Percutaneous coronary intervention (PCI) is the most commonly performed therapeutic procedure in the contemporary management of significant coronary disease.1 In Australia, 170 PCI procedures per 100 000 population are performed through 4.3 PCI centres per million population.2 In 2015, over 47 000 procedures were performed nationally. Interventional technology has advanced drastically, from balloon angioplasty, to bare metal and drug-eluting stents, through to the recent development of fully bioresorbable stent scaffolds. Increasingly sophisticated platforms have sought to improve on the outcomes of the preceding generation of devices by refining their design, structure, and component materials. This review discusses the evolution of PCI technology, the efficacy and safety of currently available devices, and the rationale for new generation platforms. A list of acronyms used is provided in Box 1 and a brief historical summary of coronary stent technology is given in Box 2.

This narrative review used a PubMed search of original and review articles from 1970 to 2016, as well as specialist society publications and guidelines from the European Society of Cardiology, American College of Cardiology, and the Cardiac Society of Australia and New Zealand to formulate an evidence-based overview of contemporary stent technology, as applied to clinical practice.

Plain old balloon angioplasty

The treatment of obstructive coronary disease was revolutionised when Andreas Gruntzig first performed coronary balloon angioplasty in 1977, providing an alternative to bypass surgery. However, the outcomes from plain old balloon angioplasty were compromised by high rates of restenosis in up to 30–50% of patients at 3–6 months,3,4 mediated by dissection, elastic recoil, late vascular remodelling, and neointimal proliferation. Additionally, abrupt vessel closure due to balloon-induced dissection or elastic recoil occurred in 5–10% of patients within minutes to hours of angioplasty, often resulting in acute myocardial infarction (MI) precipitating the need for urgent surgical revascularisation.1

Bare metal stents

Stainless steel coronary stents, or bare metal stents (BMSs), were developed to overcome the issues posed by balloon angioplasty and maintain vessel patency, and Sigwart and colleagues heralded the second technological advance in interventional cardiology when they implanted the first coronary stent in a human coronary artery in 1986.5 Implantation of BMSs served to prevent acute vessel closure by sealing the balloon-induced dissection flaps, as well as to reduce the rate of restenosis by scaffolding the balloon-dilated artery and preventing late recoil. Consequently, coronary stents improved procedural safety and efficacy and rapidly eliminated the need for cardiothoracic surgical back-up.6,7 This led to stents being used in more than 85% of PCI procedures by the 1990s.8

First generation drug-eluting stents

Although stent implantation represented an advance, a 20–30% incidence of restenosis with BMS persisted.9 The new entity of in-stent restenosis (ISR) was the result of stent-mediated arterial injury inducing neointimal hyperplasia (in-stent growth of smooth muscle cells and extracellular matrix) and led to the development of drug-eluting stents (DESs).1 This pathophysiology is shown in Box 3.

These devices consisted of a metallic stainless steel frame, an anti-proliferative drug such as sirolimus or paclitaxel, and a permanent polymer that acted to control local drug release. The third paradigm shift of interventional cardiology was signalled when the first DES was implanted in 1999.10

A pivotal study (the RAVEL trial) showed that the sirolimus-eluting stent (SES) significantly reduced the incidence of ISR (0 v 26.6%; P < 0.001).11 This was closely followed by the development of the paclitaxel-eluting stent (PES).

The efficacy of these first generation DESs compared with BMSs has been confirmed in randomised trials and registry databases.12,13 A 2007 meta-analysis examined 38 randomised trials of 18 023 patients comparing SESs and PESs with BMSs. Over a follow-up period of 1–4 years, there was a significant reduction in target lesion revascularisation (TLR) seen with both SESs (hazard ratio [HR], 0.40; 95% CI, 0.32–0.51) and PESs (HR, 0.58; 95% CI, 0.46–0.72) compared with BMS.12 A registry analysis of 3751 propensity-matched pairs of patients who either received a first generation DES or a BMS also confirmed the superior efficacy of DESs, with a significant reduction in TLR at 2 years (7.4% v 10.7%; P < 0.001). In particular, the benefit was seen in high risk patients with two or three risk factors for restenosis — presence of diabetes, small vessels and long lesions.13

Registry data confirmed the safety and efficacy of first generation DESs in an Australian context, demonstrating significant reductions in major adverse cardiovascular events compared with BMS (odds ratio [OR], 0.68; 95% CI, 0.56–0.81).14

These significant reductions in incidence of vessel restenosis with DESs allowed for stent implantation in more complex coronary anatomy, previously untreatable due to prohibitive restenosis rates. Subsequent uptake of this technology was so widespread that by 2005, 95% of PCI in the Australian private sector was with first generation DES.15,16 However, this optimism was shaken in 2006 by the release of a pooled analysis of findings from randomised trials of DESs by Camenzind and colleagues17 that showed a significantly increased risk of death and Q-wave MI at late follow-up in patients receiving an SES compared with those implanted with a BMS (6.3% v 3.9%; P = 0.03). The analysis also identified a distinct entity of very late stent thrombosis (VLST) beyond 1-year following DES implantation, with a steady annual risk of 0.5–0.6% up to 5 years.18

