed in 1924 [131].

Current guidelines recommend surgical embolectomy in patients with failed thrombolysis and in those with contraindications to thrombolysis. As surgical embolectomy represents a relatively simple operation and outcome is not critically affected by the site of surgical care, delays in treatment by hospital transfer should be avoided as long as an experienced surgeon and cardiopulmonary bypass are available [132]. Peripheral extracorporeal membrane oxygenation support is a rapid, effective option in critical situations for ensuring circulation and oxygenation until surgical embolectomy can be performed [133].

Surgical embolectomy represents a valuable treatment option in high-risk PE patients with comparable in-hospital mortality rates and significantly less bleeding complications than thrombolysis [134]. In patients with failed thrombolysis, surgical embolectomy significantly improves the haemodynamic status but is associated with increased bleeding rates [135, 136].

Pulmonary embolectomy has also shown promising results in patients with PE and RV dysfunction without persistent hypotension or shock [137]. Initially, pulmonary embolectomy was associated with high early mortality rates [135, 138, 139]. With expansion of indications for surgical embolectomy in patients with RVD but no severe shock, early mortality rates of 6% to 8% have been reported [135, 138, 139]. In patients with CTEPH a dedicated pulmonary endarterectomy (PEA) (which differs from thrombectomy as it targets the intimal-medial layer of the vessel as the surgical dissection plane rather than the thrombus surface) has to be performed by an experienced surgeon [140].

Catheter-based revascularisation

The removal of obstructing thrombi by percutaneous catheter intervention is a promising treatment alternative to surgical embolectomy for patients with high-risk PE to reverse RV failure and cardiogenic shock [141, 142, 143]. Catheter-based revascularization techniques comprise approaches with local thrombolysis and those without thrombolysis. Catheter-techniques without thrombolysis, including thrombus fragmentation, rheolytic or rotational thrombectomy, or suction thrombectomy, are indicated when contraindications for thrombolysis exist [144]. For patients without absolute contraindications to thrombolysis, catheter-based thrombolysis might be a promising therapeutic option. A summary of available devices and techniques for catheter-based revascularization of PE is given in Table 7 .

A “clean” angiographic result is not the goal of catheter embolectomy. Instead, the aim of this procedure is instantaneously to reduce pulmonary vascular resistance and right ventricular afterload, and to increase cardiac output and systemic arterial pressure. The intervention is finished as soon as haemodynamic improvement is obtained, regardless of the extent of residual thrombi in the pulmonary vasculature [145, 146]. Substantial improvement in pulmonary blood flow may result from a visually modest angiographic result.

During pulmonary angiography or catheter thrombectomy, continuous monitoring of haemodynamic parameters and ECG is required. The intervention necessitates a vascular approach with selective catheterisation of the pulmonary arteries and injection of a contrast agent. The common femoral veins are the preferred venous access sites using a 6 French introducer sheath for patients who are scheduled for unilateral catheter placement or a 10 French double-lumen introducer sheath for those who are scheduled for bilateral catheter insertion [146]. In the case of ilio-femoral deep vein thrombosis, the contralateral common femoral vein may be considered for venous access.

One practical approach is the use of a “pharmaco-mechanical” strategy, using local low-dose thrombolytics (if lytic eligible) along with the EKOS ultrasonic catheters ( Figure 4 ). Typically 10-15mg tissue plasminogen activator (tPA) are used per pulmonary artery, infused over 12 hours. There is bench data to suggest that tPA in conjunction with the EKOS infusion catheter is much more effective than local tPA alone [147]. Retrospective analyses revealed better thrombus removal and less treatment-related complications for ultrasound-assisted thrombolysis compared to conventional catheter-directed thrombolysis [148].

Current experience is limited [149] because no randomised controlled trial has compared catheter embolectomy with surgical embolectomy or thrombolytic therapy in this setting. Promising results of a small non-randomised observational cohort study [150] demonstrated a similar clinical outcome for high-risk PE after percutaneous catheter intervention compared to surgical embolectomy. Because catheter interventions were commonly combined with pharmacological thrombolysis, the efficacy of the mechanical intervention alone remains unclear [149, 150]. A small study [151] suggests that mechanical catheter intervention alone without concomitant thrombolysis can lead to immediate improvement in systemic arterial pressure. An analysis of studies evaluating the safety and efficacy of percutaneous catheter interventions showed an overall clinical success rate, defined as immediate haemodynamic improvement, of > 80%. The reported mortality rates range from 0 to 25% [141]. The recently published ULTIMA trial showed for the first time in a randomized fashion that an ultrasound-assisted catheter-directed thrombolysis in patients with acute PE was superior to anticoagulation with heparin alone in improving RV dysfunction at 24 hours [152].

Complications of percutaneous catheter interventions

General complications of percutaneous catheter interventions are associated with the passage of the pulmonary artery catheter and then thrombectomy itself. The most serious complication is the perforation or dissection of a branch of the pulmonary artery, which may lead to massive pulmonary haemorrhage or immediate death. The risk of perforation increases when the diameter of treated pulmonary vessels is < 6 mm [153]. To reduce the risk of perforation and dissection, thrombectomy is exclusively recommended in the main and lobar pulmonary arteries, and not in the segmental pulmonary arteries [141, 143]. Pericardial tamponade is a further hazard In particular, the right ventricular outflow tract is thin and fragile, and caution is warranted when pushing any device into the pulmonary trunk. An additional risk involves the distal embolisation of proximal thrombi that can exacerbate the patient’s haemodynamic instability during thrombectomy [145]. In order to avoid perforation and damage of susceptible structures, catheter interventions should only be performed by interventionists specialised in high-risk PE and percutaneous catheter techniques. Furthermore, the operator should be able to handle emergent pericardiocentesis in case of a perforation and should be familiar with measures to achieve rapid reversal of anticoagulation. Device-related complications also include substantial blood loss in the case of prolonged aspiration, or even mechanical haemolysis. Mechanical haemolysis may lead in turn to hypotension and acute pancreatitis [154]. Arrhythmia may occur during catheter passage through the right heart. Further complications are bleeding caused by heparin anticoagulation, contrast-induced nephropathy, anaphylactic reaction to iodine contrast, and vascular access complications, such as haematoma, pseudoaneurysm, or arteriovenous fistula [144].

