Maximising safety and efficacy in the treatment of wet AMD

January 2009Br J Cardiol 2009;16(Suppl 2):S1-S2 Leave a comment

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Authors: Rachel Arthur

Sponsorship Statement: An unrestricted educational grant has been provided by Pfizer Ophthalmics to the BJC for the production of this supplement. Professor Frank Ruschitzka, Professor Stephan Michels and Dr Frank Enseleit received editorial support from the BJC to prepare the review on pages S3-S8. Professor David Shima, Professor Johannes Waltenberger, Dr Sobha Sivaprasad and Dr John Wroblewski presented at a Pfizer Ophthalmics sponsored symposium (held at Eurentina, Vienna, Austria, 2008) and received editorial support from the BJC to prepare the reports from their presentations of pages S9-S15.

The prevalence of neovascular age-related macular degeneration (wet AMD) is predicted to rise to more than 300,000 patients in the UK alone by the year 2025. The personal and economic costs are considerable. It leads to worsening of vision-related function and overall wellbeing, with one third developing clinical depression. The majority of patients progress to legal blindness in the affected eye within two years of diagnosis, and healthcare utilisation costs are seven times higher in affected patients compared to age-matched controls. Thus, the development of new treatments for wet AMD, and of access to such treatments, is clearly important.

Vascular endothelial growth factor (VEGF) plays a critical role in stimulating abnormal neovascularisation, inflammation and vascular permeability, all factors involved in the pathogenesis of wet AMD. Inhibition of VEGF with intravitreal ranibizumab, pegaptanib and (off-licence) bevacizumab is currently first-line therapy for this condition.

However, VEGF plays a pivotal role in maintaining vascular integrity, particularly under conditions of ischaemia and hypoxia. This is particularly significant since most (but not all) studies have suggested that patients with wet AMD have a higher incidence of coronary heart disease and stroke, and because treatment with VEGF inhibitors may be required for some years in an elderly cohort of patients.

This supplement provides clinicians with detailed information about some of the current issues in this field. It discusses the determination of cardiovascular risk related to current treatment of wet AMD; the properties and functions of the VEGF system, including its complex roles in neuroprotection and inflammation; the effects of VEGF and anti-VEGF treatments on the vasculature, indicating that VEGF inhibition could have unwanted effects such as prothrombotic and vasoconstrictive effects; and, finally, findings on efficacy and safety of intravitreal pegaptanib in the treatment of wet AMD. This agent binds with high specificity to isoform 165 of VEGF, the isoform preferentially involved in choroidal neovascularisation.

Disclaimer: UK prescribing information current at the date of publication of this supplement can be found by downloading the PDF. Medinews Cardiology Limited advises healthcare professionals to consult up-to-date Prescribing Information and the full Summary of Product Characteristics available from the manufacturers before prescribing any product. Medinews Cardiology Limited cannot accept responsibility for any errors in prescribing which may occur.

Current treatment of wet age-related macular degeneration: determining the cardiovascular risk

January 2009Br J Cardiol 2009;16(Suppl 2):S3-S8 Leave a comment

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Authors: Frank Enseleit, Stephan Michels, Frank Ruschitzka

Age-related macular degeneration (AMD) is a common ocular condition that may destroy central vision and has a devastating effect on the patient’s quality of life. More than eight million Americans, particularly those over the age of 55 years, suffer from age-related macular degeneration, and the overall prevalence of advanced AMD is projected to increase by more than 50% by the year 2030.¹ In the UK, the annual incidence of neovascular AMD was calculated to be around 24,000 in 2005, with a prevalence of 243,000; this is predicted to rise to over 300,000 by 2025.² The majority of patients with neovascular AMD progress to legal blindness in the affected eye within two years of diagnosis, and there is a 43% probability of progression to neovascular AMD in the other eye within five years.¹ Until recently, the only pharmacological-based therapy for treatment of patients with neovascular degeneration has been photodynamic therapy with verteporfin.

Although the pathophysiology is still poorly understood, it is increasingly clear that vascular endothelial growth factor (VEGF) plays an important role in promotion of the neovascularisation and vessel leakage that lead to loss of central vision. Therefore, intravitreal antiangiogenic therapy (injection of antiangiogenic agents directly into the vitreous) is currently the primary therapy for neovascular AMD. Currently, the most common therapeutic agents are ranibizumab, pegaptanib and bevacizumab (used off-label). Anti-VEGF agents administered systemically for other indications in oncology have been associated with serious systemic adverse events and death.³ Since breakdown of the blood-ocular barrier is common in wet AMD, repeated intravitreal anti-VEGF therapy may lead to a small amount of systemic VEGF inhibition, possibly resulting in serious long-term adverse events, though these have not yet been shown in clinical studies.⁴ We here review the pathogenesis of the disease, the therapeutic options currently used in clinical practice and the possible safety concerns about anti-VEGF therapy in patients with neovascular AMD.

Methods

The leading journals that publish basic science and clinical research in the area of cardiovascular and ophthalmological diseases, and MEDLINE using PubMed, were scanned. The main terms used were “age-related macular degeneration”, “cardiovascular disease”, “ranibizumab”, “bevacizumab”, “pegaptanib” and “VEGF”. The publications were largely selected from the past five years, but older publications which are commonly referenced or highly regarded were not excluded. The reference lists of articles identified by this search strategy were screened and relevant articles were selected. Review articles are cited to provide the reader with information and references beyond the scope of this review.

Age-related macular degeneration

Br-J-Cardiol-2009-16-S2-S3-S8-figure-1 — Figure 1: Age-related macular degeneration (AMD): the right eye (left image) shows a large fibrosis subsequent to untreated neovascular AMD. Visual acuity is counting fingers. The left eye (right image) has characteristic signs of a newly developed neovascular AMD. The patient complains about recent loss of vision.

Early age-related macular degeneration is characterised by the presence of a few (< 20) medium-size drusen or retinal pigmentary abnormalities. Intermediate age-related macular degeneration is characterised by at least one large druse, numerous medium-size drusen, or by geographic atrophy that does not extend to the centre of the macula. As reviewed recently by de Jong,⁵ damage to the retinal pigment epithelium and a chronic aberrant inflammatory response can lead to large areas of retinal atrophy (called geographic atrophy), the expression of angiogenic cytokines such as vascular endothelial growth factor, or both. These processes may manifest as advanced AMD, which can either be non-neovascular (dry, atrophic or non-exudative) or neovascular (wet or exudative). Advanced non-neovascular AMD is characterised by drusen and geographic atrophy extending to the centre of the macula. Advanced neovascular AMD is characterised by choroidal neovascularisation and its sequelae.⁶ Figure 1 shows the fundus image of a patient with a large fibrosis, the end stage of neovascular AMD, in one eye and recent onset of neovascular AMD in the second eye.

Risk factors for AMD

Several risk factors for the development and progression of AMD have been established in recent years, including advanced age, white race, heredity and a history of smoking. The prevalence of early AMD has been reported to increase from 8% among people 43-54 years of age to 30% among people 75 years or older. Similarly, the prevalence of advanced AMD increases from 0.1% among people 43-54 years of age to 7.1% among people 75 years or older. AMD is more common in whites than Hispanics or Asian persons, whereas blacks have the lowest prevalence of the disease.⁷ Data from the Human Genome Project revealed that polymorphisms in the complement factor H (CFH), complement factor B (CFB) and the complement component C2 genes may account for 75% of AMD cases.⁸ A polymorphism (Ala69Sr) on the age-related maculopathy susceptibility 2 gene (ARMS2 or LOC387715) has also been strongly associated with development of AMD.⁹

Patients with a history of more than 10 pack-years of smoking have an increased risk for the development of AMD and even passive smokers also appear to have a doubled risk of AMD.¹⁰ Other modifiable risk factors for advanced AMD include arterial hypertension,¹¹ obesity,¹² high dietary fat intake¹³ and low plasma concentrations of antioxidants and zinc.^14,15

Cardiovascular risk factors

Coronary heart disease (CHD) is the leading cause of mortality in the US and Europe for both men and women. Although in England and Wales mortality rates of CHD continue to fall among older age groups, the actual burden of coronary heart disease is increasing due to the ageing of the population.¹⁶ The rate of improvement in CHD mortality appears to be declining, and may even be reversing among younger women.¹⁶ Atherosclerosis is the underlying cause of most ischaemic events and can result in angina, myocardial infarction, congestive heart failure, cardiac arrhythmias or sudden cardiac death. Risk factors for cardiovascular disease (CVD) have been extensively reviewed in numerous publications.^17-19 Data from the INTERHEART study revealed that the major cardiovascular risk factors smoking, hypertension, hypercholesterolaemia, diabetes mellitus, abdominal obesity, sedentary lifestyle and several psychosocial factors account for >92% of cardiovascular events worldwide.¹⁹ In the same study, daily consumption of fruits and vegetables, regular alcohol consumption and regular physical activity were associated with a reduced cardiovascular mortality. Most important, these findings were noted in men and women, in old and young people, and all over the world.