Subsequently, several large meta-analyses provided reassurance by demonstrating comparable outcomes with DESs and BMSs. The largest of these revealed a similar risk of death at both short and long term follow-up.12 This was further supported by the largest registry data of 262 700 patients that found lower rates of death (12.9% v 17.9%; P < 0.0001), MI (7.3% v 10.0%; P < 0.0001) and repeat revascularisation (23.0% v 24.5%; P = 0.007) with a DES compared with a BMS over a 30-month follow-up.19

The discrepancy between the later data and the initial results by Camenzind and colleagues17 is multifactorial. First, the use of dual antiplatelet therapy (DAPT) differed between trials, with patients receiving just 8 weeks of DAPT in the RAVEL study,11 while the protocol in later trials involved up to 12 months of DAPT. Second, while Camenzind and colleagues examined only Q-wave MI as an endpoint, most other studies demonstrating the safety of DES examined all MI as an endpoint. Third, Camenzind and colleagues produced a study-based meta-analysis that examined aggregate data from published reports rather than data from individual patients, which is susceptible to inter-study heterogeneity. Fourth, before the standardised definitions by the Academic Research Consortium in 2007,20 the initial definitions and adjudication of stent thrombosis (ST) between studies were not uniform. Last, the incidences of death, MI and ST are still relatively infrequent and subsequently some small trials are not powered to detect small differences in event rates, leading to a difference in outcomes between studies.

Second generation drug-eluting stents

ST remains a major safety concern with both BMSs and DESs Although rare (its incidence is between 0.5% and 1% per year),21 it is an unpredictable event with significant morbidity and mortality; 10–30% of patients with definite ST will die, and a proportion will experience an unexpected out-of-hospital death.22

The pathophysiology of ST is complex and multifaceted (Box 3). Early events have been associated with procedural factors and suboptimal platelet inhibition. Late and very late ST is seen more frequently with first generation DES compared with BMS, and has been related to incomplete strut re-endothelialisation, polymer-induced chronic inflammation and hypersensitivity reaction, stent malapposition, and accelerated neoatherosclerosis.21,23

Newer platforms (second generation DESs) include the zotarolimus-eluting stent (ZES) and the everolimus-eluting stent (EES). These were developed to overcome the late safety and efficacy concerns with SESs and PESs, using less toxic anti-proliferative drugs, more biocompatible polymer coatings, and thinner and more flexible metal alloy struts.24 Optical coherence tomography has been used to demonstrate vascular healing over time (Box 4).

EESs have become the most widely used DES worldwide.25,26 They are implanted in more than 500 000 patients every year in the United States27 and are used in 80–90% of all PCI procedures in Australia.

Pooled analysis of the 2-year results from pivotal randomised trials showed improved outcomes with the EES, with significant reductions in rates of MI (relative risk [RR], 0.57; 95% CI, 0.45–0.73), TLR (RR, 0.59; 95% CI, 0.47–0.73) and ST (RR, 0.35; 95% CI, 0.21–0.60) compared with first generation PESs.28 The ZES was compared with the first generation PES in the ENDEAVOR IV trial, demonstrating non-inferiority based on 9-month follow-up data of ISR (13.3% v 6.7%; P = 0.075) and TLR (6.6% v 7.1%; P < 0.001).29 At 5-year follow-up, the rates of target vessel failure (defined as a composite of cardiac death, MI and clinically driven target vessel revascularisation) (17.3% v 21.3%; P = 0.061) were similar, but there were significantly fewer target vessel MI and cardiac deaths with the ZES (6.4% v 9.2%; P = 0.049).30

Second generation DESs have also been compared head-to-head in large randomised trials. The RESOLUTE All-Comers and TWENTE trials compared the EES with the ZES in real-world broad patient populations, demonstrating comparable outcomes between the two stents in terms of TLF (defined as the composite of cardiac death), target vessel MI, or clinically indicated TLR (8.3% v 8.2%; P for non-inferiority < 0.001), and 12-month mortality (2.8% v 1.6%; P = 0.08).31,32 Optical coherence tomography has been used to demonstrate vascular healing over time (Box 4).

Given these clinical advances, second generation DESs are widely accepted as the percutaneous treatment of choice for obstructive coronary disease and have replaced SESs and PESs globally.33

Despite the clinical improvements of second generation DESs, issues with long term safety and efficacy persist. The Bern–Rotterdam cohort of 4212 real-world patients who received an EES experienced a definite or probable ST rate of 6.3% and a VLST rate of 2.0% over a 4-year follow-up period. Although the VLST rate was significantly lower compared with that for first generation PESs (4.0%; P < 0.0001) and SESs (2.8%; P = 0.02), it nonetheless represents an ongoing 0.67% annual risk of ST beyond 1 year.18 Further, there remains an associated annual TLR incidence rate of 1.3% beyond 1 year.34 Several large scale randomised trials demonstrate an accrual of adverse events arising from the treated target lesion after implantation of a contemporary second generation metallic DES at a rate of 2–3% per year for at least 5 years with no apparent plateau evident.34–36

Significant advantages have been achieved with second generation DESs. However, the persistence and accrual of late events, thought to result largely from the presence of a permanent metallic implant, have further prompted a new generation of devices. These include bioresorbable polymer and polymer-free DESs, and fully bioresorbable scaffolds.