Non-high-risk pulmonary embolism

Non-high-risk PE patients have a favorable short-term prognosis. The subcutaneous administration of weight-adjusted doses of LMWH or fondaparinux is the recommended treatment for normotensive patients with PE [52]. As alternative to the combination of parenteral anticoagulation with a vitamin K antagonist, NOACs represents a valuable treatment option in those patients in whom no primary reperfusion therapy is planned. Table 4 may help to identify patients that are suitable for anticoagulant therapy with NOACs. Further treatment decisions should be based on further risk stratification into low-risk or intermediate risk patients.

Low-risk pulmonary embolism

If patients are haemodynamically stable, have no signs of RV dysfunction and negative biomarkers, anticoagulation alone is the treatment of choice. Thrombolytic therapy has demonstrated no clinical benefit for this patient population [99]. If proper outpatient care and anticoagulant treatment can be provided, early hospital discharge should be considered. A prospective study showed that outpatient management of PE is feasible and safe for the majority of these patients [155].

Intermediate-risk pulmonary embolism

Haemodynamically stable patients with evidence of RV dysfunction or myocardial injury are classified as intermediate-risk patients. Whereas thrombolysis is accepted as gold standard treatment for unstable patients, the benefits of thrombolytic therapy in intermediate-risk patients are controversial. Despite normal systemic arterial blood pressure, patients with RV dysfunction have a higher mortality than those with normal RV function [15, 90]. Therefore, intermediate risk patients will be further stratified into intermediate-high and intermediate-low risk patients ( Figure 1 ) to identify the appropriate therapy.

Intermediate-high risk patients

There is growing evidence that intermediate-high risk patients may benefit from a primary reperfusion therapy. The PEITHO trial [128] revealed systemic thrombolysis as beneficial therapy in intermediate-high risk patients to prevent life-threatening haemodynamic decompensation or collapse. However, this benefit is counterbalanced by an increased risk of haemorrhagic stroke or major non-intracranial bleeding. Based on these results, thrombolytic therapy may be favourable in selected patients with intermediate-high risk PE, particularly in those with low bleeding risk. This observation emphasizes the need for rapid and reliable risk stratification in all patients with PE. In critical patients with high bleeding risk surgical pulmonary embolectomy or percutaneous catheter-directed treatment may be considered as revascularization option. Particularly, catheter-directed ultrasound-accelerated thrombolysis has been identified to be superior in reversing RV dilatation at 24 hours, without an increase in bleeding complications compared to anticoagulation with heparin alone [152].

Intermediate-low risk patients

Anticoagulation alone is the treatment of choice. There is no evidence to recommend primary reperfusion therapy as well as bed rest.

Incidental clinically unsuspected pulmonary embolism

The widespread use of CT scans has led to an increased number of incidentally diagnosed, clinical unsuspected PE during diagnostic work-up for other diseases [156]. Incidental discovery of PE was most frequently observed in patients with cancer, but also in patients with paroxysmal atrial fibrillation and heart failure [157, 158]. Despite a lack of clear evidence, the guidelines carefully recommend that patients with cancer and those with emboli at the lobar or more proximal level should be managed in the same way as symptomatic PE [52].

Long-term anticoagulation and secondary prophylaxis

VTE recurs in approximately one fourth of patients within five years after the initial venous thromboembolic event [159], which justifies long-term anticoagulant treatment of patients with PE to prevent fatal and non-fatal recurrent VTE events. Anticoagulant therapy of VTE is classified into three stages. Following the initial therapy, the long-term treatment, and if necessary extended anticoagulation have to be established.

The transition from initial therapy to long-term treatment occurs traditionally in two overlapping steps. Immediate full anticoagulation with a parenteral anticoagulant as initial therapy. Simultaneously with parenteral anticoagulation, oral anticoagulation with vitamin K antagonists is initiated, which remains the mainstay of secondary prophylaxis. Heparin and vitamin K antagonist therapy should initially overlap because vitamin K antagonists also reduce the activity of anticoagulant proteins C and S. Full therapeutic efficacy at an international normalised ratio of 2.0 to 3.0 is achieved after five days of therapy [160]. Heparin treatment can be discontinued when the INR has been in the therapeutic range on two measurements at least 24 hours apart. Since treatment with a vitamin K antagonist requires laboratory monitoring and dose adjustment and may be complicated by drug and food interactions, outpatient therapy remains challenging. Whether oral anticoagulation can be stopped or must be taken indefinitely depends on the underlying disease and the risk of recurrence [160]. The guidelines [52] recommend anticoagulation for at least three months in patients with unprovoked PE or with PE secondary to a transient (reversible) risk factor. For patients with PE and cancer, weight-adjusted LMWH anticoagulant therapy should be considered for the first 3 to 6 months. Before stopping treatment clinicians must balance the long-term risks of recurrent VTE if anticoagulation is stopped against the burden and risks of ongoing therapy [161]. In those patients at high-risk of recurrent VTE, an extended anticoagulation therapy should be considered as long as the bleeding risk is not excessive. Extended anticoagulation should regularly be reevaluated, based on changes in the balance between the risks of recurrence and bleeding. Lifelong treatment anticoagulation is recommended for patients with a second episode of unprovoked PE [52]. A risk score has been proposed for the estimation of the risk of recurrence after a first symptomatic PE, based on thrombus location, gender and D-Dimer at three months [159].