Risk factors associated with CVD and AMD

As early as the 1970s, researchers wondered whether AMD might be part of an underlying systemic vascular process or a result of factors that also influence the development of CVD.^20,21 The Framingham Eye Study found an association between AMD and systemic blood pressure and its sequel left ventricular hypertrophy.²¹ The NHANES-I study reported a positive association between AMD and systemic hypertension, and between AMD and cerebrovascular disease.²²In a large population-based study, the odds ratio of carotid artery plaques was 4.7 times higher in patients with wet AMD, while peripheral arterial disease was associated with a 2.5 times increased risk for AMD.²³

The potential link between AMD and CVD was highlighted further in two recent large US studies. The Atherosclerosis Risk in Communities (ARIC) study in more than 10,000 patients demonstrated that subjects with late AMD were significantly more likely to be diagnosed with incident coronary heart disease over 10 years than patients without late AMD (30.9% vs. 10.0%, respectively),²⁴ and also showed a higher incidence of stroke (4.1% vs. 2.1%).²⁵ The US Medicare Study, a population-based cross-sectional and cohort study involving more than 1.5 million Medicare enrolees ≥ 65 years, found a 20% increased risk of incidental myocardial infarction in patients with neovascular AMD.²⁶Importantly, the Blue Mountains Eye Study, which included more than 3,600 baseline participants in a population-based cohort study of common eye diseases in an Australian population aged ≥ 49 years of age, demonstrated that early AMD predicted a doubling of cardiovascular mortality (relative risk [RR] 2.3, 95% confidence intervals [CI] 1.03 – 5.19) over the next decade after controlling for traditional risk factors.²⁷ Late AMD predicted five-fold higher cardiovascular mortality (RR 5.57, 95% CI 1.35 – 22.99) and ten-fold higher stroke mortality (RR 10.21, 95% CI 2.39 – 43.6) after adjusting for age and gender only.²⁷ Other studies, however, have found no relationship between AMD and CVD.^28-34

A potential link between AMD and cardiovascular disease would have important therapeutic implications given current concern that some intravitreal anti-VEGF treatments for wet AMD could increase cardiovascular, and particularly cerebrovascular, risk.³⁵

Indeed, VEGF may be regarded as a double-edged sword. Although it is key in the pathogenesis of wet AMD, it at the same time plays a pivotal role in maintaining vascular integrity, particularly under conditions of ischaemia and hypoxia. Thus, any beneficial effects of anti-VEGF therapies in the eye must be weighed against potential long-term systemic effects of these agents, particularly when potent “pan”-anti-VEGF therapies such as ranibizumab and bevacizumab may exert unwanted systemic extra-ocular effects due to the blocking of the cardioprotective functions of VEGF.

The endothelium is increasingly recognised not only as a target (with vascular remodelling occurring in response to an injury and resulting in atherosclerosis), but as a mediator in the pathogenesis of vascular damage.³⁶ Indeed, endothelial cells play an important homeostatic role in the cardiovascular system through the expression of numerous molecules and release of mediators such as nitric oxide (NO), superoxide and endothelin-1 (ET-1). Studies demonstrating dysfunction of these mediators in patients at risk or with fully developed forms of cardiovascular disease strongly suggest involvement of endothelium-derived factors in the pathogenesis of atherosclerosis and its sequelae.

Functional alterations of the endothelial L-arginine / NO pathway may be important in cardiovascular disease since NO can inhibit substantially several components of the atherogenic process such as vascular smooth muscle cell contraction, proliferation and migration; platelet aggregation and adhesion; monocyte adhesion and oxidative modification of low-density lipoprotein (LDL). Hence, reduced endothelial NO release may accelerate the progression of atherosclerotic lesions. Most importantly, NO is the downstream mediator of VEGF and is considered an important defence system in maintaining vascular integrity.³⁷

VEGF was first described as a tumour-derived factor with potent ability to induce endothelial cell permeability,³⁸ proliferation and angiogenesis.^39,40 VEGF induces angiogenesis, and increases vascular permeability and inflammation: all of these are thought to contribute to the progression of the neovascular form of AMD. VEGF levels are raised in the retinal pigment epithelium and choroidal blood vessels of the macula and in the ocular fluid of most patients with proliferative diabetic retinopathy and retinal vein occlusion.

While VEGF occurs in several biologically active forms, a recombinant, humanised monoclonal antibody fragment (Fab), ranibizumab, neutralises all forms of the growth factor. In 2006, two trials with ranibizumab showed that monthly intravitreal injections prevented vision loss and, in many cases, significantly improved the visual acuity of patients with neovascular AMD.^41,42 Bevacizumab is a full-length monoclonal antibody that – like ranibizumab – binds and inhibits all isoforms of VEGF, but with a lower affinity, and has a longer half-life compared to the fragment form.

Br-J-Cardiol-2009-16-S2-S3-S8-figure-2 — Figure 2: Optical coherence tomography (OCT): High resolution OCT allows an optical biopsy of the retina in cross section. The images shown are of the same patient as in figure 1. Before intravitreal injection of 1.25mg bevacizumab (Avastin®) the upper images clearly indicates intraretinal oedema and a choroidal neovascularisation (CNV). One month following treatment intraretinal oedema has completely resolved and the CNV has regressed.

The Food and Drugs Administration (FDA) approved intravenous bevacizumab for patients with metastatic colorectal cancer in February 2004. The same year the first use of systemic bevacizumab for mostly bilateral neovascular AMD was reported.⁴³Rapid regression of choroidal neovascularisation was associated with a visual acuity improvement of 1-2 lines. A common adverse effect was an increase in systolic blood pressure.^44,45 The studies were too small, however, to exclude other serious systemic complications, including increased risk of thromboembolic events, haemorrhage, proteinuria, wound healing complications, and gastro-intestinal perforation.⁴⁶ In 2005 the first report on the intravitreal use of bevacizumab in neovascular AMD was reported.⁴⁷ The driving force for the “off-label” use of bevacizumab was, in addition to its obvious clinical effectiveness (figure 2), its low price of less than 50 USD per intravitreal injection. In the meantime, several retrospective and prospective studies indicate good functional outcomes.^48-52

So far there has been no evidence for an increased risk for systemic adverse events, but studies are overall too small and follow-up is too short to fully evaluate potential systemic adverse events. Recent meta-analyses indicated comparable functional outcomes and safety with bevacizumab and ranibizumab.^53,54 Several large prospective randomised clinical trials comparing bevacizumab and ranibizumab are currently ongoing. Intravenous use of bevacizumab in cancer patients may have serious systemic complications, including increased risk of thromboembolic events, hypertension, haemorrhage, proteinuria, wound healing complications and gastro-intestinal perforation.⁵⁵ Whether these systemic complications are relevant to wet AMD patients receiving very low doses by intravitreal injection is unknown. The absence of systemic and ocular adverse events in prospective studies is reasssuring, but the long-term safety of intravitreal bevacizumab remains to be established.^48,50,52

Pegaptanib was granted marketing authorisation by the European Medicines Agency on 31 January 2006 for the treatment of neovascular AMD. Pegaptanib is a pegylated modified oligonucleotide that binds with high specificity and affinity to extracellular vascular endothelial growth factor (VEGF₁₆₅), inhibiting its activity. VEGF₁₆₅ is the VEGF isoform preferentially involved in pathological ocular neovascularisation. Pegaptanib blocks mainly VEGF₁₆₅, reducing the growth of pathological blood vessels and associated bleeding and leakage.

The main prospective clinical trials in patients with AMD have been conducted using pegaptanib and ranibizumab.^41,42,56,57 Indirect comparison of pegaptanib and ranibizumab, indicates about a 3-line difference in visual acuity outcomes in favour of ranibizumab. Pegaptanib appears to be associated with fewer adverse effects although a direct comparison has never been studied. The three pivotal studies on ranibizumab reported a dose-related increased frequency of cardiovascular events (including stroke) and bleeding relative to the placebo group, although these increases were not statistically significant.

Indeed, whilst these new treatments represent an important breakthrough in wet AMD management, the overall safety of intravitreal anti-VEGF drugs remains unclear. First, although the drug is administered by injection through the sclera into the vitreous cavity, systemic absorption does occur, with potential for systemic adverse effects. In particular, human data are scant. Most importantly, since anti-VEGF treatment is potentially required for years, chronic treatment, particularly with non-selective VEGF inhibitors, may cause adverse effects that may only become clinically apparent over time. Second, because these trials were not designed to detect small differences in risk, much larger cohorts would be necessary to allow the evaluation of systemic adverse effects. In the reported clinical studies, the overall mortality rates were low given the advanced mean age of these populations (nearly 80 years); this could be mainly due to the exclusion of patients with a history of, or with risk factors for, cardiovascular disease.

Potential implications in neovascular AMD

It is of note that VEGF, mostly through its downstream mediator NO, has many essential physiological functions in maintaining vascular integrity, including the potential formation of collateral vessels crucial for the maintenance of perfusion to ischaemic tissues, as in acute myocardial infarction, in particular.⁵⁸ Intriguingly, while VEGF is crucial in maintaining vascular homeostasis, particular in clinical conditions associated with ischaemia and hypoxia, its role in maintaining plaque stability is currently a matter of debate.⁵⁹ Conceptually, in view of the cardioprotective role of VEGF, non-selective “pan”-anti-VEGF antagonism with ranibizumab or bevacizumab could be of even greater concern than blocking VEGF with selective antagonists such as pegaptanib. However, whether and to what degree more selective VEGF inhibition translates into fewer unwanted systemic effects and thus results in better cardiovascular outcomes remains unproven.

It is of note that cardiovascular safety of anti-VEGF drugs has not yet been addressed in randomised clinical trials. Unfortunately, the numbers of cardiovascular events in these AMD trials without pre-specified cardiovascular safety end points are too small to provide any clinically relevant evidence of safety. Indeed, the absence of evidence does not show evidence of absence. While trials for ranibizumab reported a marginally higher rate of arterial thromboembolic events in the higher dose treatment arm, this trend did not reach statistical significance.⁶⁰ (These trials were not powered to detect small differences in risk.) The issue is complicated further by a recent retrospective reanalysis of systemic safety outcomes with ranibizumab, which did not use the full dataset but nevertheless showed a significant increase in non-ocular haemorrhage in treated patients compared with controls (p=0.01), suggesting some impairment of systemic VEGF function.⁶¹ Although the doses involved in intravitreal injections of anti-VEGF agents are smaller than intravenous doses, intravitreal injection leads to peak serum concentrations several orders of magnitude greater than physiological levels of VEGF (11–27 ng/ml vs. 100 pg/ml in healthy adults).^62,63 The potential capacity of both drugs to saturate circulating VEGF hints at the possibility of adverse systemic effects.

Trials with the only selective inhibitor, pegaptanib, have not as yet shown any cardiovascular safety signals.⁵⁶Importantly, however, all trials both with less selective or “pan”-anti-VEGF agents were underpowered and thus it is not possible to rule out existing cardiovascular safety concerns. Uncertainty about the cardiovascular risk of intravitreal anti-VEGF treatment will remain until additional systemic safety data become available. These adverse events may be explained by endothelial dysfunction induced by anti-VEGF drugs.