Bioresorbable polymer drug-eluting stents

As a polymer coat is implicated in the pathogenesis of late adverse events (Box 3) after DES implantation (especially VLST) by providing a potential chronic inflammatory stimulus,23 DESs coated with bioresorbable polymers (such as poly(d,l-lactide-co-glycolide) or poly-l-lactic acid) have been developed. Degradation of the polymer occurs simultaneously with controlled release of the anti-proliferative drug. Following completion of drug elution, only the stent platform remains in the coronary artery. Bioresorbable polymer EESs and SESs are approved for implantation in Australia. A biolimus-eluting stent (BES) is also commercially available. However, despite extensive research37 and subsequent Therapeutic Goods Administration approval of the BES, there has been minimal uptake within the Australian context. Several other bioresorbable polymer DESs have been trialled and used clinically outside Australia.

The EVOLVE II trial found that when compared with an EES with a permanent polymer, the bioresorbable polymer DES had similar efficacy and safety up to 12 months, as measured by the primary endpoint of TLF (6.7% v 6.5%; P for non-inferiority = 0.0005), as well as definite or probable ST (0.4% v 0.6%; P = 0.50).38 Recent data from the randomised BIOSCIENCE trial established non-inferiority of a bioresorbable polymer SES compared with a contemporary permanent polymer EES, with similar rates of TLR (RR, 0.99; 95% CI, 0.71–1.38; P = 0.95 and P for non-inferiority = 0.0004).39 Despite theoretical advantages, bioresorbable polymer DES have yet to deliver decreased late events when compared with second generation permanent polymer DES and longer term data are still needed.

Polymer-free drug-eluting stents

An alternative strategy to eliminate polymer-mediated chronic inflammation has been the development of the polymer-free DES. The challenge in this class of devices has been achieving adequate levels of anti-proliferative drug without the polymer vehicle to ensure neointimal hyperplasia and ISR are inhibited.

In the randomised LEADERS FREE trial, which recruited 2466 patients who were at high risk of bleeding, the composite primary safety endpoint of cardiac death, MI or ST (9.4% v 12.9%; HR, 0.71; CI 95%, 0.56–0.91; P = 0.005) and the primary efficacy endpoint of TLR (5.1% v 9.8%; HR, 0.50; 95% CI, 0.37–0.69; P < 0.001) occurred less frequently in patients treated with a polymer-free umirolimus-eluting stent than in those treated with the BMS.40 Patients were only treated with 1 month of DAPT. This represents promising data for patients who are considered high risk for bleeding, and deemed unsuitable for prolonged use of DAPT. However, this polymer-free umirolimus-eluting stent has yet to be approved for use in Australia, and the shorter duration of DAPT in this patient population cannot be extrapolated to other devices in the absence of further data and research.

Fully bioresorbable scaffolds

While there have been considerable efforts to eliminate the use of permanent polymers, contemporary second generation DESs remain the default device for PCI. However, concerns over late adverse events (particularly VLST) after permanent metallic prostheses have led to interest in fully bioresorbable stent technology in the past decade, potentially representing a fourth technological paradigm in interventional cardiology.

Referred to as scaffolds, these devices provide the local drug delivery and mechanical support of metallic DES in the first 12 months and completely resorb 3 years after implantation (Box 5). As the scaffold struts resorb, they are replaced by cellular and connective tissue, allowing restoration of normal vasomotor function and increased luminal dimensions over 5 years due to compensatory vascular remodelling and plaque regression. These positive changes are not possible with metallic stents, which permanently cage the vessel and serve as a substrate for persistent inflammation, neoatherosclerosis and strut fracture. The theoretical rationale for bioresorbable scaffolds is that these provide improved long term outcomes compared with DESs, as they remove any nidus for late unfavourable clinical events (ISR and VLST). Additional potential benefits may include avoidance of exceptionally long segment metallic stenting (“full metal-jacket”), thereby maintaining later surgical and percutaneous revascularisation options, and compatibility with non-invasive computed tomography angiographic imaging (limited by metallic stents), and restricting very long term reliance on long term DAPT.

The first non-drug-eluting bioresorbable scaffold was implanted in a patient in 2000.41 Since then, a significant number of bioresorbable scaffolds have been developed. However, only the everolimus-eluting bioresorbable vascular scaffold (BVS) is available commercially in Australia.

The ABSORB III trial, in which 2008 patients were assigned in a 2:1 ratio to treatment with either a BVS or an EES, demonstrated similar rates of the primary outcome of TLF (7.8% v 6.1%; P for non-inferiority = 0.007) as well as of ST at 1 year (1.5% v 0.7%; P = 0.13).42 A meta-analysis of pooled data for 3389 patients comparing BVS with EES implantation similarly showed equivalent rates of TLF (RR, 1.22; 95% CI, 0.91–1.64; P = 0.17) and the composite outcome of death, MI and revascularisation (RR, 1.09; 95% CI, 0.89–1.34; P = 0.38).42 Prospective Australian registry data of 100 patients treated with a BVS also demonstrated good outcomes in the local context. Procedural success was high (95.3%), with no mortality, 1% scaffold thrombosis and 4% TLR within the 12-month follow-up period.43,44