Over the past years the new oral anticoagulants, including dabigatran, rivaroxaban, and apixaban, have been intensively evaluated as treatment option for long-term as well as extended therapy of patients with VTE [162, 163, 164]. In contrast to VKA, treatment initiation with rivaroxaban and apixaban are started in the acute phase without initial parenteral coagulation and an overlapping switch. Administration of dabigatran is recommended following acute phase parenteral anticoagulation. For long-term anticoagulation NOACs were found noninferior to conventional therapy with vitamin K antagonist for VTE treatment and are associated with less bleeding [165, 166]. In the setting of extended therapy, dabigatran, rivaroxaban, and apixaban are superior to placebo for the prevention of recurrent VTE and are associated with low rates of major bleeding. There is growing evidence that the dose of NOACs can be lowered for extended VTE treatment to reduce the bleeding risk without compromising efficacy [162]. On the contrary, a lower dose of vitamin K antagonist for extended VTE therapy was associated with reduced efficacy without evidence of less bleeding [167].

Inferior vena cava filters

Inferior vena cava (IVC) filters were originally developed for selected patients with absolute contraindications to anticoagulation, failure of anticoagulation or complication whilst on anticoagulation, who have a venous thromboembolic event, or prophylactically for patients with a high risk of PE. It is important to emphasise that the use of an IVC filter does not obviate the need for anticoagulation, unless a major complication has ensued [161]. In particular, after implanting an IVC filter as a temporary alternative, anticoagulation should be started as soon as the risk of bleeding has resolved.

IVC filters are used in the indication of DVT or PE to reduce the risk of recurrent PE. Filters are implanted percutaneously just below the junction of the IVC and the lowest renal vein. In cases of renal vein thrombosis or where thrombus exists at the level of the renal veins, filters can be placed in a suprarenal position. The right internal jugular vein or the right femoral vein is the preferred point of vascular access, but left-sided venous approaches or approaches using arm veins can be used depending on patient anatomy. Bedside ultrasound-guided placement and bedside intravascular ultrasound-guided placement may improve the safety and efficacy of this procedure [168, 169].

Filters span the luminal diameter of the IVC and are designed to mechanically trap thrombus from the lower half of the body, reducing the risk of emboli from reaching the pulmonary circulation. Filters per se do not have any anticoagulant effects or prevent the recurrence of DVT and emboli [170].

There are numerous IVC filters currently available ( Table 8 , Figure 5 ) which are principally of two types: permanent or retrievable. Additionally, filters differ in terms of material, maximum radial diameter, and MRI compatibility.

The implantation of permanent IVC filters may provide lifelong protection against recurrent PE, but not against the sequelae of lower limb venous disease. The latter include recurrent DVT (in 20% of implantations) and post-thrombotic syndrome (in 40% of patients) [171]. Procedural complications include access site haematomas (2.4% to 4.2% of cases), access site thrombosis (3.8% to 4.2%) and filter displacement (1.1% to 4.6%) [172].

Retrievable filters were designed to reduce the long-term complications associated with permanent filters, in particular the increased risk of DVT [173, 174, 175]. It is recommended that retrievable devices should be removed within 2 weeks of implantation (an example of the retrieval technique is illustrated in ( Figure 6 ). The availability of retrievable filters led to an increased use of IVC filters with lower threshold for filter placement [176, 177], although up to 70% of retrievable filters were not removed [178]. Reasons for this may be that removal of these filters requires a second interventional procedure leading to additional costs and human resources, radiation exposure, and procedural risks. Furthermore, some retrievable filters cannot be removed for technical reasons such as angulation or thrombus [179, 180].

The risk/benefit ratio of IVC filters is unclear. A large randomised study[173] demonstrated a reduced risk of recurrent PE at the cost of an increased risk of recurrent DVT, with no effect on overall survival. Current guidelines do not recommend the routine use of IVC filters in patients with PE (Class III, Level B). Even the recommendation for IVC filter implantation in patients with absolute contraindications to anticoagulation and a high risk of VTE recurrence is cautious (Class IIb, Level B) [52].

Primary prophylaxis

Patients at risk, including nearly all hospitalised patients, should receive mechanical or pharmacological prophylaxis for VTE to reduce the incidence of symptomatic DVT and/or PE. Especially in post-operative patients, the risk of VTE persists several weeks after hospital discharge [173]. Mechanical strategies include the use of compression stockings and intermittent pneumatic compression, which can reduce the risk of DVT by 60% [181]. Unfractionated heparin, LMWH, fondaparinux, and warfarin are recommended as pharmacological prophylaxis for VTE, in combination with mechanical devices in high-risk patients [160]. Furthermore, the effectiveness of NOACs in the prevention of VTE after orthopaedic surgery has been demonstrated [182, 183, 184, 185].

In addition, subanalyses of the Jupiter trial [7] have demonstrated that treatment with rosuvastatin prevents venous thrombotic events in apparently healthy persons with elevated C-reactive protein.

FOCUS BOX 2Prevention of recurrent pulmonary embolism

The new acute PE risk stratification is utilising right ventricular function, the PESI score and biomarkers to predict outcome and guide treatment strategies [52]
Annual risk of recurrence after symptomatic pulmonary embolism 8.70% [186]
Annual risk of bleeding with anticoagulation 3.36% [187]
Anticoagulation for at least 3 months in patients with unprovoked PE or with PE secondary to a transient (reversible) risk factor [52]
The new oral anticoagulants (Dabigatran, Rivaroxaban, Apixaban and Edoxaban) have diminished bleeding rates in the presence of at least equal efficacy, and selected NOACs are efficacious for long-term prevention of recurrence at reduced doses [119]

Pulmonary hypertension

SUMMARY

“The end is where we start from” refers to the vast loss of functional pulmonary vessels which has already taken place in >80% of patients with pulmonary arterial hypertension (PAH) at the point when clinical symptoms of pulmonary hypertension (PH) occur for the first time.