Pan anti-VEGF therapy has shown to stabilise vision in about 95% of patients with neovascular macular degeneration compared to 70% with selective VEGF inhibition. The results are most impressive compared to laser led photocoagulation 15 years ago, which led to an unselective destruction of the retina and a primary loss of vision in order to stop progression of neovascular AMD. This obvious benefit from an ophthalmological perspective stands in contrast to potential cardiovascular risks. Only adequately powered randomised clinical trials that prospectively address cardiovascular safety will provide the evidence to show whether the proven benefits of VEGF antagonism in the eye may come at the cost of potential systemic adverse effects, particularly increasing atherosclerosis and its clinical sequelae. Until this trial evidence becomes available, ophthalmologists should avoid continuous VEGF suppression by using individualised treatment protocols⁶⁴ and should synchronise their efforts with cardiologists to reduce the cardiovascular burden of patients with wet AMD.

Conflict of interest
None declared.

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Larsson A, Skoldenberg E, Ericson H. Serum and plasma levels of FGF-2 and VEGF in healthy blood donors. Angiogenesis 2002;5:107–10.
Wong TY, Liew G, Mitchell P. Clinical update: new treatments for age-related macular degeneration. Lancet 2007;370:204–6.
Fung AE, Lalwani GA, Rosenfeld PJ et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol2007;143:566–83.

VEGF function in ocular health and disease: implications for therapeutic intervention in wet AMD

January 2009Br J Cardiol 2009;16(Suppl 2):S9-S10 Leave a comment

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Authors: David T Shima

Vascular endothelial growth factor (VEGF) plays a pivotal role in stimulating abnormal neovascularisation, a key characteristic of neovascular age-related macular degeneration (so-called wet AMD).¹ VEGF is a secreted protein that is able to diffuse and trigger mitogenic activity in endothelial cells.² It is produced by multiple retinal cell types, and blood vessels in the retina have several receptors for VEGF. It is known that VEGF inhibition can both prevent and reverse breakdown of the blood–retinal barrier.³ Indeed, elevated VEGF levels have been linked to neovascularisation and vascular permeability.(4-8) Consequently, it is proposed that VEGF inhibition could block the underlying pathogenic process of wet AMD.

However, VEGF is an intercellular signalling factor with numerous functions throughout the body. These functions can be both physiological and pathological: examples of these functions are provided in table 1.

Table 1. Properties and functions VEGF

The VEGF system

VEGF is not a single protein but rather exists in a number of different isoforms (figure 1). These isoforms differ in the number of amino acids contained in the mature secreted protein and, most importantly, in their solubility and heparin-binding properties.^9,10 The solubility of the isoform influences its ability to diffuse in the extracellular space and heparin-binding properties influence the extracellular matrix interactions of the individual isoform. The balance of solubility and heparin binding provides the spatial cues to initiate a precisely branched vessel network.¹¹ A further level of complexity is added by the existence of proximal and distal splice forms: proximal splice forms are pro-angiogenic whereas distal splice forms are anti-angiogenic.¹²A switch in splicing from anti-angiogenic to pro-angiogenic isoforms of VEGF may be associated with diabetic retinopathy.¹²

Figure 2. There are a number of different receptors for VEGF in the eye. Different isoforms of VEGF have varying affinities for different receptor types

Figure 1. Vascular endothelial growth factor (VEGF) exists in multiple isoforms that differ in their solubility and heparinbinding characteristics

In the eye, VEGF₁₂₁ and VEGF₁₆₅ are the major isoforms: VEGF₁₄₅ and VEGF₂₀₆ are not detected in the eye. High-affinity receptors for VEGF are expressed by endothelial cells. VEGF receptor 1 (VEGFR-1) and VEGF receptor 2 (VEGFR-2) bind to all isoforms of VEGF. In contrast, neuropilin-1 binds specifically to VEGF₁₆₅ via the exon-7-encoded domain of VEGF, which VEGF₁₂₁ lacks. Neuropilin-1 is thus recognised as a VEGF₁₆₅-specific receptor.⁹

VEGF and neuroprotection

The complexity of the VEGF system, utilising different isoforms and receptors, permits many functions for VEGF, some of which are beneficial and others detrimental. Recently, new roles in motor neuron development have been elucidated for VEGF. Studies in mice indicate that VEGF is involved in the coalescence of motor nuclei: disruption of the VEGF system results in a delay in migration of these cells.¹³ These findings could have important implications for neuron preservation in the eye.

When the eye is subjected to an ischaemic insult, retinal neurons become apoptotic; in the presence of VEGF, apoptosis is greatly reduced.¹⁴ However, if a long period of ischaemia (60 minutes) is preceded by a short period of ischaemia (five minutes), there appears to be a level of protection afforded, known as ischaemic preconditioning. VEGF is thought to play a very important neuroprotective role in this ischaemic preconditioning. Indeed, if VEGF is injected into the eye following ischaemic insult, the majority of neuronal cell death can be prevented. It has been found that VEGFR-2 is present not only in the blood vessels but also on neurons and glia within the retina, providing a potential mechanism for this neuroprotective effect. By contrast, chronic suppression of the VEGF system leads to retinal ganglion cell death, which could have important implications for the use of anti-VEGF therapy in wet AMD.

VEGF and inflammation

Br-J-Cardiol-2009-16-S2-S9-S10-figure-3 — Figure 3. VEGF164 blockade preferentially inhibits pathologic retinal neovascularisation

Evidence suggests that the VEGF₁₆₅ isoform has pro-inflammatory properties.¹⁵ VEGF₁₆₅ blockade preferentially inhibits pathologic retinal neovascularisation. Indeed, VEGF₁₆₅-selective blockade and non-selective VEGF blockade inhibit pathologic neovascularisation to a similar extent (figure 3).⁸ In VEGF₁₆₄-deficient mice (VEGF₁₆₄ in mice is equivalent to VEGF₁₆₅ in humans), no neovascularisation in the flat mount retina is observed, in contrast to wild-type mice where abnormal angiogenesis and vascular tuft formation are present.¹⁵

VEGF₁₆₅ has been shown to be the most potent of the VEGF isoforms at creating leukocyte-based inflammation.¹⁵ It is likely that the pro-inflammatory activity of VEGF₁₆₅contributes to the development of wet AMD. Inflammation plays an important role in AMD.¹⁶

Conclusion

VEGF has numerous physiological roles that must be considered when developing treatments for chronic conditions that may affect VEGF functionality in the body. More research is required to develop understanding of the different roles of VEGF isoforms in normal physiological functioning and the pathogenesis of disease.

At present, pan-VEGF inhibitors are used in both oncological and ophthalmological settings. There is a growing list of safety concerns as experience with these agents increases, although at present the benefits are considered to outweigh the risks. The risk/benefit will need to be continuously monitored as these agents are used longer-term, as preventive agents and for the potential treatment of diabetic retinopathy which is currently being investigated in the clinic. More selective VEGF inhibitors may provide an attractive option for treating patients with a higher risk profile.

Conflict of interest

Professor Shima: none declared.

References

Ambati J, Ambati BK, Yoo SH et al. Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv Ophthal 2003;48:257–93.
Ferrara N, Houck K, Jakeman L, Leung DW. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 1992;13:18–32.
Qaum T, Xu Q, Joussen AM et al. VEGF-induced blood-retinal barrier breakdown in early diabetes.Invest Ophthalmol Vis Sci 2001;42:2408–13.
Adamis AP, Shima DT, Tolentino MJ et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol 1996;114:66–71.
Krzystolik MG, Afshari MA, Adamis AP et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch Ophthalmol 2002;120:338–46.
Aiello LP, Pierce EA, Foley ED et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA1995;92:10457–61.
Amano S, Rohan R, Kuroki M, Tolentino M, Adamis AP. Requirement for vascular endothelial growth factor in wound- and inflammation-related corneal neovascularization. Invest Ophthalmol Vis Sci 1998;39:18–22.
Ishida S, Usui T, Yamashiro K et al. VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med 2003;198:483–9.
Robinson CJ, Stringer SE. The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 2001;114:853–65.
Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999;13:9–22.
Ruhrberg C, Gerhardt H, Golding M et al. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev 2002;16:2684–98.
Perrin RM, Konopatskaya O, Qiu Y, Harper S, Bates DO, Churchill AJ. Diabetic retinopathy is associated with a switch in splicing from anti- to pro-angiogenic isoforms of vascular endothelial growth factor. Diabetologia2005;48:2422–7.
Schwarz Q, Gu C, Fujisawa H et al. Vascular endothelial growth factor controls neuronal migration and cooperates with Sema3A to pattern distinct compartments of the facial nerve. Genes Dev 2004;18:2822–34.
Nishijima K, Ng YS, Zhong L et al. Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol 2007;171:53–67.
Shima D, unpublished data.
Anderson D. A role for inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002; 134: 411–31.

Wet AMD: anti-VEGF treatments in the elderly population

January 2009Br J Cardiol 2009;16(Suppl 2):S11-S13 Leave a comment

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Authors: Johannes Waltenberger

In 1971 Folkman proposed that tumour growth was dependent upon angiogenesis, and consequently suggested that preventing angiogenesis might prevent tumour growth.1 This concept led to research into manipulating angiogenesis in order to influence tumour progression, and subsequently other therapeutic areas, including cardiology and ophthalmology. In 1983 vascular permeability factor (VPF) was discovered, followed by vascular endothelial growth factor (VEGF) in 1989. It later transpired that they were in fact the same molecule.

Effect of VEGF on the vasculature

Br-J-Cardiol-2009-16-S2-S11-S13-figure-1 — Figure 1. Vascular endothelial growth factor (VEGF) stimulation of endothelial cells has a number of effects, primarily protective

VEGF plays a primarily protective role in the vasculature (figure 1).² It is known that VEGF stimulation of the endothelium has an antithrombotic effect. It stimulates endothelial cells to proliferate and migrate, which is crucial for the renewal of the endothelium. VEGF also has an anti-apoptotic effect, allowing endothelial cells to survive for longer periods of time. VEGF stimulation of endothelial cells is involved in the induction and release of nitric oxide and prostacyclin, enabling the endothelial cells to interact with other cells.^3,4 Furthermore, VEGF has an antiproliferative effect on smooth muscle cells and regulates vessel wall permeability.⁵ It is therefore clear that inhibition of VEGF is likely to have unwanted effects on the vasculature: it would be prothrombotic, pro-apoptotic and vasoconstrictive.