Despite early optimism, challenges exist for the current first generation BVS. The device has a thick strut (a design feature necessary to maintain radial strength) and higher crossing profile resulting in a significantly lower procedural success rate (94.9% v 97%; P = 0.003) compared with that of the EES.42 Additionally, the meta-analysis by Stone and colleagues45 demonstrated a safety concern with higher rates of device thrombosis at 1 year (1.3% v 0.6%; HR, 2.11; 95% CI; 0.92–4.83; P = 0.08) and MI (5.7% v 4.0%; RR, 1.34; 95% CI, 0.97–1.85; P = 0.08) with the BVS, but neither of these were statistically significant. More recently, Lipinski and colleagues46 presented an expanded meta-analysis that found no significant difference in all-cause mortality with a BVS compared with a DES (OR, 0.40; 95% CI, 0.15–1.06; P = 0.06), but an increase in definite or probable ST (OR, 1.91; 95% CI, 0.82–4.46; P = 0.03). The observation of increased scaffold thrombosis is also supported by a large clinical registry.47

Available evidence has shown equivalent efficacy of the BVS against the current best-in-class DES at 12 months. Significantly, users in these trials were still learning the optimal BVS implantation techniques; meticulous attention to device sizing, vessel preparation and routine high pressure post-dilatation may further improve early and 12-month outcomes.45,48 Regardless, longer term results (up to 5 years), particularly in trials involving real-world patients, are needed before generalised adoption of BVSs can be recommended in routine clinical practice. Separately, the broader challenge to BVS technology and engineering will be the transition to second generation devices with thinner struts, increased expansile capacity, improved delivery and shorter biodegradation times.

Conclusion

The ideal coronary stent technology is one that can achieve optimal efficacy without compromising long term patient safety. It must be easy and predictable to deliver, applicable to a broad range of clinical and anatomical settings, meet the needs of future imaging and revascularisation options, permit the restoration of normal vascular function, and limit the requirement for prolonged DAPT. Despite the established excellent efficacy and safety profile of current gold standard second generation DESs, the narrative of PCI continues to evolve in a bid to build on previous successes. The emerging third generation of DESs has the potential to improve on the performance of current DESs. However, it remains to be seen if the novel bioresorbable scaffolds will truly represent a new paradigm of coronary intervention and become a mainstream PCI device.

Box 3 –
Schematic representation of late adverse events following stent implantation

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Section 1 shows delayed healing with incomplete endothelialisation of stent struts and protruding stent struts, which present a potential nidus for thrombus formation. Section 2 shows physiological arterial healing with smooth and homogeneous coverage of stent struts by smooth muscle cells and extracellular matrix, which is described as benign neointimal hyperplasia (NIH). Section 3 shows in-stent neoatherosclerosis, which is susceptible to subsequent plaque rupture and thrombotic luminal stenosis. Section 4 demonstrates excessive neointimal hyperplasia leading to in-stent restenosis. Section 5 shows stent malapposition, which results in exposed stent struts, which also present as a potential nidus for thrombus formation.

Source: Virmani R. Bioabsorption process: tissue responses in pre-clinical models. Proceedings of the 8th China Interventional Therapeutics Congress, Beijing, China, 31 Mar – 3 May, 2010.

Box 4 –
Optical coherence tomography evaluation of a second generation drug-eluting stent

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Optical coherence tomography evaluation of stent efficacy and vascular healing over time at 6 months (A), 9 months (B), and 12 months (C), as shown by good strut coverage by endothelialisation, and good apposition against the vascular wall.49 There are no protruding stent struts as schematically illustrated in , and there is benign neointimal hyperplasia without in-stent restenosis.

Source: Image courtesy of Abbott Vascular.

Box 5 –
Optical coherence tomography evaluation of an everolimus-eluting bioresorbable vascular scaffold

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Stent struts are shown at baseline. At 6 months and 2 years, there are progressively fewer struts, indicating gradual resorption. At 5 years, no struts remain, showing that the scaffold has been completely bioresorbed.

Source: Image courtesy of Abbott Vascular.

In contrast to the systemic circulation, the pulmonary circulation is a low-pressure circuit, which normally operates with a mean pressure below 20 mmHg. Pulmonary hypertension (PH) is defined haemodynamically by an elevated mean pulmonary artery pressure of ≥ 25 mmHg at rest. The presence of PH, irrespective of the cause, is associated with poor prognosis,1 often due to right heart failure in the face of persistently elevated afterload. There are multiple causes of PH, which has been classified into five groups according to the initiating cause and whether the predominant part of the pulmonary circulation affected is pre-capillary or post-capillary (Box 1).2

Pulmonary arterial hypertension (PAH; Group 1 PH) is caused by vascular proliferation and obstruction predominantly affecting the arterial side of the pulmonary circulation. PAH is defined as PH with a normal left atrial pressure (pulmonary artery wedge pressure ≤ 15 mmHg) and an elevated pulmonary vascular resistance (PVR) > 3 Wood units in the absence of other causes of pre-capillary PH. The most common forms are idiopathic PAH (iPAH), familial PAH and PAH secondary to connective tissue disease, most commonly systemic sclerosis. PAH is rare, with a prevalence between 16 and 26 cases per million people, but iPAH has a dismal prognosis if left untreated, with a median survival of only 2.8 years.3 Chronic thromboembolic pulmonary hypertension (CTEPH; Group 4 PH) occurs due to incomplete resolution of pulmonary embolism, with subsequent remodelling of pulmonary arteries. Most such episodes of pulmonary embolism are clinically overt, but can be clinically silent.4

When PAH was last reviewed in the MJA,5 there were very few treatment options available. Over the past 10 years, many oral and additional intravenous therapies that have improved the prognosis for those with this condition have become available in Australia. For this review, we searched PubMed for original and review articles from 1984 to 2016, as well as specialist society guidelines, to formulate an evidence-based overview of PAH treatment as applied to clinical practice. We focus on Group 1 and Group 4 PH, for which there is good evidence for pharmacological treatment. While we acknowledge that Group 2 PH is the most common type in our community,1 there is no convincing evidence of benefit for treatment directed at Group 2 or Group 3 PH.