According to the current guidelines for the diagnosis and treatment of pulmonary hypertension [188] the diagnostic classification separates precapillary pulmonary hypertension, i.e., pulmonary hypertension due to pulmonary vascular disease mainly affecting the precapillary arteriolar compartment (i.e., groups 1, 3, 4 and 5), from postcapillary disease which originates distal to the capillaries, and entails morphological changes in the precapillary compartment only after a significant pressure increase in the venous compartment (i.e., group 2). Currently, a single haemodynamic parameter, i.e., wedge pressure [189] which is commonly flawed by methodological errors [190] is used to distinguish between pre and postcapillary disease. This distinction is key because treatments are completely different for the two classes of disease [188]. For example, epoprostenol, the life-saving treatment for PAH [191] , was shown to be detrimental in congestive heart failure [192].

INTRODUCTION

Major advances have taken place in the area of pulmonary hypertension (PH) over the past decade. Our understanding of the pathophysiological mechanisms underlying the condition has improved significantly, has led to new treatment strategies [188].

DEFINITION

PH is a haemodynamic and pathophysiological state that can be found in multiple clinical conditions, and is defined by an invasively measured mean pulmonary arterial pressure (PAP) ≥25 mmHg at rest [188]. The normal resting mean PAP is 14 ± 3 mmHg with an upper limit of normal of approximately 20 mmHg. No standardised definition exists of PH on exercise. Borderline PH with mean PAP values in the upper normal should be carefully followed when further risk factors for PAH are present. Preliminary data suggests that borderline PH with resting mean PAP greater than 17 mmHg may be associated with adverse events and reduced survival [193].

Hemodynamically, PH is classified into pre-capillary PH, characterized by a mean pulmonary arterial wedge pressure (PAWP) ≤15 mm Hg, and post-capillary PH, as indicated by a PAWP >15 mm Hg. This distinction is important because medications that have been approved for pre-capillary disease do not work in post-capillary disease. PAH represents a rare form of pre-capillary PH, defined by a pulmonary PAWP ≤15 mmHg and additionally a PVR > 3 Wood units (WU) in the absence of other causes of precapillary PH such as lung diseases, chronic thromboembolism or other rare diseases [188]. However, evidence exists that a PAWP of 12mmHg may be a better cutoff to safely classify pre-capillary PH [194, 195]

Post-capillary PH related to left heart and valve disease may be further stratified into isolated post-capillary PH, classified by a diastolic pressure gradient (DPG) < 7 mmHg and/or a PVR ≤ 3 WU, or a combined post-capillary PH with a pre-capillary component (DPG ≥ 7 mmHg and/or a PVR > 3 WU) [188, 194].

CLINICAL CLASSIFICATION OF PULMONARY HYPERTENSION

The early clinical signs and symptoms of PH are scarce, and >80% of patients have advanced disease with World Health Organization functional classes >III at first presentation [2]. Pulmonary arterial hypertension (PAH) should be considered in the differential diagnosis of unexplained fatigue, exertional dyspnoea, syncope, angina and progressive limitation of exercise capacity, particularly in patients without signs of common cardiovascular or respiratory disorders.

Recently published guidelines for the diagnosis and treatment of pulmonary hypertension have provided an updated classification [188], and recommendations for contemporary diagnosis and treatment of PH [196]. PH is classified into five groups according to pathological and pathophysiological characteristics, with several new genetic entities that were added, e.g. group 1’ which is veno-occlusive disease and/or pulmonary capillary haemangiomatosis as a consequence of mutations in the EIF2AK4 gene (eukaryotic translation initiation factor 2 alpha kinase 4) ( Table 9 ) Group 1 has been extended to include idiopathic, heritable, drug-, toxin- and radiation-induced and associated forms. Group 2 has been amended by congenital/acquired left heart inflow and outflow tract obstruction. Group 3 has taken on Developmental lung diseases. Hemolytic anemia associated PH was eliminated from group 1.

Due to subset-specific treatments, an exact diagnosis and group assignment are of major importance. Patients from group 1 have a benefit from specific (“targeted”) vasodilator therapy, whereas in patients from groups 2, 3 and 5 treatment of the underlying cardiac and pulmonary disease is indicated.

EPIDEMIOLOGY

The incidence and prevalence of group 1 PAH, which includes idiopathic, heritable, drug-induced PAH, as well as PAH associated with a variety of conditions and diseases, are estimated at 2.4 cases/million annually and 15 cases/million in France [2]] and 7.6 cases/million annually and 26 cases/million in Scotland [197]. Idiopathic PAH (IPAH, formerly primary pulmonary hypertension, PPH) is the prototype of PAH. In the subgroup of associated PAH conditions, the leading disease is systemic sclerosis. The prevalence of PAH in the developing world is probably greater because risk factors for PAH, such as HIV, schistosomiasis, and sickle cell disease, are more prevalent in these countries [198]. The mortality at 1 year for PAH is 15% [199]

The prevalence of group 2 PH, which is caused by left heart disease, is very high in patients with left ventricular (LV) dysfunction. About 60% of patients with severe LV systolic dysfunction and up to 70% of patients with isolated LV diastolic dysfunction develop PH, which is a prognostic factor [200]. In left-sided valvular heart diseases the prevalence of PH depends on the severity of the defect and of the symptoms. Nearly all patients with severe symptomatic mitral valve disease and up to 65% of those with symptomatic aortic stenosis have concomitant PH [201, 202, 203].

Group 3 PH due to lung diseases and/or hypoxaemia as occurring in patients with chronic obstructive pulmonary disease (COPD) carries a prevalence of 20% and increases >50% in advanced COPD [204, 205]. Interstitial lung disease is associated with PH in between 32% and 39% [206].