Endothelial cells have a major role in angiogenesis. However, circulating monocytes also carry VEGF receptors and contribute to the formation of collateral vessels. In the heart and peripheral circulation, collateral vessels are protective, for example by providing additional tissue perfusion in the presence of blood vessel blockage. Indeed, VEGF stimulation can be used therapeutically to promote the growth of collateral vessels.⁶ If the femoral artery of a mouse is ligated (to induce claudication), perfusion can be significantly increased following the intravenous application of VEGF for seven days.⁷ Furthermore, this elevated perfusion appears to be largely mediated via VEGF receptor 1 (VEGFR-1), which is present on the surface of both endothelial cells as well as circulating monocytes.

Br-J-Cardiol-2009-16-S2-S11-S13-table-1 — Table 1. Summary of phase II and III trials of therapeutic angiogenesis

A number of phase II and III trials of therapeutic angiogenesis have been conducted, many using VEGF receptor-stimulating agents, but with mixed results (table 1).^8-17 Consequently, there is no currently accepted pro-VEGF therapy with proven efficacy in the clinical situation. It is thought that a reason for treatment failure may have been the relatively short timeframe of VEGF application: in order for VEGF to exert a biological effect on collateral vessel growth, it needs to be present for at least one week in sufficient concentrations. All the therapies trialled so far have resulted in only a short spike in VEGF concentration. With improvement of the duration of VEGF receptor stimulation, better results might be seen.

Br-J-Cardiol-2009-16-S2-S11-S13-figure-2 — Figure 2. Serum VEGF levels rise in the presence of ischaemia, as demonstrated following myocardial infarction(18)

In the presence of ischaemia, VEGF levels rise, suggesting that hypoxia stimulates the VEGF system (figure 2).¹⁸ However, VEGF also appears to be present in non-ischaemic tissue, suggesting that a baseline level of VEGF is required to maintain normal vascular function. Reduction in this baseline level of VEGF is likely to result in adverse effects on the circulatory system.

There are a number of different strategies that can be utilised to inhibit VEGF signalling. These include: anti-VEGF antibodies, soluble VEGF receptors, aptamers, VEGF receptor antibodies and inhibitors of the VEGF receptor signalling pathway (tyrosine kinase inhibitors).^19,20

Effects of VEGF on the lung

VEGF inhibition has been used for the treatment of various cancers.²¹ An interesting finding from the treatment of lung cancer is that a baseline level of VEGF activity appears to be required for the maintenance of normal lung function. Following the introduction of a VEGF receptor-inhibiting agent, lung cell apoptosis has been seen to occur.²² Thus, inhibition of VEGF could lead to emphysema and lung destruction.

Effects of VEGF on atherosclerosis

Br-J-Cardiol-2009-16-S2-S11-S13-figure-3 — Figure 3. Possible mechanisms for effects of VEGF on atherosclerotic plaque stability

A number of factors are known to be present within atherosclerotic plaques that stimulate the development and growth of plaques. Among these is VEGF. It has been proposed that, in the atherosclerotic plaque, VEGF stimulates endothelial proliferation and migration, leading to an increase in plaque angiogenesis, matrix degradation and immature vessels and resulting in plaque instability. In turn, plaque instability can lead to thrombotic events, including myocardial infarction and ischaemic stroke. However, it is also possible that VEGF could provide an increase in plaque stability by decreasing endothelial cell apoptosis and improving endothelial cell function, resulting in the prevention of vascular regression (figure 3).

In trials where VEGF was added to atherosclerotic plaques, no evidence for further progression of the plaque or evidence of increased instability has been observed.^23-25However, extrapolation from oncological findings predicts that inhibiting VEGF would result in capillary regression, capillary thrombosis and intraplaque necrosis (figure 4). This would lead to an increase in thrombotic events in those receiving VEGF-inhibiting therapy.

The age-related macular degeneration population

Coronary atherosclerosis is a frequent finding in the elderly population, and the risk of coronary atherosclerosis rises with age. The one-day mortality of acute myocardial infarction is around 35%.²⁶ The one-year mortality of patients above 75 years of age with ST-elevation myocardial infarction (STEMI) is 52.4% for conservative treatment and 19.2% for primary percutaneous intervention.²⁷

Figure 4. Impact of VEGF on atherosclerotic plaque development and stability

At the time of diagnosis of age-related macular degeneration (AMD), the average patient is 75 years of age, with a life expectancy of 11.8 years.^28,29 Neovascular AMD (wet AMD) is often associated with significant co-morbidities, such as diabetes and cardiovascular disease.³⁰ Wet AMD may be treated with VEGF inhibitors, which, although administered intravitreally, are absorbed systemically and thus could potentially have systemic effects.

Summary

Angiogenic growth factors are important functional stimuli for vascular cells. As well as stimulating angiogenesis, they are involved in maintenance of the integrity of the vasculature. Inhibition of angiogenic growth factors efficiently inhibits tumour angiogenesis and reduces tumour growth. However, inhibition of angiogenic growth factors may lead to vascular dysfunction and vascular complications such as atherosclerotic plaque rupture and acute ischaemic syndromes.

This should be an important consideration when administering VEGF-inhibiting treatment for wet AMD, in a population that is already at high risk for cardiovascular events.

Conflict of interest
Professor Waltenberger is an advisor to Pfizer.

References

Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–6.
Kliche S, Waltenberger J. VEGF receptor signalling and endothelial function. IUBMB Life 2001;52:61–6.
Kroll J, Waltenberger J. A novel function of VEGF receptor-2 (KDR): rapid release of nitric oxide in response to VEGF-A stimulation in endothelial cells. Biochem Biophys Res Commun 1999;265:636–9.
Zachary I, Mathur A, Yla-Herttuala S, Martin J. Vascular protection: a novel nonangiogenic cardiovascular role for vascular endothelial growth factor. Arterioscler Thromb Vasc Biol 2000;20:1512–20.
Becker PM, Waltenberger J, Yachechko R et al. Neuropilin-1 regulates vascular endothelial growth factor-mediated endothelial permeability. Circ Res 2005; 96:1257–65.
Babiak A, Schumm AM, Wangler C et al. Coordinated activation of VEGFR-1 and VEGFR-2 is a potent arterigenic stimulus leading to enhancement of regional perfusion. Cardiovasc Res 2004;61:789–95.
Tsurumi Y, Takeshita S, Chen D et al. Direct intravascular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion. Circulation 1996; 94:3281–90.
Henry TD, Annex BH, Azrin MA et al. Double-blind, placebo-controlled trial of recombinant human vascular endothelial growth factor: the VIVA trial. J Am Coll Cardiol 1999; 33:384A.
Simons M, Annex BH, Laham RJ et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor: double-blind, randomised, controlled clinical trial. Circulation 2002; 105:788–93.
Seiler G. Promotion of collateral growth by granulocyte-macrophage colony stimulating factor in patients with coronary artery disease. Circulation 2001;104: 2012–17.
Grimes CL. Angiogenic Gene Therapy (AGENT) in patients with stable angina pectoris. Circulation 2002; 105:1291–7.
Hedman M. Safety and feasibility of catheter-based local intracoronary VEGF gene transfer in the prevention of post-angioplasty and in-stent restenosis and in the treatment of chronic myocardial ischaemia. The Kuopip angiogenesis trial (KAT). Circulation (in press).
Stewart DJ A phase 2, randomised, multicentre, 26-week study to assess the efficacy and safety of BIOBYPASS (AdGVVEGF121) delivered through minimally invasive surgery versus maximum medical treatment in patients with severe angina, advanced coronary artery disease and no options for revascularisation. Circulation 2002;106: 23–6.
Kastrup J. Euroinject One trial. Late breaking clinical trials session. American College of Cardiology 2003, Chicago. J Am Coll Cardiol 2003; 41:1604.
Lederman RJ. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 2002;359: 2053–8.
Makinen K. Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery. Mol Ther 2002; 6:127–33.
Rajagopalan S. Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease (RAVE). Late breaking clinical trials session. American College of Cardiology 2003, Chicago. J Am Coll Cardiol 2003;41:1604.
Kranz A, Rau C, Kochs M, Waltenberger J. Elevation of vascular endothelial growth factor-A serum levels following acute myocardial infarction. Evidence for its origin and functional significance. J Mol Cell Cardiol 20 00;32:65–72.
Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005;438:967–74.
Moreira IS, Fernandes PA, Ramos MJ. Vascular endothelial growth factor inhibition—a critical review. Anticancer Med Chem 2007; 7: 223–45.
Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004; 25: 581–611.
Kasahara Y, Tuder RA, Taraseviciene-Stewart L et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000;106:1311–19.
Lucerna M, Zernecke A, de Nooijer R et al. Vascular endothelial growth factor-A induces plaque expansion in ApoE knock-out mice by promoting de novo leukocyte recruitment. Blood 2007;109:122–9.
Dunmore BJ, McCarthy MJ, Naylor AR, Brindle NP. Carotid plaque instability and ischemic symptoms are linked to immaturity of microvessels within plaques. J Vasc Surg 2007;45:155–9.
Petrovan RJ, Kaplan CD, Reisfeld RA, Curtiss LK. DNA vaccination against VEGF receptor-2 reduces atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 2007;27:1095–100.
Löwel H, Meisinger C. [Epidemiology and demographic evolution exemplified for cardiovascular diseases in Germany]. Med Klin (Munich) 2006;101:804–11.
Zeymer U, Gitt A, Winkler R et al. [Mortality of patients who are older than 75 years after ST elevation myocardial infarction in clinical practice]. Dtsch Med Wochenschr 2005;130:633–6.
Zlateva GP, Javitt JC, Shah S et al. Comparison of comorbid conditions between neovascular age-related macular degeneration patients and a control cohort in the Medicare population. Retina 2007;27:1292–9.
van Wijngaarden P, Coster DJ, Williams KA. Inhibitors of ocular neovascularization: promises and potential problems. JAMA 2005;293:1509–13.
Hyman L, Schachat AP, He Q, Leske MC, for the Age-Related Macular Degeneration Risk Factors Study Group. Hypertension, cardiovascular disease, and age-related macular degeneration. Arch Ophthalmol 2000;118:351–8.

Efficacy and safety of intravitreal pegaptanib sodium in the treatment of neovascular age-related macular degeneration

January 2009Br J Cardiol 2009;16(Suppl 2):S14-S15 Leave a comment

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Authors: Sobha Sivaprasad, John J Wroblewski

Introduction

Pegaptanib sodium (Macugen®) was approved for the treatment of neovascular AMD (wet AMD) in Europe in 2006. It is administered by intravitreal injection into the affected eye once every six weeks at a dose of 0.3 mg.¹ Pegaptanib is a pegylated modified oligonucleotide that binds with high specificity and affinity to extracellular vascular endothelial growth factor (VEGF) isoform 165, inhibiting its activity. VEGF is a secreted protein that induces angiogenesis, vascular permeability and inflammation, all of which are thought to contribute to the progression of wet AMD.