Old and new pathophysiological concepts in pulmonary arterial hypertension

PAH is a disease of endothelial dysfunction and abnormal remodelling of the pulmonary vessels, leading to luminal narrowing, loss of normal vasodilator responses and obliteration of pulmonary arterioles, all resulting in elevated PVR. There is migration and proliferation of vascular smooth muscle cells, appearance of myofibroblasts and increases in extracellular matrix, leading to intimal hyperplasia, medial hypertrophy and adventitial fibrosis. Inflammatory infiltrates are a histological feature of PAH.6 It is thought that in situ thrombosis may also lead to vessel loss.7 It has long been recognised that three major endothelial signalling systems within the vessel walls are dysfunctional in PAH, and these have been the major targets for drug therapies (Box 2). Increased activity of the endothelin system promotes vasoconstriction and vascular smooth muscle cell proliferation.8 A further mechanism important in iPAH is reduction in the synthesis and availability of nitric oxide, which has potent pulmonary vasodilator and antiproliferative effects.9 The endothelial cells in iPAH demonstrate a reduction in prostaglandin I2, another vasodilator with antiproliferative properties.10 While the disease primarily affects blood vessels, it generally results in death due to right heart failure.11

Recently, there has been interest in the factors responsible for initiating and driving the process that results in PAH. The most common cause of familial PAH is mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, a member of the transforming growth factor beta (TGF-β) signalling family and thought to be responsible in 80% of cases, although mutations associated with PAH have been described in other genes in the TGF-β superfamily.12 However, there have been many specific BMPR2 mutations identified, with the most common accounting for only 8% of familial PAH, making genetic screening for this disease impractical. Not all carriers of the abnormal genes develop PAH, suggesting additional influences are necessary for phenotypic expression, possibly reflecting a “multiple hit” process, similar to that seen with many cancers.13 It has been shown that BMPR2 is downregulated in other forms of PAH, suggesting that this may also be important in non-inherited forms of PAH. Dysregulated immunity and inflammation may also be important in the development of PAH.14 Patients with PAH have been observed to have elevated levels of serotonin. Disruption of the normal serotonin transporter affects the development of PH in animal models, signifying that the interaction between serotonin and vascular smooth muscle cells may be important in the development of PAH.6,14

Chronic thromboembolic pulmonary hypertension

In a small proportion of patients who experience an acute pulmonary embolism, the thrombus will fail to resolve afterwards. This was initially thought to be true for about 0.5% of patients with pulmonary embolism, but a landmark report suggested almost 4% of patients will develop evidence of CTEPH in the 2 years after a pulmonary embolism.15 Patients with CTEPH may typically present with only partial recovery from a pulmonary embolism, followed by a (“honeymoon”) period of stability (which may last months or even years), then subsequent decline. At least 25% of patients have no history of an acute embolus, presenting with progressive breathlessness.4 Although increased propensity to thrombosis seems to predispose to CTEPH (32% of patients in a large international registry had a thrombophilic disorder),4 the underlying abnormality appears to be related to abnormal thrombin or abnormal thrombinolysis — a clot forms in the pulmonary artery but is incompletely broken down, resulting in a complex obstructing lesion in the artery.

Survival at 3 years without surgery is 70%, but this rises to 89% if surgery is performed.16 Although no randomised controlled trial (RCT) has been conducted, pulmonary endarterectomy (PEA), where feasible, is regarded as the treatment of choice, and initial investigations should focus on suitability for PEA. The presence of PH may be evident on echocardiography, but confirmation requires right heart catheterisation.17 Persistent segmental or larger unmatched perfusion defects seen on a nuclear ventilation–perfusion (VQ) scan are highly suggestive of operable CTEPH (a negative VQ scan virtually excludes operable CTEPH, except where the pulmonary artery trunk or both the left and right pulmonary arteries have high grade obstruction).17 A negative computed tomography pulmonary angiography scan does not exclude operable CTEPH and, as such, is not the best screening modality. Pulmonary angiography is currently the gold standard for assessing the extent and surgical accessibility of the obstructing lesions.18

PEA performed in experienced centres carries a surgical mortality of 2–5%.19,20 Most patients return to near normal functional capacity (New York Heart Association [NYHA] Class I or II) after surgery.21 PEA involves extensive endarterectomy from the main pulmonary artery down to segmental branches. It is performed under hypothermic circulatory arrest (18°C) in a few expert centres in Australia.