The incidence of CTEPH is estimated at 5 per million and year [3]. CTEPH is derived from pulmonary embolism, but may also occur in the absence of symptomatic PE [207].

Due to the heterogeneity of group 5 PH with unclear and/or multifactorial mechanisms, epidemiological data are scarce.

DIAGNOSIS

A series of examinations is necessary in patients with suspected PH. Assignment to a PH subset is of major importance for optimal therapy. An integrated diagnostic algorithm [208] as shown in Figure 7 summarises recommended diagnostic steps.

Clinical presentation

Pulmonary hypertension commonly goes clinically silent until advanced stages of the disease. More than 75% of patients first present in NYHA classes III and IV. Cardinal symptom is breathlessness on exertion. Other common symptoms are fatigue, weakness and angina pectoris as a correlate for RV ischaemia. Syncope, pre-syncope, vertigo, peripheral oedema and haemoptyses may occur in advanced stages [209], as well as symptoms at rest (WHO class IV). Physical examination reveals a palpable parasternal RV impulse, an accentuated pulmonary component of second heart sound, a right-sided fourth heart sound, and tricuspid regurgitation. Signs of right heart failure, including increased jugular venous pressure, hepatomegaly, peripheral oedema, ascites, and peripheral cyanosis [210]. Lung auscultation and oxygen saturation are usually normal in idiopathic PAH.

Any of the above symptoms can be caused by many other diseases, such as coronary artery disease, emphysema, pneumonia, congestive heart failure and asthma. Therefore, the diagnosis of PH is often delayed until symptoms become severe and extensive vascular damage has occurred [211]. However, early diagnosis and treatment are believed to be crucial [212]. Various tests can be used for the initial evaluation of patients suspected of having PH. Chest x-rays and ECG are diagnostic tools with low accuracy for the diagnosis of PH, however, due to their broad availability and low cost, they can be employed as first diagnostic steps.

Diagnostic algorithm/Imaging

PAH should be considered in the differential diagnosis of dyspnoea, syncope, angina, and/or progressive limitation of exercise capacity. In particular, patients with associated conditions and/or risk factors for development of PAH, such as family history, connective tissue disease, congenital heart disease, HIV infection, portal hypertension, haemolytic anaemia, or a history of intake of drugs and toxins, should be systematically examined. ECG, chest radiograph, transthoracic echocardiogram, pulmonary function tests and high-resolution chest CT are recommended to identify potential patients of group 2 with left heart disease or group 3 with lung diseases. In patients with diagnosed scleroderma, annual screening (echocardiogram, DLCO, and BNP) is recommended [188]. According to a recent algorithm ( Figure 7 ), a V/Q-scan is indicated as a first step to rule out CTEPH [213]. If elevated pressure in the pulmonary circulation is suspected, an RHC is necessary. After a diagnosis of PH has been confirmed, additional specific diagnostic tests are to be performed to determine the specific aetiology of PH ( Table 10 ) [188]. Since PAH, and particularly IPAH, is a diagnosis of exclusion, it is essential to follow this algorithm to facilitate the diagnostic investigation.

Electrocardiogram

Typical signs of PH in the ECG are RV hypertrophy and strain, right axis deviation and right atrial dilatation. Supraventricular arrhythmias may be present in advanced stages and are associated with clinical deterioration [214]. The absence of any abnormalities in the ECG does not exclude PH. About 13% of patients with a confirmed diagnosis of PH have initially been shown to have normal ECGs [215]. Due to its low sensitivity (55%) and specificity (70%), ECG may provide only suggestive or supportive evidence of PH [215]. However, ECG criteria in combination with biomarkers and echocardiography have been shown to improve specificity substantially [216]. These tools help avoid one of ten invasive haemodynamic assessments, which are performed for suspicion of precapillary disease.

Pulmonary function tests

Diffusion capacity of the lung for carbon monoxide (DLCO) is an important diagnostic and prognostic variable in PH patients [217, 218]. The differential diagnosis for PH patients with abnormal DLCO < 45% includes PVOD, PAH associated with scleroderma and parenchymal lung disease [188].

Chest X-ray

The chest x-ray is abnormal in 90% of patients with IPAH at the time of diagnosis [209]. The chest x-ray may reveal hilar enlargement, which reflects pulmonary artery dilation. Right atrium and RV enlargement may be detected in more advanced cases. The chest x-ray also plays an essential role in the exclusion of lung diseases that form an important part of the differential diagnosis.

Echocardiography

Transthoracic Doppler echocardiography is the predominant screening modality in early stages of diagnosis. Importantly, echocardiography should be used to determine the probability of PH, but echocardiography alone is not sufficient to support a treatment decision [188]. Three levels of probability of PH (low, medium, and high) are established based on peak tricuspid regurgitation velocity (TRV) at rest and, as mandated in the guidelines, on the presence of additional echocardiographic variables, including PH signs in ventricles (eccentricity index), the pulmonary artery diameter and the inferior vena cava and right atrium (collapsibility upon inspiration). Grading of the probability of pulmonary hypertension in symptomatic patients with a suspected diagnosis based on echocardiographic parameters is outlined in Table 11.

In patients with a high probability of PH, it is recommended to perform an invasive diagnostic evaluation [188]. In patients with low probability of PH, an alternative diagnosis should be considered. In patients with intermediate probability of PH and risk factors or associated conditions for PAH or CTEPH, further investigations including RHC are recommended.

Surrogates of right ventricular function e.g. tricuspid annular plane systolic excursion, global longitudinal strain of the RV free wall or color tissue Doppler S wave of tricuspid annulus may be useful to follow up right ventricular function over time [219]. Furthermore, significant progress has been made in use of knowledge-based reconstruction of 3D RV structure and function from 2D images [220]. Studies have suggested that 3D echo imaging of the RV is feasible, and its results compare well with magnetic resonance imaging (MRI) [220].