VEGF165 is the VEGF isoform preferentially involved in pathological ocular neovascularisation. In animals, this selective inhibition with pegaptanib proved as effective at suppressing pathological neovascularisation as pan-VEGF inhibition; however, pegaptanib spared the normal vasculature whereas pan-VEGF inhibition did not.¹

Efficacy

The Vascular Endothelial Growth Factor Inhibition Study in Ocular Neovascularization (VISION) trial showed that 70% of patients with wet AMD treated for 12 months with six-weekly pegaptanib sodium responded to treatment (lost <15 letters). This compared with only 55% of control (sham) subjects. Furthermore, 6% of patients receiving pegaptanib experienced an improvement in their vision (gained ≥15 letters).²

In a retrospective analysis performed to acquire data on ‘real-life’ experience with pegaptanib, data were collected from 164 patients with any angiographic subtype of sub-foveal choroidal neovascularisation secondary to AMD from five European countries.³ Patients were recruited consecutively with best-corrected visual acuities (BCVA) in the study eye of 20/40 to 20/800. All patients received 0.3 mg pegaptanib as first-line treatment and had a follow-up duration of at least six months. At 24 weeks, 90.2% of patients had met the response criterion of a loss of fewer than 15 letters (last observation carried forward [LOCF] analysis). The mean change in visual acuity at 24 weeks was a loss of 1.7 letters, with 63.4% not losing any letters (maintaining their vision) and 38.4% gaining at least five letters (improving their vision). Only 3% of patients experienced a severe visual loss.

The addition of another 92 patients from further centres to the analysis increased the proportion of patients losing fewer than 15 letters to 93.75% at 24 weeks. The proportion at least maintaining vision was similarly increased to 73% and the proportion improving vision (gain ≥5 letters) increased to 35.5%. At 54 weeks, 91.4% of patients had lost fewer than 15 letters, 71.4% had at least maintained their vision and 27.14% had improved their vision (gained five or more letters).

These real-life visual acuity findings with investigator-determined pegaptanib use suggest that better outcomes than those observed in the VISION study could be achievable.

Safety

There are potential safety concerns regarding the long-term use of anti-VEGF therapy. While, in the treatment of wet AMD, the anti-VEGF agent is administered directly into the eye, there is inevitably some systemic absorption.⁴Ranibizumab (Lucentis) is a humanised recombinant monoclonal antibody fragment with high affinity for the VEGF-A isoforms, which is licensed for the treatment of wet AMD.^5,6 In clinical trials, this pan-VEGF inhibitor has been associated with a higher incidence of arterial thromboembolic events (2.5%) compared with control treatment (1.1%) at one year.⁵ It is thought that the relative selectivity of pegaptanib for VEGF₁₆₅ should reduce the likelihood of such adverse events.

Pegaptanib safety data from the VISION trial indicate that at one and two years there is no evidence of an increase in events associated with systemic VEGF inhibition, such as thromboembolic events and hypertension.^2,7 Indeed, four-year safety results with pegaptanib have shown no changes in the previously reported safety profile (personal communication, JJ Wroblewski).

Conclusion

Pegaptanib has been shown to be safe and effective in the treatment of wet AMD. Despite the absence of a control group and limited number of patients continuing to four years’ treatment in the VISION trial, analysis of the safety data is consistent with previous reports: the injection procedure was well tolerated by the patients and there is no evidence of an increased risk of ocular or systemic adverse events. In particular, there is no evidence that pegaptanib is associated with the major systemic adverse events that could accompany pan-VEGF inhibition.

Conflict of interest
Dr Sivaprasad has received research and travel grants from Novartis and Pfizer.

References

Ishida S, Usui T, Yamashiro K et al. VEGF₁₆₄-mediated inflammation is required for pathological not physiological ischemia-induced retinal neovascularization. J Exp Med 2003;198:483–9.
Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinson M, Guyer DR; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med2004;351:2805–16.
Sivaprasad S, Saeed A, Beatty S et al. Intravitreal pegaptanib sodium for choroidal neovascularization secondary to age-related macular degeneration – a pan-European experience. Poster presented at Association for Research in Vision and Ophthalmology 2008 Annual Meeting. April 2008; Fort Lauderdale, FL, US.
van Wijngaarden P, Coster DJ, Williams KA. Inhibitors of ocular neovascularization: promises and potential problems. JAMA 2005;293:1509–13.
Novartis. Summary of Product Characteristis. Lucentis. Available from: http://emc.medicines.org.uk/emc/industry/default.asp?page=displaydoc.asp&documentid=19409
Lowe J, Aranjo J, Palma M et al. RhuFabV2 inhibits VEGF-isoform stimulated HUVEC proliferation. Invest Ophthalmol Vis Sci 2003; 44:B274 (Abstract 1828).
VEGF Inhibition Study in Ocular Neovascularization (VISION) Clinical Trial Group, D’Amico DJ, Masonson HN et al. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology 2006;113:992–1001.

Moving forward in pulmonary arterial hypertension

January 2009Br J Cardiol 2009;16(Suppl 1):S2-S3 Leave a comment

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Authors: Henry Purcell

Sponsorship Statement: The symposium was sponsored by GlaxoSmithKline, who also sponsored the writing of this report and this supplement. Volibris™ ▼ is a registered trademark of Gilead (Nasdaq: GILD), used under license by the GlaxoSmithKline group of companies. Ambrisentan has been licensed to GlaxoSmithKline by Gilead Sciences Inc. in all countries of the world, except the United States (US).

Pulmonary arterial hypertension (PAH) is a comparatively rare, chronic, progressive disease of unknown aetiology, which is characterised by increased pulmonary vascular resistance and which may ultimately lead to right heart failure and premature death.¹ In a recent French registry the estimated prevalence was 15 cases per million, with approximately twice as many women as men being diagnosed.² PAH is increasingly diagnosed in older people, who may have considerable co-morbidities compared to the younger PAH patients traditionally seen.²

Diagnosis can be challenging as its symptoms are often non-specific: they may include breathlessness, fatigue, weakness, angina, syncope and abdominal distension. In the mid-1980s, before the availability of ‘targeted’ therapy, median life expectancy from diagnosis in patients with idiopathic PAH (formerly termed primary pulmonary hypertension [PPH]) was only 2.8 years.³ In 1996, continuous intravenous prostacyclin (epoprostenol) was the first drug to demonstrate outcome benefit in PAH.⁴ Subsequently, over the past ten years, randomised, placebo-controlled trials of other prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase inhibitors have shown significant benefit to patients with PAH, with improvements in exercise capacity, functional class and other parameters.⁵ For those patients who fail to respond to medical therapy, double-lung or heart-lung transplantation may be an option.⁶

This supplement is a report from the symposium ‘Moving forward in pulmonary arterial hypertension’, held on 1^st September 2008 during the European Society of Cardiology Congress in Munich, Germany. The meeting was chaired by Dr Sean Gaine, Mater Misericordiae University Hospital, Dublin, Ireland, and Dr Simon Gibbs, Imperial College London and Hammersmith Hospital, London, UK and was sponsored by an educational grant from GSK.

The symposium highlighted how understanding of the pathobiology of PAH has evolved over the past two decades, as has the treatment of this condition. With the availability of newer treatment agents, and with increasing use of combination therapy to enhance clinical benefit, along with the need to begin treatment earlier, the PAH picture continues to unfold. It offers many challenges for the years to come, which makes this one of the most rapidly evolving fields within cardiology, and indeed within medicine as a whole. We hope that this is an objective and informative review of the symposium.

Br-J-Cardiol-2009-16-S1-S2-S3_WHO_Table — WHO Functional Classification of Pulmonary Hypertension

References

Galie N, Simmoneau G. Pulmonary hypertension. In: The ESC Textbook of Cardiovascular Medicine. Eds Camm AJ, Luescher TF, Serruys PS. Blackwell Publishing, 2006.
Humbert M, Sitbon O. Chaouat A et al. Pulmonary Arterial Hypertension in France. Results from a National Registry. Am J Respir Crit Care Med 2006;173:1023–30.
D’Alonzo GE, Barst RJ, Ayres SM et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343–9.
Barst RJ, Rubin LJ, Long WA et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296–302.
National Pulmonary Hypertension Centres of the UK and Ireland. Consensus statement on the management of pulmonary arterial hypertension in clinical practice in the UK and Ireland. Heart 2008;94:i1–i41.
Galie N, Torbicki A, Barst R et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology.Eur Heart J 2004;25:2243–78.

What scientific progress have we made in PAH?

January 2009Br J Cardiol 2009;16(Suppl 1):S4-S6 Leave a comment

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Authors: BJCardio editorial team

Reviewing this topic, Professor Lewis J Rubin, University of California, San Diego, US, looked at both the successes and failures of the past 20 years. He described how, as little as two decades ago, there was no treatment algorithm for PAH: “we had absolutely no understanding of the fundamental mechanisms responsible for the development of PAH” and approaches to treatment were based on a simplistic extrapolation from systemic hypertension and left-sided heart disease.

Since then, there has been a steady exploration of the molecular mechanisms underlying PAH, which has led to development of effective targeted therapeutic options such as endothelin receptor antagonists and prostacyclin derivatives. In Professor Rubin’s view, these options represent a major success, but he hoped that there would be further progress. Many patients may not respond to these therapies, and it remains a serious and life-threatening disease.

The characterisation of PAH into its clinical, pathobiological and epidemiological components has provided the opportunity to intervene therapeutically and to delay disease progression. Three factors appear to be associated with the increased pulmonary vascular resistance seen in PAH, including vasoconstriction, remodelling of the pulmonary vessel wall and thrombosis in situ. Early catheterisation studies led to the clinical characterisation of PAH, while landmark epidemiological studies such as the National Institutes of Health (NIH) Registry¹ have helped to define the natural history of this disease and its risk factors and to define treatment targets.