In patients with persistent PH after PEA, or in those unsuitable for surgery, selective pulmonary vasodilators may be useful. For most selective vasodilators, case series have shown at least haemodynamic improvements. In a 16-week RCT, riociguat (a novel soluble guanylate cyclase stimulator) resulted in haemodynamic improvements, as well as a significant increase in 6-minute walk distance (6MWD) of 46 m.22 The 6MWD is a simple test performed under standardised conditions of the distance walked over flat ground in 6 minutes; it is often used in PH trials. Concern remains that patients who are suitable for surgery should not be initially offered vasodilator therapy, as both the drug and the delay to PEA may lead to an inferior outcome.17 Pulmonary artery balloon angioplasty may offer a viable alternative to PEA in some circumstances, where several discrete, more distal lesions are inaccessible surgically. However, the role of balloon angioplasty as a substitute for PEA is currently unclear, especially in older patients who are less well suited to, or accepting of, major surgery. More systematic study of this matter is warranted.23

Current drugs for pulmonary arterial hypertension

The existing treatments for iPAH target signal pathways proven to be involved in the disease’s pathophysiology (Box 2). Ultimately, normal life expectancy and normal quality of life are the objectives of therapy. Realistically, moving patients to a low risk of mortality with, at worst, mild functional limitation (NYHA Class I–II) is the present target of therapy.24

Patients whose PH may be Group 1 or Group 4 in aetiology should be referred to a specialised PH centre for diagnosis and treatment. Patient education and use of expert centre support are essential for optimal outcomes and minimal side effects using currently available drug treatments (Box 3).

Calcium channel blockers

There is a small group of patients with iPAH (6%) who appear to respond well to high doses of dihydropyridine calcium channel blockers and who may have durable benefit from this therapy.25 These patients are identified using a vasodilator challenge at the time of right heart catheterisation. Patients with no acute vasodilator response should not be treated with high dose calcium channel blockers.

Endothelin receptor antagonists

The oral endothelin receptor antagonists (ERAs) bosentan and ambrisentan (and the newer ERA macitentan) inhibit the signal pathway by blocking endothelin receptors. Monotherapy with bosentan and ambrisentan has produced improvements in 6MWD, PVR and time to clinical deterioration.26,27

Phosphodiesterase type 5 inhibitors

Phosphodiesterase type 5 (PDE5) breaks down cyclic guanosine monophosphate (cGMP) and therefore decreases the vasodilator effects of nitric oxide. The oral PDE5 inhibitors sildenafil and tadalafil decrease cGMP degradation, which increases the activity of the nitric oxide system and clinically improves 6MWD in patients with iPAH.28,29 Tadalafil also increases time to clinical deterioration compared with placebo.29

Prostanoids

The two major prostanoids used in Australia are epoprostenol and iloprost. Epoprostenol is the most effective single agent for treatment of PAH, but it requires delivery of a continuous intravenous infusion via a central venous catheter. It has been shown to improve 6MWD, haemodynamics, quality of life and survival.30 Recently, a more thermostable formulation of epoprostenol has become available, which may be more convenient to use as it eliminates the need for a cold pack to maintain the drug’s temperature at the required level. Inhaled iloprost improves functional class, 6MWD and time to clinical deterioration,31 but requires up to nine inhalations per day.

Anticoagulants

Early pathological studies showed thrombosis within small lung vessels in patients with PAH,32 leading to treatment with anticoagulants becoming part of standard therapy. Anticoagulation in patients with iPAH may be of benefit, with some observational series indicating improvements in survival, but uncertainty persists due to the low level of evidence.7,25,33 Use of anticoagulation in patients with PAH and scleroderma is more controversial.34 Recent guidelines for the treatment of iPAH state that oral anticoagulation with warfarin may be considered in treatment algorithms.35

New drugs for pulmonary arterial hypertension

While calcium channel blockers, intravenous epoprostenol, the oral ERAs bosentan and ambrisentan, and PDE5 inhibitors sildenafil and tadalafil are well established in the treatment of iPAH in Australia, new drugs have recently been introduced or will soon be available (Box 3). Direct comparison with currently available treatments is difficult, as most current treatments were tested in relatively small trials of short duration, using surrogate endpoints based largely on haemodynamic or functional measures. In contrast, trials of newer agents have been larger and in many cases have used mortality and morbidity endpoints, such as time to clinical deterioration, to demonstrate efficacy. Direct comparison is also difficult due to the widespread use of background PAH therapies in recent studies.

Macitentan

Macitentan is a recently introduced non-selective ERA developed with the aims of improving effectiveness and reducing the side effects, toxicities and drug interactions associated with earlier ERAs. Macitentan has been assessed in the SERAPHIN trial, the largest RCT of ERAs, in which two macitentan doses (3 mg and 10 mg) were compared with placebo in 742 patients with Group 1 PH over a median treatment period of 115 weeks.36 Occurrence of the primary outcome (first occurrence of a composite of death, lung transplantation, atrial septostomy, initiation of intravenous or subcutaneous prostanoids, or worsening of PAH) was reduced by 30% (P = 0.01) with 3 mg and by 45% (P < 0.001) with 10 mg of macitentan. This was mostly driven by a reduction in occurrence of worsening of PAH. Worsening of PAH was defined as a decrease in 6MWD of at least 15%, worsening of PAH symptoms and the need for additional PAH treatment. Reductions in hospitalisation were also seen with macitentan treatment. About two-thirds of patients in this study were already taking other PAH treatments, predominantly PDE5 inhibitors, with the remaining third taking the study drug as monotherapy. Improved outcomes with macitentan were seen in both the treatment-naive patients and those using combination therapy.36