Right heart catheterisation and vasoreactivity testing

The diagnosis of pulmonary hypertension is based on right heart catheterisation [219]. Right heart catheterisation (RHC) is associated with low rates of morbidity (1.1%) and mortality (0.055%) when performed in experienced centres [221]. The following parameters should be assessed during RHC: pulmonary artery pressure (systolic, diastolic and mean), right atrial pressure, pulmonary artery occlusion pressure (PCOP), and RV pressure. Cardiac output should be measured in quadruplicate by thermodilution or by the Fick method which is obligatory when systemic-to-pulmonary shunt is present). The measurement of superior vena cava, pulmonary artery, and systemic arterial blood oxygen saturations and pulmonary vascular resistance is recommended. The assessment of PAWP is essential to discriminate between pre and postcapillary PH. A PAWP >15 mmHg suggests elevated LV filling pressures, and generally excludes the diagnosis of precapillary PAH, except for extremely rare cases where pre and postcapillary PH coexist. During RHC the vasoreactivity of the pulmonary circulation is assessed in patients with precapillary PH. Recommendations for RHC and vasoreactivity test are summarised in Table 12. The use of nitric oxide is recommended for vasoreactivity testing. A positive acute response is defined as a decrease of the mean PAP ≥10 mmHg to reach an absolute value of mean PAP ≤40 mmHg with an increased or unchanged cardiac output [222]. A positive acute test result predicts a high likelihood of a clinical and haemodynamic response to calcium channel blockers, but does not guarantee a response. The simultaneous performance of a coronary angiography is indicated in patients with a high-risk profile for coronary artery disease, or in case of listing for double lung transplantation or pulmonary endarterectomy (PEA) in patients with CTEPH.

Ventilation/perfusion lung scan

A V/Q-scan should be performed in patients with PH to exclude CTEPH ( Figure 7). V/Q-scan has a higher sensitivity than CT and remains the screening method of choice for CTEPH [223].

Contrast-enhanced computed tomography/High-resolution computed tomography

These examinations provide detailed information about the pulmonary artery trunk, proximal and distal pulmonary arteries, and morphology of the heart and lung parenchyma. In patients with PH, the diameter of the pulmonary artery trunk is significantly enlarged and correlates well with pulmonary artery pressure measurements [224]. For identifying CTEPH, contrast CT angiography is an important diagnostic tool, although less sensitive than pulmonary angiography.

Cardiac magnetic resonance imaging

Cardiac magnetic resonance imaging has been shown to be highly accurate and reproducible in the measurement of RV morphology and function, and allows non-invasive assessment of RV mass. In patients with PAH, cardiac magnetic resonance provides useful prognostic information at baseline and at follow-up [225, 226].

Pulmonary angiography

Pulmonary angiography is important to examine the pulmonary vasculature for identifying patients who may benefit from PEA or percutaneous balloon pulmonary angioplasty in the setting of CTEPH [188].

Genetic testing and counseling

Genetic testing for IPAH, heritable pulmonary arterial hypertension and veno-occlusive PH are recommended upon diagnosis of the disease [188]. Patients with IPAH should be screened for BMPR2, ACVRL1 and ENG mutations. Heterozygous BMPR2 mutations represent the most common genetic disorders and account for approximately 75% of familial PAH. In patients with sporadic or familial pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis screening for EIF2AK4-mutations (eukaryotic translation initiation factor 2 alpha kinase 4) is recommended. No underlying genetic basis has been detected in patients with PH in groups 2 to 5.

Genetic counseling should be offered to selected PAH patients by a specialized multidisciplinary team, involving PH specialists, genetic counsellors, geneticists, psychologists and nurses in line with local legislation [227].

PROGNOSIS AND TREATMENT

Comprehensive prognostic evaluation and risk assessment is critical for further therapeutic strategies and therefore highlighted by current guidelines [188]. It has become apparent that a single variable does not provide sufficient diagnostic and prognostic information. Therefore, the severity of PAH should be regularly assessed in expert PH centres at baseline and every 3-6 months based on a multidimensional approach, including clinical assessment, exercise tests, biochemical markers and echocardiographic and haemodynamic evaluations. PAH patients should be stratified into low- (< 5%), intermediate- (5%-10%), and high-risk (> 10%) patients according to their calculated risk of 1 year mortality as followed:

Low risk: No signs of right heart failure, no progression of symptoms, New York Heart Association (NYHA)/WHO functional class (FC) I, II, 6MWD >440 m, peak VO2 >15 ml/min/kg, NT-proBNP <300 ng/L, no pericardial effusion, normal right atrial (RA) size, RA pressure <8 mm Hg, CI ≥2.5 L/min/m2, and SvO2 >65%.

Intermediate risk: No signs of right heart failure, occasional syncope, slow progression of symptoms, WHO FC III, 6MWD 165-440 m, peak VO2 11-15 ml/min/kg, NT-proBNP 300-1400 ng/L, no or minimal pericardial effusion, RA area >26 cm², RA pressure >14 mm Hg, CI <2.0 L/min/m2, and SvO2 <60%.

High risk: Clinical signs of right heart failure, rapid progression, repeated syncope, WHO FC IV, 6MWD <165 m, peak VO2 <11 ml/min/kg, NT-proBNP >1400 ng/L, pericardial effusion, right arterial pressure >14 mm Hg, cardiac index (CI) <2.0 L/m/m2, and mixed venous oxygen saturation (SvO2) <60%.