The next pathobiological phase identified the role of endothelial dysfunction, demonstrating impaired production of prostacyclin and nitric oxide (NO) and overproduction of endothelin. For the first time, this offered pathobiological targets for the treatment of this disease. Similarly, the concept of vascular growth and proliferation meant that PAH was viewed not as a single dynamic disease but rather as a much more complex process. Finally, a further area of critical importance was identification of the role of genetics in PAH, and potentially in other forms of pulmonary hypertension.

The natural history of primary pulmonary hypertension (PPH) was evaluated in the NIH Registry from 1981-87.¹ Reporting just over 20 years ago, it showed that of the 194 patients included in the study, 63% were female and 37% were male, and the mean age was 36 years. Median untreated survival after diagnosis was 2.8 years. It also highlighted “the haemodynamic severity of the disease relative to the normal range”. (Pulmonary hypertension [PH] today is defined by a mean pulmonary artery pressure >25 mmHg at rest or >30 mmHg with exercise.)²

By the time patients presented, they had advanced disease and the Registry findings¹ also underscored the fact that there was an unacceptable delay from the onset of symptoms to the time of diagnosis, said Professor Rubin. This was true 20 years ago and “unfortunately it’s still true today. It is one of our major failings that we still see patients present with advanced disease. We need to have a major focus on early diagnosis and early treatment…which is becoming more and more feasible”.

Some forms, such as systemic sclerosis-associated pulmonary arterial hypertension (SScPAH), carry an even worse prognosis than that of patients with idiopathic PAH.³ We should be able to identify such at-risk patients earlier if we invoke the right approaches to managing the condition.⁴ Another important element in disease management is characterising the limitations and abnormalities that patients have. There are a number of determinants or markers of survival in PAH(table 1). The six-minute walk distance, for example, has been used as an objective measure of exercise capacity and Professor Rubin stated that those who can walk longer do considerably better than those who cannot. Also, exercise distance improves with treatment. Haemodynamic markers include indices of right heart function, notably right atrial pressure and mean pulmonary artery pressure (mPAP). Echocardiographic indices include right atrial size. Useful biomarkers such as brain natriuretic peptide (BNP) are now being incorporated into management paradigms and also as end points in clinical trials.

PAH classification

Br-J-Cardiol-2009-16-S1-S4-S6-table-1 — Table 1: Determinants/markers of survival in pulmonary arterial hypertension (PAH)

There have been major developments in the classification of pulmonary hypertension since the First World Symposium on Diagnostic Classification in Geneva in 1973, which basically divided the disease into primary and secondary pulmonary hypertension, depending on whether or not the patient had identifiable causes or risk factors.⁴ Things have moved on to a more complex classification.⁵Although some may regard this classification as too complex, Professor Rubin believes that the classification is useful because it serves as the differential diagnosis, which is critical for assessing patients with pulmonary hypertension, who may share certain features in common or be quite different (table 2). This classification is a living document, he explained; it changes, and continues to change, as our thinking and experience evolve.

PAH pathophysiology

Br-J-Cardiol-2009-16-S1-S4-S6-table-2 — Table 2: Pulmonary arterial hypertension (PAH) current classification

PAH is largely a vasoproliferative disease, a process which is characterised by growth and proliferation of all the layers of the vessel wall.⁶ We have learned much about what may contribute to the transition from the normal to the remodelled pulmonary vessel. Studies have demonstrated a variety of abnormalities which are intrinsic to the smooth muscle cell or the endothelial cell, requiring cross-talk between the two cells. The hallmark is proliferation and probably altered apoptosis. Possibly, in the early phase of the disease, an intrinsic abnormality of contraction may occur as well, although this has not been confirmed.

Three important pathways have been identified in pulmonary hypertension (table 3).⁷

These pathways are known from animal studies, and clinical trials have shown that targeting these three pathways does lead to improvements in patients with PAH.^8-12

Br-J-Cardiol-2009-16-S1-S4-S6-table-3 — Table 3: Pathogenic pathways and treatment for pulmonary arterial hypertension (PAH)

The endothelin pathway, or the so-called overproduction of endothelin, can be targeted with endothelin receptor antagonists. Underproduction of prostacyclin is addressed by the use of a prostacyclin analogue; and targeting underproduction of nitric oxide (NO) by augmenting the signal for its production and inhibiting its breakdown via a phosphodiesterase (PDE) inhibitor. There is of course a “whole variety of other pathways” which have been suggested to be abnormal and implicated in PAH, and many abnormalities have been demonstrated. The challenge for the future is to prioritise these and to try and gain an understanding of which of these abnormalities are causative.

Conflict of interest

LJR serves on advisory committees for Actelion, Pfizer, MD Primer, Encysive, Novartis and Gilead.

Diagram of the pathophysiology of pulmonary arterial hypertension showing circulating cells and mediators

References

D’Alonzo GE, Barst RJ, Ayres SM et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343–9.
Galie N, Torbicki A, Barst R et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology.Eur Heart J 2004;25:2243–78.
Kawut SM, Taichman DB et al. Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest 2003;123:344–50.
Hatano S, Strasser R, Eds. Primary pulmonary hypertension. World Health Organization, Geneva, 1975.
Simonneau G, Galie N, Rubin L et al. Clinical classification of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:S5–S12.
Humbert M, Morrell N, Archer S et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:S13–S24.
Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425–36.
Galie N, Olschewski H, Oudiz RJ et al. Ambrisentan for the treatment of pulmonary arterial hypertension. Results of the ARIES Study 1 and 2. Circulation 2008;117:3010–19.
Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896–903.
Barst RJ, Langleben D, Frost A. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;169:441–7.
Galie N, Ghofrani HA, Torbicki A et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148–57.
Barst RJ, Rubin LJ, Long WA et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334:296–302.

Increasing complexities in PAH management

January 2009Br J Cardiol 2009;16(Suppl 1):S7-S9 Leave a comment

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Authors: BJCardio editorial team

Current data show that PAH patients are now older than previously reported, and more patients are identified with associated co-morbidities, according to Professor Marius Hoeper, Hannover Medical School, Germany. One recent study in more than one thousand patients showed that over one half had two or more co-morbidities.¹ About one third had systemic hypertension, 16% had hypothyroidism, 15% scleroderma, 14% were clinically depressed (possibly as a consequence of pulmonary hypertension) and a further 13% had diabetes.¹ Some centres also report that the spectrum of PAH patients seems to be changing, he said. Whereas in the past idiopathic PAH was more common, in recent years PAH in association with connective tissue disorders and congenital heart disease has been more frequently observed in many centres.²

The severity of pulmonary vascular resistance at presentation also seems to be (slightly) declining, which suggests that the disease is being diagnosed earlier. However, the vast majority of patients are still in functional class III or IV at diagnosis.² Professor Hoeper emphasised the improvements in available medical treatments, which have broadened from the limited options of intravenous epoprostenol and calcium channel blockers to include a wide range of prostanoids and the newer drug classes of endothelin receptor antagonists (three are currently available in some countries) and PDE-5 inhibitors.

Br-J-Cardiol-2009-16-S1-S7-S9-table-1 — Table 1: Selection of treatments in pulmonary arterial hypertension (PAH)

It is very difficult to select PAH treatments, said Professor Hoeper, as there are only limited data to provide guidance. However, a number of factors are taken into consideration and these are shown in table 1.

Since many patients are being treated with combinations, the possibility of drug-drug interactions increases.³ Similarly, the mode and convenience of administration must be considered; for example many patients might prefer oral administration. Treatment costs and approval status are also considerations. There are disparities in the indications for these drugs across Europe, which is potentially a source of disagreement for several more years.

For prescribers, it is important to know that the drugs work and to see haemodynamic evidence of improvement. Looking at data from randomised controlled trials (RCTs), Professor Hoeper expressed the view that improvements in pulmonary artery pressure (PAP) are often very modest. Reviewing data from the SUPER-1 trial with sildenafil,⁴ some improvements in exercise capacity are observed but he argued that we do not yet know the most efficacious dose.

Endothelin receptor antagonists

Br-J-Cardiol-2009-16-S1-S7-S9-table-2 — Table 2: Characteristics of bosentan, sitaxentan and ambrisentan

Professor Hoeper then described the characteristics of the three clinically developed endothelin receptor antagonists (ERAs), bosentan, sitaxentan and ambrisentan (table 2).^5-7 These drugs have different chemical structures, with bosentan and sitaxentan belonging to the sulfonamide class and ambrisentan belonging to the propanoic acid class. Receptor affinities may confer differences in efficacy but presently this is difficult to determine. Six-minute walk distance data from placebo-controlled trials show very similar changes in most of the trials.^8-10 Likewise, we do not yet have long-term survival data from RCTs, just the open-label extension data from several short-term RCTs. The survival observed at one year is in the high nineties: it appears to be very similar for the three ERAs, which makes choice of drug difficult.