Riociguat

The effectiveness of PDE5 inhibitors may be limited because PAH is a state of nitric oxide deficiency, and inhibiting breakdown of the already reduced levels of cGMP may not be the most effective strategy. Riociguat acts directly to stimulate soluble guanylate cyclase and thus increase cGMP independent of nitric oxide levels.37 Riociguat has been tested in patients with Group 1 PH in the PATENT-1 trial.38 This study compared two doses of riociguat with placebo in 443 patients, of whom half were treatment naive. Most of those taking the active drug were treated with 2.5 mg three times a day (254 patients). Riociguat resulted in a placebo-corrected increase in 6MWD of 36 m after 12 weeks of treatment (P < 0.001). In addition, improvements were seen in PVR, time to clinical deterioration, functional class, N-terminal pro-brain natriuretic peptide levels and quality of life with riociguat treatment.38

Selexipag

Although intravenous epoprostenol is a highly effective treatment for PAH, the logistics and infective complications associated with chronic intravenous administration limit its use.30 Other intravenous, oral and subcutaneous prostanoids have been limited by difficulties in their administration or intolerable side effects.31,39 More recently, a non-prostanoid prostacyclin receptor agonist, selexipag, has been studied in patients with PAH. The 1152 patients with Group 1 PH in the event-driven GRIPHON trial were randomly allocated to receive selexipag or placebo and followed for a median of 70.7 and 63.7 weeks, respectively.40 About 80% were already using specific PAH therapies, and the remaining 20% were treatment naive. Selexipag was uptitrated to 1600 μg twice daily or the highest tolerated dose. Selexipag treatment was associated with a 40% lower risk of the primary composite endpoint of death, hospitalisation for PAH, disease progression, initiation of parenteral prostanoid or long term oxygen therapy, or lung transplantation. The magnitude of benefit did not differ across different achieved doses, suggesting that the maximum tolerated dose is the correct dose for the patient. Several side effects, including jaw pain, nausea, diarrhoea, vomiting and myalgia, were more common in those treated with selexipag.

Combination therapy

In diseases such as cancer, human immunodeficiency virus, systemic hypertension and heart failure, treatment with combinations of drugs has proven to be more effective than treatment with a single agent. There is now evidence that combining specific therapies for PAH is more effective than monotherapy. Combination therapy may be used either sequentially or as initial therapy at the time of diagnosis. The strongest evidence for initial combination therapy comes from the AMBITION trial, which showed that an initial combination of ambrisentan and tadalafil was superior to either agent alone, with a 50% reduction in the occurrence of a primary endpoint event (first event of clinical failure) for those taking combination therapy compared with the monotherapy group.41 There were also beneficial effects on secondary endpoints.

In recent trials of new therapies, the rate of background PAH therapy has been significant, with about 80% of patients in the GRIPHON trial of selexipag,40 50% of patients in the PATENT-1 trial of riociguat,42 and 64% of patients in the SERAPHIN trial of macitentan36 having the trial drug added to background PAH therapy. Benefit has been observed in both those taking background therapy and treatment-naive patients, suggesting new drugs should be added to existing treatments, rather than substituted for them; a position that is supported by current international guidelines and consensus statements.35,43 A small pilot study in France showed excellent outcomes with initial triple combination therapy, including an intravenous prostenoid.44 A large study of initial combination double versus triple therapy (TRITON), comparing macitentan and sildenafil with selexipag or placebo, will commence recruitment in the next few months and we hope will help define the role for more aggressive initial oral therapies.

Access to treatment in Australia

There have been no head-to-head clinical trials of sufficient size or quality to make any scientifically based judgement on which of the available drugs can be considered first-line therapy for PAH, and local practice around the world is often based on cost. It is also not known how many patients in Australia are using each type of therapy, as the databases that exist likely do not reflect the whole country.

Two issues affect patient access to specific PAH therapies in Australia. While recent trial data indicate that combination therapy is superior to monotherapy, currently only treatment with one agent at a time is funded through the Pharmaceutical Benefits Scheme (PBS). However, based on our experience, we are aware that a significant number of Australian patients are using more than one PAH treatment, some of which is self-funded, some funded through hospitals and some sourced through compassionate access schemes. There are no systematic data on the use of combination therapy by patients.

Recent changes to the PBS have simplified the ongoing treatment of patients with PAH, with a reduction in administrative and repeat testing burden. Patients who have commenced PAH treatment or who have changed drugs must demonstrate disease stability (as described in the PBS explanatory notes) or improvement using 6MWD and echocardiography and/or right heart catheterisation after 6 months of treatment. Ongoing treatment at 12 months and beyond will no longer require demonstration of stability. Repeat assessment should, however, continue to be performed on clinical grounds and in accordance with practice guidelines.35

Future treatments

Present therapies rarely induce remission and never cure, to use a cancer analogy, and overall 3-year survival with their use is about 75%.36 Alternative treatment pathways identified through basic research are being evaluated. Initial enthusiasm for the tyrosine kinase inhibitor imatinib has been dampened by the high rate of side effects in a clinical trial setting.45 Several other compounds are in pre-clinical or early clinical evaluation.46

For patients whose PAH is not well controlled using available therapies, transplantation (double lung or heart–lung) remains an option. With improvements in organ availability in Australia, this is both feasible and likely; however, chronic lung allograft dysfunction still limits median survival to about 8 years.47 Developments in regenerative medicine may allow repopulation of a donated lung (rendered acellular) with autologous stem cells,48 an exciting approach currently in pre-clinical development.