A major objective in the treatment of patients with PAH is to maintain a low-risk profile and thus prolong life [188]. Recent data suggest that a morbidity event up to month 3 after treatment escalation carried a greater than 4-fold increased risk of death within the next 20 months. Early intervention, regular monitoring, and escalation of treatment are key factors that influence survival, and evaluation of risk plays a driving role at each of these key stages.

TREATMENT

The first approach of PH therapy includes referral to an expert centre and general therapeutic measures including avoidance of pregnancy, immunization against influenza and pneumococcal infection as well as psychosocial support. When arterial blood oxygen pressure is consistently <8 kPa, continuous long-term oxygen therapy should be started.

Treatment strategies for PAH are depicted in Figure 8. High doses of calcium antagonists are indicated as first-line medical therapy in those patients with IPAH, HPAH, and drug/toxin-associated PH that respond to initial acute vasodilator testing. Achievement/maintenance of a low-risk profile (see chapter Prognosis) is considered as adequate treatment response. Reevaluation of therapy should be performed 3-4 months after initiation of therapy by RHC, including vasoreactivity testing. PAH treatment is recommended in patients with WHO-FC I/II and significant haemodynamic improvement. In those patients with FC III/IV or no significant haemodynamic stabilization, the initiation of PAH specific therapies, primarily targeting a relief of right ventricular afterload by vasodilation via stimulation of soluble guanylate cyclase, prostacyclins and analogues, and inhibitors of phosphodiesterases and endothelin receptors, is recommended.

The most recent treatment algorithm for PAH patients recommends the initiation of a mono- or combination therapy depending on calculated individual risk, rather than on WHO class alone. In high-risk patients, combination therapy including parenteral prostacyclins should be started immediately. Treatment has to be continuously upscaled untila low risk state is achieved. Low-and intermediate risk patients should receive upfront combination therapy, preferentially with ambrisentan and tadalafil [228], but given the appropriate setting, monotherapy is acceptable. When treatment goals are not met with monotherapy, double therapy, and finally triple sequential therapy should be started. Recommendations for specific drug mono- and combination therapies for PAH are comprehensively outlined in current guidelines for the diagnosis and treatment of pulmonary hypertension [188]. For patients with PH in groups 2 and 3, PAH-specific drugs are not recommended.

Interventional treatments of PH have been limited to interventions for pediatric pulmonary vascular disease, and to graded balloon atrial septostomy for selected cases of severe pulmonary arterial hypertension [229]. Recently, goal-orientated therapeutic approach using sequential combinations of bosentan, sildenafil, and inhaled iloprost [230] are giving way to more aggressive upfront combination regimens [188]. Evidence is accumulating that a “hit-hard-and-early strategy with multiple agents” for the treatment of severe PAH may be associated with better survival [231, 232].

In patients with inadequate response to treatments, end-of-life decisions, and consideration of referral for lung transplantation should be discussed.

Any treatment-resistant pulmonary hypertensive condition may be considered for balloon atrial septostomy (BAS). The creation of an inter-atrial right-to-left shunt can decompress the right heart chambers, and increase LV preload and CO [233]. Systemic O2 transport is improved despite arterial O2 desaturation and decreases sympathetic hyperactivity. The recommended technique is graded balloon dilation atrial septostomy, which carries a reduced risk compared with the original blade technique. Recently, modified atrial septal occluders [234], or interatrial stents have been used to prevent the need for repeated procedures which pose an unacceptable risk to these vulnerable patients. BAS should be avoided in end-stage patients showing a baseline mean RAP of >20 mmHg and O2 saturation at rest of <80% on room air. Patients should be on optimal medical therapy, which may include pre-conditioning with IV inotropic drugs, prior to BAS. Evidence shows improvements in CI and decreases in right atrial pressure with improvement in 6MWT. The impact of BAS on long-term survival has not been established in RCTs [235]. To perform BAS, it is not sufficient to be experienced in structural heart disease interventions in general. Clinicians must be trained in the management of patients with severe pulmonary vascular disease, as they pose additional challenges to catheter laboratory procedures [233]. In the current world BAS is hardly performed any more for PAH.

PAH is a life-threatening condition that requires both regular monitoring and timely escalation of treatment in order to limit or ideally reverse progressive vascular remodelling and right-heart failure. Recent predictive algorithms from large national registries [236, 237] suggest gender, PAH subtype, functional class, haemodynamics, biomarkers, 6MWD, renal function, and parameters such as pericardial effusion and carbon monoxide lung diffusion capacity as being prognostic indicators, and they are currently being tested as on-treatment predictors. Additionally, new research is leading to evolution in diagnosis and treatments. One of these may be advanced imaging of pulmonary vascular pruning, which may lead to treatment being started significantly earlier [238].

A recent algorithm [208] for the treatment of CTEPH is depicted in Figure 9. All patients with newly diagnosed CTEPH should be seen by an expert referral center that is defined as high-volume centre treating at least 50 patients with PAH or CTEPH and receiving at least two new referrals per month with documented PAH or CTEPH [188]. Generally, CTEPH is a surgical disease curable by PEA. In expert referral centers, PEA is associated with low in-hospital mortality rate of 4.7% [239]. A multidisciplinary team approach should guide the assessment of operability and decisions regarding other potential therapeutic strategies. Optimal medical therapy for CTEPH includes anticoagulants, diuretics, and oxygen. Lifelong anticoagulation is recommended in all CTEPH patients, even after PEA [239], while the routine use of IVC filters is not recommended [52]. For patients with non-operable CTEPH, due to distal surgically inaccessible disease or unfavorable risk:benefit ratio for PEA, or patients who have persistent or recurrent PH after PEA, percutaneous balloon pulmonary angioplasty (BPA) may offer a valuable treatment option.