Br-J-Cardiol-2009-16-S1-S7-S9-table-3a-c — Table 3a: ALT and AST elevations during long-term follow-up with bosentan in the BREATHE-1 trial Table 3b: ALT and AST elevations during long-term follow-up with sitaxentan in Table 3c: ALT and AST elevations during long-term follow-up with ambrisentan in the ARIES trials

Factors such as safety also need to be taken into consideration. In Professor Hoeper’s view, rises in hepatic aminotransferases (e.g. alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) are a problem with these drugs in general and something that has to be monitored when on the drug continuously. The STRIDE 2 trial,⁹ sought to determine the optimal dose of the ERA, sitaxentan in PAH patients, and included an open-label bosentan arm for observation only. Although powered for efficacy, the study did report safety results as well, which showed that the incidence of elevated aminotransferases (>3 x upper limit of normal [ULN]) was 6% in the placebo group; 5% in the sitaxentan 50 mg group; 3% in the sitaxentan 100 mg group; and 11% for open-label bosentan. But in the long-term extension data,¹⁰ the difference seemed to be less pronounced (tables 3a-3c). For ambrisentan, the newest of the three ERAs, it appears that the incidence of aminotransferase elevation is lower than for the other two but this drug still has to stand the test of long-term administration, Professor Hoeper noted.-

Another factor of concern, in his view, is drug-drug interaction, which is “becoming an issue in the treatment of pulmonary hypertension at the present time”. Bosentan and sitaxentan have the propensity to interact with warfarin (table 4):this is important because up to 75% of PAH patients are being treated with warfarin or other anticoagulants.¹¹ With bosentan, the dose of warfarin has to be increased¹² whereas with sitaxentan, the dose of warfarin has to be decreased in order to avoid bleeding problems.¹³ There is also an interaction between bosentan and sildenafil, which leads to lower concentrations of the latter.¹⁴ We don’t know if this has any clinical relevance, said Professor Hoeper, and this interaction is not seen with sitaxentan⁶ or ambrisentan.⁷

Br-J-Cardiol-2009-16-S1-S7-S9-table-4 — Table 4: ERA and drug-drug interactions*

Summarising, he said that the majority of PAH patients in functional classes II/III are receiving oral medications such as PDE-5 inhibitors or ERAs. There are not sufficient data to compare their long-term efficacy, but there appears to be no difference in terms of efficacy among the three ERAs.Other factors such as side effects and costs must also be taken into consideration. Monotherapy, regardless of the agent used, is often not sufficiently effective in some of these patients, according to Professor Hoeper. Current clinical data from combination studies are limited but the results are promising. He presented findings from the REVEAL Registry,⁷ a multicentre, observational US-based study, looking at PAH treatment. It showed (figure 1) from a sample of 1,226 patients, that at the time of enrolment, 44% were receiving only oral medications and 31% a prostacyclin combined with other agents. PAH-specific medications included 9% calcium channel blockers, 44% prostacyclin analogue, 47% ERAs and 46% PDE-5 inhibitors; 47% of patients were being treated with monotherapy. Eight percent of patients were receiving no PAH-specific medications.¹⁵

Br-J-Cardiol-2009-16-S1-S7-S9-figure-1 — Figure 1: Combination therapy: a frequently used strategy in the treatment of pulmonary arterial hypertension (PAH)

He commented that more than half of the patients were receiving combination therapy although there are as yet insufficient data to support this. The number of drugs and therefore the number of potential combinations of drugs that could be used is increasing rapidly (figure 2). The cost of combination therapy is likely to compound the challenges faced by physicians managing PAH patients, in Professor Hoeper’s view.

Br-J-Cardiol-2009-16-S1-S7-S9-figure-2 — Figure 2: Combining various therapies in pulmonary arterial hypertension (PAH)

Findings from a small study of nine patients with idiopathic PAH from his centre¹⁶ showed that adding sildenafil to bosentan improves six-minute walk distance. In a similar study from Johns Hopkins University¹⁷ in patients with idiopathic PAH and in others with scleroderma, benefit was shown in the latter patients but not in the idiopathic cohort, suggesting that the PAH population is becoming increasingly complex and that not all forms of PAH may respond similarly to medical therapy. Also, new treatment options are rapidly emerging but comparative data are lacking. He believes that many questions will remain unanswered for some time.

“Treatment goals are becoming more ambitious year by year, and this is one of the reasons why combination therapy is now increasingly used. As PAH therapy is more complex than ever, this makes a strong case to treat these patients in experienced centres,” he said.

Conflict of interest
MMH has received lecturing fees and consultancy honoraria from Actelion, Bayer, Encysive, GSK, LungRx and Pfizer.

References

Elliott GC. Chest 2007; 132: 631S.
Thenappan T, Shah SJ, Rich S, Gomberg-Maitland M. A USA-based registry for pulmonary arterial hypertension. Eur Respir J 2007;30:1103–10.
Gibbs JSR. Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Heart 2008;94:1–41.
Galie N, Ghofrani HA, Torbicki A et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148–57.
www.emea.europa.eu/humandocs/PDFs/EPAR/tracleer/H-401-PI-en.pdf
www.emea.europa.eu/humandocs/PDFs/EPAR/thelin/H-679-PI-en.pdf
www.emea.europa.eu/humandocs/PDFs/EPAR/volibris/H-839-PI-en.pdf
Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896–903.
Barst RJ, Langleben D, Badesch D et al: STRIDE-2 Study Group. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 2006;47:2049–56.
Galie N, Olschewski H, Oudiz RJ et al. Ambrisentan for the treatment of pulmonary arterial hypertension. Results of the ARIES Study 1 and 2. Circulation 2008;117:3010–19.
Johnson RS, Mehta S, Granton JT. Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review. Eur Respir J 2006; 28:999–1004.
Murphey LM, Hood EH. Bosentan and warfarin interaction. Annals Pharmacotherapy 2003;37:1028–31.
Waxman AB. A review of sitaxsentan sodium in patients with pulmonary arterial hypertension. Vasc Dis Risk Manage 2007;3:151–7.
Paul GA, Gibbs JSR, Boobis AR et al. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol 2005;60:1007–12.
McGoon MD. REVEAL Registry: treatment history and treatment at baseline. Chest 2007;132:631S.
Hoeper MM, Faulenbach C, Golpon H et al. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 2004;24:1007–10.
Mathai SC, Girgis R, Fisher MH et al. Addition of sildenafil to bosentan monotherapy in idiopathic pulmonary arterial hypertension. Eur Respir J 2007;29:469–75.

The optimal time to treat PAH patients

January 2009Br J Cardiol 2009;16(Suppl 1):S10-S12 Leave a comment

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Authors: BJCardio editorial team

Professor Nazzareno Galiè, University of Bologna, Italy, outlined the pathophysiological mechanisms of pulmonary arterial hypertension (PAH). These are initiated by the progressive obstructive changes of the pulmonary resistance vessels which lead to the increase in afterload of the right ventricle (RV). In turn, this responds with functional and structural adaptations, leading ultimately to heart failure and death.¹ The hope is to have some treatment to help in reverse remodelling. Over the past 15 years or so there have been 22 randomised controlled studies, using a variety of PAH agents. He showed some ‘hypothesis-generating’ data from trials, using historical controls (prior to 1992) and then including patients treated with prostacyclin and more recently (after 2000) with oral agents. Although these patients are not identical or comparable at baseline, it appears that survival of patients who are referred to us today is much better than survival 15 or more years ago,² said Professor Galiè.

Br-J-Cardiol-2009-16-S1-S10-S12-figure-1 — Figure 1: NYHA Functional Class at presentation in pulmonary arterial hypertension (PAH)

Despite greater awareness of PAH in recent years and the availability of targeted therapies, the majority of patients are at an advanced symptomatic stage by the time they are diagnosed.³ A French registry of 674 patients has highlighted that 75% of patients were in New York Heart Association (NYHA) Class III or IV at presentation (figure 1).³

Clinical investigations to date have focused largely on these more compromised patient populations. However, some recent studies have included patients in the early symptomatic stages of the disease. This is supported by findings from the University of Bologna pulmonary vascular diseases centre (figure 2) showing in recent months (“probably because there is more attention to the disease”), that referral of patients in the early symptomatic stages of the disease appears to be increasing, said Professor Galiè. Studies with epoprostenol show significantly improved survival rates when patients are treated at NYHA class III compared to class IV.⁴

EARLY and…

Br-J-Cardiol-2009-16-S1-S10-S12-figure-2 — Figure 2: NYHA Functional Class of patients with pulmonary arterial hypertension (PAH) at the Pulmonary Vascular Diseases Center, University of Bologna (n=83)

He presented further data from trials including the EARLY study, showing benefit of treatment in less compromised individuals in World Health Organization (WHO) Functional Class (FC) I and II. EARLY was a double-blind, randomised controlled trial of six months’ treatment with bosentan (n=93) or placebo (n=92) in patients with WHO FC II PAH.⁵ The primary end points were pulmonary vascular resistance (PVR) at six months (expressed as percentage of baseline) and change from baseline to month six in six-minute walk distance. Results showed the mean PVR at six months was 83.2% of baseline value with bosentan and 107.5% with placebo (p=0.0001); mean six-minute walk distance increased by 11.2 m with bosentan and decreased by 7.9 m with placebo, giving a non-significant mean treatment effect of 19.1 m (p=0.0758).⁵ Significant benefits were seen, with reductions in pulmonary vascular resistance, in those patients who had haemodynamic assessments. More patients remained stable, without signs of clinical deterioration, in the bosentan group than in the placebo group (effect of bosentan on time to clinical worsening p=0.0114, log rank test).

Figure 3: EARLY: Effect of bosentan on NT-proBNP concentration

Exploratory end points in EARLY also included change from baseline to month six in N-terminal-prohormone brain natriuretic peptide (NT-proBNP). This too improved significantly, reflecting haemodynamic benefit, in the bosentan-treated patients (p=0.0003, Wilcoxon) (figure 3).⁵

Thirteen percent of patients in the bosentan group reported serious adverse effects (SAE), most commonly syncope; the SAE rate was 9% with placebo, the most common problem being right ventricular failure. Two deaths occurred during the study period, one in each patient group. Increases in aminotransferases >3x ULN occurred in 13% of bosentan-treated patients, compared to 2% in the placebo group.

…ARIES studies reviewed

Professor Galiè then presented results from the ARIES studies with ambrisentan.⁶ This compound is structurally different to the other ERAs, bosentan and sitaxentan – it is a propanoic acid class molecule rather than a sulfonamide (figure 4).⁷

Figure 4: Ambrisentan is structurally different from bosentan and sitaxentan

Ambrisentan is a selective endothelin A receptor antagonist which is administered orally once daily for treatment of PAH. The drug has been investigated in the recently reported ARIES-1 and ARIES-2 studies. ARIES-1 was conducted predominantly in North America, and ARIES-2 conducted mainly in Europe. The studies were concurrent, double-blind, and placebo-controlled. They randomised 202 and 192 PAH patients, respectively, to ambrisentan 5 or 10 mg (ARIES-1) or ambrisentan 2.5 or 5 mg (ARIES-2) orally once daily for 12 weeks. (Only the 5mg and 10mg doses are licensed for treatment of PAH.)