The recognition that up to 30% of patients with apparently idiopathic PAH have an identified gene defect raises the prospect of gene therapy.49 Mutations of the BMPR2 gene are the commonest, and correcting this defect with gene therapy has been suggested — using an adenovirus, a vector can transfect the relevant cell.50 However, this leads to an immunological response, which means this approach will be unsuitable for recurrent treatments. Endothelial progenitor cells may help repair the vascular endothelium, and there are data from human studies on this approach.51 More recently, the use of endothelial progenitor cells as vectors for gene therapy has been proposed, with a human study recently attempting to introduce an inducible nitric oxide synthase (iNOS) gene into the pulmonary vascular endothelium.52

Conclusion

The past 10 years have seen the introduction into routine clinical practice of new oral and intravenous therapies for PAH, based on the endothelin, nitric oxide and prostacyclin pathways, leading to improvements in functional capacity and survival. Emerging evidence supports more widespread use of combination therapy, as both initial and sequential treatment, although there are significant barriers to this use in Australia. CTEPH remains an important cause of PH to identify because of its potential for successful treatment using surgery, medication and possibly angioplasty. There is enthusiasm for exploring new pathways that are important in PAH to identify new agents that may address more basic elements of pathophysiology and arrest or reverse the process of pulmonary blood vessel obstruction and obliteration.

Box 2 –
Diagrammatic representation of the key abnormal pathways targeted in treatment of pulmonary arterial hypertension and the mode of action of current and new drugs

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AC = adenylate cyclase. ATP = adenosine triphosphate. cAMP = cyclic adenosine monophosphate. cGMP = cyclic guanosine monophosphate. eNOS = nitric oxide synthase. ET = endothelin. GTP = guanosine triphosphate. IP = IP receptor. NO = nitric oxide. PDE5 = phosphodiesterase type 5. sGC = soluble guanylate cyclase.

Current performance standards are high and promising new technologies are finding it difficult to compete

The narrative review in this issue of the MJA by Chen and Jepson1 outlines the enormous advances made in stent technology since Sigwart and colleagues published the first report on the clinical use of coronary stents in 1987.2 Driven by technological progress and rigorous scientific study, coronary stents have advanced rapidly to the stage where a patient’s coronary stenosis can be safely and reliably opened.

A 60-year-old man is brought to the emergency department with severe chest pain, his electrocardiogram showing marked anterior ST elevation. He has a ventricular fibrillation arrest and is shocked into sinus rhythm. Catheterisation laboratory staff are on their way and, within minutes of arrival, a coronary angiogram shows complete occlusion of the left anterior descending artery. A guide-wire is inserted and flow is established after balloon inflation. His pain is settling as a drug-eluting stent is inserted. He is discharged on Day 3.

Despite benefiting dramatically from stent technology, our patient’s future is not without risks and challenges. He needs to take dual antiplatelet drugs for 1 year and postpone elective surgery. Over the next 5 years, he faces a stent thrombosis rate of 1.4–4.0%, and an almost 20% chance of adverse events including death, myocardial infarction (MI) or repeat procedures.3–5 As Chen and Jepson point out in their review, there appears to be an ongoing risk of ischaemic events for some years after successful stent implantation. The cause of this is likely a combination of stent factors including chronic inflammation, uncovered struts and neoatherosclerosis within the stent, as well as progression of atherosclerotic disease elsewhere. In a long term follow-up of patients treated with second generation stents, around 50% of adverse events were not related to the stent but were due to plaque progression at other coronary sites.6 This emphasises the importance of secondary prevention strategies for the long term health and wellbeing of patients treated with stents.

Progress in stent technology has made percutaneous coronary intervention (PCI) a relatively easy and safe procedure with visually impressive results for doctors and patients. Greater adoption of radial artery access has also contributed to the added safety of these procedures.7 It can be difficult to resist the temptation to insert stents in order to obtain aesthetically satisfying results in imperfect coronary arteries. Yet there is evidence from a randomised trial to suggest that PCI in patients with stable coronary disease does not reduce the risk of death, MI or other major cardiovascular events compared with optimal medical treatment.8 The challenge for physicians is not how to place a stent, but deciding when to intervene to produce the best outcomes for patients in a cost-effective way. Assessment of patients for evidence of ischaemia and use of fractional flow reserve measurement in coronary arteries should have a larger influence in decision making than reliance on visual assessment of coronary arteries at the time of angiography.

We also need to better understand the disease that we are treating. It is simplistic to think that stent insertion will remain the optimal treatment for all forms of coronary disease such as thin-cap plaque rupture, fibrous plaque, calcified plaque, thrombus, erosions, spontaneous dissection, long lesions, chronic total occlusions, bifurcation lesions and restenosis. Greater use of intracoronary imaging before and after stent insertion can help us to better diagnose the nature of coronary stenosis, with the future prospect of optimising treatment for individual patients.

Current generation drug-eluting stents have set such a high standard in safety and efficacy for such a wide range of lesions that new technologies will find it difficult to show superiority without large and long term clinical trials. Bioresorbable vascular scaffolds are an example of a very promising technology that is finding it difficult to compete with second generation stents in a wide range of lesion types. Bifurcation stents are another promising advance, but a recent randomised trial showed that a dedicated bifurcation stent was associated with a higher risk of MI compared with a conservative one-stent strategy.9

The success of stent technology has made PCI one of the most commonly performed procedures in medicine today and we look forward to further developments in this field. Yet, ironically, we would also welcome future reports of a decline in stent insertion in Australia, as this would indicate that as a society, we are starting to win the battle against coronary artery disease. With the rising tide of obesity and diabetes, this appears unlikely in the foreseeable future.