BPA represents a classical angioplasty technique that aims to improve pulmonary blood flow by dilation of occluded or stenotic pulmonary arteries.Staged interventions with repeat catheterisations and dilatations (3-10 sessions at intervals of ≥1 week) are generally needed to achieve optimal pulmonary perfusion and haemodynamic results. BPA utilizes 0.014-inch guidewires and compatible semi-compliant balloons sized from 1.2 to 8.0mm. An 8F sheath is inserted into the internal jugular, subclavian or femoral vein [n=2]). After a standard right heart catheterization, the Swan-Ganz catheter is replaced by an 8F short guiding catheter or a sheath with an internal 6F (Mach 1 peripheral MP; Boston Scientific, Natick, MA) guiding catheter. Heparin (2000 U) is administered when the sheath is inserted, and 1000 U of heparin are added every hour during the procedure. The guide is advanced to the pulmonary artery (from the groin primarily to the left PA, from the jugular approach primarily to the right PA) over a 0.035-inch wire (Radifocus Guide Wire M; Terumo, Tokyo, Japan). In general, the lobe with the worst perfusion, identiﬁed by lung perfusion scintigraphy, is primarily addressed. The right lower lobe represents a major target for BPA because of its size and physiological blood flow compartment size. In severely compromised patients, the primary goal is to reduce pulmonary pressure by targeting simpler lesions first. After passing the lesion with the guide wire, its correct placement must be proven before angioplasty. The branch is selected by the 6F guiding catheter and a hand-injected angiography is performed in an anterior-posterior and lateral projection. Typical pulmonary arterial vascular lesions are ring-like stenoses, fibrous webs and complete occlusions appearing as break-offs ( Figure 10) or pouches. A 0.014-inch wire (SionBlue Asahi Intecc, Tokyo, Japan) is advanced across the lesion and the lumen size of the vessel is imaged with IVUS (Eagle Eye Platinum; Volcano, San Diego, CA). Because organized thrombi are isoechoic, ChromaFlo (Volcano, San Diego, CA) computer software is employed to clearly visualize and distinguish lumen and thrombi, and identify the distal reference diameter. To minimize the risk for vessel injury and reperfusion pulmonary oedema, undersized balloon catheters should be initially used followed by larger balloons according to lesion size and residual pressure (2 to 4 mm, TREK, Boston Scientific, Natick, MA, and Aviator Plus, Cordis/Johnson & Johnson, New Brunswick, NJ;). The maximal balloon size is 50% of the original size of the vessel diameter in cases with a mean pulmonary artery pressure ≥40mmHg, and 70% of the original size of the vessel diameter in all other cases. The balloon is inflated by hand until an indentation disappeares or the balloon is fully expanded. The mechanism of BPA is “breaking, compressing and dissecting the intravascular obstructions” ( Figure 11 ) rather than expanding and dissecting the medial and adventitial vessel layers as in coronary intervention [240]. The procedure is stopped when 4-8 targets has been addressed, or when oxygen desaturation >4% or hemoptysis occurs.BPA can significantly reduce pulmonary artery pressure in patients with CTEPH as shown in an international multicentre study [241], and in more recent reports of the refined technique [242, 243, 244]. Improvement in New York Heart Association functional class, six-minute walk capacity [241], respiratory efficiency [245], and improvement of right ventricular function [246] have been observed after successful balloon pulmonary angioplasty. Given the increasing age of the population, the 36.6% of non-operable patients in Europe [247], and the availability of drug-eluting balloons, BPA is an emerging technique in Europe.

Despite their wide off-label use in Europe [247], drugs approved for PAH are not recommended for CTEPH outside clinical trials, except in specific situations [188].

Riociguat, an oral stimulator of the NO receptor soluble guanylate cyclase is the first approved medication that is recommended by current guidelines to treat non-operable CTEPH as well as patients with persistent or recurrent pulmonary hypertension after PEA [188]. Riociguat has been found to significantly improve exercise capacity and hemodynamic parameters [248, 249]. The MERIT trial has recently demonstrated efficacy and safety of macitentan in non-operable CTEPH (NCT02060721).

FOCUS BOX 3Pulmonary hypertension

Pulmonary hypertension is defined by an invasively measured mean pulmonary arterial pressure ≥25 mmHg at rest [188]
In general, right heart catheterisation can be performed with low risk (overall mortality 0.055%) in this very ill patient group [221]
Pulmonary arterial wedge pressure (PAWP) is used to distinguish between pre and postcapillary disease [188].
“Pulmonary revasculariation” has gained new attention for PE
Acute PE: thromboysis (PEITHO trial illustrating the risk and benefits of intravenous thrombolysis with tenecteplase) and mechanical thrombectomy (ULTIMATE trial) [128].
CTEPH: Balloon pulmonary angioplasty is evolving as an alternative for patients who are no candidates for surgical pulmonary endarterectomy

Personal perspective - Irène M. Lang

While pulmonary embolism is a common clinical entity, pulmonary hypertension is rare. Despite the overall poor prognosis (e.g., 2-year survival as low as 50% [237] , and a low societal impact), medical treatments of PH have significantly improved survival and quality of life of affected patients [188].

Interventional procedures of PAH are limited. Ongoing trials (e.g., Trophy-1, NCT02835950) are testing the feasibility and safety of pulmonary artery ablation to reduce pulmonary vascular resistance [250, 251, 252]. Surgical pulmonary endarterectomy is the treatment of choice for CTEPH. Balloon Pulmonary Angioplasty for non-operable CTEPH is gaining grounds, due to the desperate need for effective treatments in an increasingly comorbid population. As of October 2016 more than 2500 BPA procedures have been documented in Europe, rigorous studies are required to position BPA within medical treatments and PEA. My personal view is that PEA, BPA and medical treatments will be complementary in the management of many patients.

Pulmonary embolism and pulmonary hypertension

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Personal perspective - Irène M. Lang

Pulmonary embolism and pulmonary hypertension

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Personal perspective - Irène M. Lang

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