The primary end point for each study was change in six-minute walk distance from baseline to week 12. Clinical worsening, WHO FC, Short Form-36 Health Survey score, Borg dyspnoea score and B-type natriuretic peptide (BNP) concentrations were also assessed. In addition, a long-term observational extension study was also performed. Table 1 shows the baseline characteristics of patients in the studies: the majority of patients had idiopathic PAH and about 40% of patients were in the early symptomatic stages, FC I or II.⁶

Br-J-Cardiol-2009-16-S1-S10-S12-table-1 — Table 1: Baseline characteristics of patients in the ARIES-1 and ARIES-2 studies

Results showed that the six-minute walk distance increased significantly in all ambrisentan-treated groups.⁶ The mean placebo-adjusted treatment effects were 31 m and 51 m in ARIES-1 for ambrisentan 5 and 10 mg, respectively; and 32 m and 59 m in ARIES-2 for ambrisentan 2.5 and 5 mg, respectively. In patients completing 48 weeks of ambrisentan monotherapy (n=280), the improvement from baseline was 39 m. Time to clinical worsening did not improve significantly in ARIES-1 but a statistically significant improvement was observed in ARIES-2. Professor Galiè explained thathe pt, in his view, this difference was exclusively related to the difference in clinical worsening among the placebo groups of ARIES-1 and ARIES-2, which had different rates of hospitalisations at 3% and 14%, respectively. He believes that there is a geographical difference in attitude towards hospitalisations in Europe and the US, and in his view it is easier to hospitalise patients in Europe compared to the United States. There was a significant improvement in WHO FC in the ARIES-1 patients receiving ambrisentan (p=0.036), while a similar but non-significant trend was seen in ARIES-2 (p=0.117).Also in ARIES-1 and ARIES-2, there was a reduction in BNP compared to placebo for all doses of the drug (p=0.003) and there was a significant improvement in quality of life in ARIES-2.

Br-J-Cardiol-2009-16-S1-S10-S12-figure-5 — Figure 5: In the ARIES-1 and ARIES-2 studies, ambrisentan was associated with a low incidence of LFT abnormalities at 12 weeks

Interestingly, in the three months of this study no increases in liver enzymes more than three times the upper limit of normal were observed in the ambrisentan groups, but there was an increase in 2.3% of placebo patients (figure 5)⁶. Peripheral oedema, headache and nasal congestion are all peripheral effects which may be related to vasodilatation;⁸ they tended to be more frequent in the ambrisentan-treated patients (table 2)^6. Twenty-two patients (16.7%) in the placebo groups and 25 patients (9.6%) in the combined ambrisentan group had at least one serious side effect. There were six deaths (4.5%) on placebo and four (1.5%) in the combined ambrisentan groups, none of them judged to be causally related to the study drug by the investigators.⁶

Br-J-Cardiol-2009-16-S1-S10-S12-table-2 — Table 2: Common adverse events in the ARIES-1 and ARIES-2 studies

Professor Galiè then described a pre-specified combined analysis of the ARIES-1 and -2 studies.⁹ He said this confirmed that there is a dose response improvement in exercise capacity at 12 weeks with ambrisentan. The combined analysis also showed a statistically significant improvement in time to clinical worsening (71% relative risk reduction) for the three doses of ambrisentan (2.5, 5 and 10 mg once daily) relative to placebo: this distinction in time to clinical worsening between the treatment groups was not dose-related.⁹ Sub-group analysis also showed that the improvement in exercise capacity was very similar in both FC II and III patients, with improvements in 6MWD at 12 weeks of between 43% and 57% for ambrisentan 5mg and 10mg doses (figure 6).¹⁰ He presented open-label data on one-year incidence of aminotransferase abnormalities showing >3 x ULN rates of 2.8% and > 5 x ULN of 0.5%.

Figure 6: In ARIES-C, ambrisentan improved exercise capacity at 12 weeks

Summarising, Professor Galiè said that the evidence is now sufficient to justify the treatment of early symptomatic (class II) patients, thereby preserving functional capacity.

Treatment delays, even of a few months, may decrease the potential benefit patients can derive from drugs. “We have to start treating these patients with pulmonary hypertension as soon as we have a reliable diagnosis,” Professor Galiè concluded.

Conflict of interest

NG has participated in advisory board activities for Actelion, Pfizer, United Therapeutics, Eli-Lilly, Bayer-Schering, Encysive and GSK.

References

Galie N, Manes A, Palazzini M et al. Pharmacological impact on right ventricular remodelling in pulmonary arterial hypertension. Eur Heart J 2007; 9: H68-H74.
Sitbon O. ERS 2007: abstract 1593 (manuscript submitted).
Humbert M, Sitbon O, Chaouat A et al. Pulmonary arterial hypertension in France : results from a national registry. Am J Resp Crit Care Med 2006; 173: 1023-30.
Sitbon O, Humbert M, Nunes H et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002; 40: 780-8.
Galie N, Rubin LJ, Hoeper MM et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008; 371: 2093-100.
Galie N, Olschewski H, Oudiz RJ et al. Ambrisentan for the treatment of pulmonary arterial hypertension. Results of ARIES 1 and 2. Circulation 2008; 117: 3010-19.
Barst RJ. A review of pulmonary arterial hypertension: role of ambrisentan. Vasc Health Risk Manag 2007; 3: 11-22.
Cho S, Atwood JE. Am J Med 2002; 113: 580-6.
Galie N. American Thoracic Society International Conference 2007, Poster 3192.
Olschewski H. American Thoracic Society International Conference 2007, Poster 2873.

Rapid access blackout clinics: a priority for the elderly

January 2009Br J Cardiol 2009;16:9–10 Leave a comment

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Authors: Declan Byrne, Diarmuid O’Shea

“Old age starts with the first fall and death comes with the second.”1

Syncopal events and falls are a major healthcare and cost burden for the National Health Service (NHS). Each year between 35% of community living adults over 65 years and 45% of adults over 80 years have such an event.2 This common medical problem accounts for up to 6% of emergency medical admissions. We have previously shown the potential impact that a dedicated syncope and falls facility for older adults can have enabling an attributable diagnosis and on emergency bed usage.3,4

In this issue Ali et al. (see pages 22–8) further emphasise the need and benefits for the development of rapid access blackout clinics. They describe a comprehensive investigation pathway and highlight the importance of making a correct diagnosis and the implications of an incorrect one. It is still the case that a diagnosis is elusive in up to 40% of cases.4,5

They point out that even in those who do receive a diagnosis it may be incorrect. This is particularly so within the older age group. In relation to the diagnosis of ‘epilepsy’ the authors highlight that up to 100,000 people in the UK live with the moniker but without the condition. This has significant implications for public health including utilisation of inappropriate and expensive therapy.

Prognostic implications

There are profound prognostic implications for those suffering from syncope – Soteriades et al., in their study, evaluated the incidence and prognosis of syncope in participants in the Framingham Heart Study.5 They found the most frequently identified causes were vasovagal syncope, cardiac syncope and orthostatic hypotension: 36% still had no demonstrable cause. There was no increased risk of cardiovascular morbidity or mortality associated with vasovagal syncope, but persons in this study who fell into the diagnostic categories of cardiac syncope or syncope of unknown cause, were at increased risk of death from any cause.

While respecting that blackouts can occur in all age categories, and accepting the clear bimodal age distribution, this area is particularly challenging in the elderly. Epidemiological data demonstrate an increasing prevalence of blackouts and falls with age. This, coupled with co-morbidities, dependency and dementia, as well as the observation that the incidence of injuries sustained in the fall increases dramatically with age,6 make this a priority area in healthcare.

A public health priority

This public health priority has been captured by the Department of Health in the UK and incorporated into Standard 6 of the National Service Framework for Older People.7 The development of rapid access blackout clinics is concordant with this standard.

The authors highlight and concur with the diagnostic approach suggested by the European Society of Cardiology and it is heartening to see that the fundamentals of clinical medicine – a good history and examination allied to judicious use of simple tests – remain the cornerstone of investigation.

A cautionary note needs to be struck when one considers patients with dementia. These are a particularly frail group with an annual fall rate of 40–60%.8 In addition, retrograde amnesia for loss of consciousness results in confusion between syncope and falls.9 This adds to the complexity of the evaluation process and recourse to a strong, interested and focused multi-disciplinary team is invaluable in relation to optimising care. This multi-disciplinary team should be led by a cardiologist, neurologist or geriatrician, but most importantly by a motivated physician with a particular interest and specific training in the area.

The rapid access blackout clinic is a prudent, sensible and reasonable response to the increasing burden posed by loss of consciousness. It should certainly add value, diagnostic efficiency, improved patient outcome and cost-effectiveness to the patient journey.

Conflict of interest

None declared.

Editors’ note

The article on rapid access blackout clinics by Ali et al. can be found on pages 22–8 of this issue.

References

Garcia Marquez G. Love in the time of cholera. Penguin Books, 1994.
O’Shea D. Setting up a falls and syncope service for the elderly. Clin Geriatr Med 2002;18:269–78.
Kenny RA, O’Shea D, Walker HF. Impact of a dedicated syncope and falls facility for older adults on emergency beds. Age Ageing 2002;31:272–5.
Allcock LM, O’Shea D. Diagnostic yield and development of a neurocardiovascular investigation unit for older adults in a district hospital. J Gerontol A Biol Sci Med Sci 2000;55:M458–M462.
Soteriades ES, Evans JC, Larson MG et al. Incidence and prognosis of syncope. N Engl J Med 2002;12:878–85.
Kannus P, Parkkari J, Koskinnen S et al. Fall induced injuries and deaths amongst older adults. JAMA 1999;281:1895–9.
Department of Health. National service framework for older people. London: DoH, 2001.
Morris JC, Rubin EH, Morris EJ, Mandel SA. Senile dementia of the Alzheimer’s type, an important risk factor for serious falls. J Gerontol 1987;42: 412–17.
McIntosh SJ, Lawson J, Kenny RA. Clinical characteristics of vasodepressor, cardioinhibitory and mixed carotid sinus syndrome in the elderly. Am J Med 1993;95:203–08.

Methods

Age-related macular degeneration

Risk factors for AMD

Cardiovascular risk factors

Risk factors associated with CVD and AMD

Potential implications in neovascular AMD

References

Table 1. Properties and functions VEGF The VEGF system

VEGF and neuroprotection

VEGF and inflammation

Conclusion

References

Effect of VEGF on the vasculature

Effects of VEGF on the lung

Effects of VEGF on atherosclerosis

The age-related macular degeneration population

Summary

References

Introduction

Efficacy

Safety

Conclusion

References

References

PAH classification

PAH pathophysiology

References

Endothelin receptor antagonists

References

EARLY and…

…ARIES studies reviewed

References

Prognostic implications

A public health priority

Conflict of interest

Editors’ note

References

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Table 1. Properties and functions VEGF

The VEGF system