Series: Volume 7, Issue 1 2016

Background: Abusive Infant Head Trauma (AIHT) is preventable, but there are few reviews of interventions to prevent AIHT.  In the Australian health system context, only one review of AIHT was found. Its primary focus was to raise awareness of AIHT, detailing AIHT incidence and outcomes, but only briefly touching on prevention. [1] This literature review attempts to fill this gap by providing the findings of a systematic search of available studies of AIHT prevention programs and approaches at the primary, secondary, and tertiary level, which may be applicable in Australian settings. Methods: International peer-reviewed journal articles were systematically searched via MEDLINE-Ovid and PubMed databases. All papers that were not original research and were not published after the year 2000 were excluded from this review. Original research was further classified into intervention research, descriptive, and measurement research. The quality of intervention research studies was assessed using two assessment tools: EPHPP (quantitative studies) and CASP (qualitative studies). Results: The search found 50 papers. Thirty-two did not meet inclusion criteria, leaving a total of 18 original research papers.  Eight were intervention research (three strong, one moderate, and four weak), ten were descriptive research, and there were no measurement studies. Conclusion: The key to AIHT prevention is through universal primary prevention, with education increasing knowledge in parents and healthcare practitioners. Of the studied programs, the Period of PURPLE Crying Program^© has been shown to be the most effective. However, further studies are required to assess the relevance of this program in Australian settings.

Background

Abusive Infant Head Trauma (AIHT) has significant morbidity and mortality outcomes. [2,3] Violent, manual shaking of an infant causes rapid and repetitive acceleration-deceleration and rotation of the head, leading to vascular and neural injuries. [2] Neurologic disability occurring in survivors can include cognitive, motor, visual, and behavioural disturbances. [2,4-6] Infants may also present with variable fractures including fractures of long bones, ribs, or vertebrae. [5] Identifying injuries of AIHT can result in children being removed from parents, loss of parental rights, and imprisonment. [4] In Australia, AIHT incidence has been estimated as 29.6 cases per 100,000 infants; this is based on hospitalised cases only. [3]

The peak incidence of AIHT occurs in the second month of life and corresponds to the normal development of increased crying in the infant. [7,8] Prolonged and inconsolable crying is reported as the most common trigger. Parents are the most common agents of infant shaking. [4,5,7,9] Therefore, AIHT is a good candidate for the development of a prevention strategy, with parents being the risk group and crying being the stimulus.

Evidence indicates that AIHT is preventable. [2,9-14] Efforts to find effective prevention strategies have increased with the growing recognition of AIHT’s clinical symptoms, its prevalence, and devastating consequences. [4] AIHT prevention strategies include primary, secondary, and tertiary methods. [9] By systematically searching and providing a summary of available research, this literature review aims to highlight what we do and do not know about AIHT prevention thereby increasing the awareness of AIHT in medical professionals and encouraging implementation of prevention programs in Australian healthcare settings.

Methods

International peer-reviewed journal articles were systematically searched via MEDLINE-Ovid and PubMed databases using the search terms: “shaken baby syndrome”, “shaken baby syndrome prevention”, “infant abusive head trauma”, and “period of purple crying program”. Article titles and abstracts were searched for AIHT prevention interventions. This search resulted in 50 articles, which were further analysed and classified. All review articles, program descriptions, discussion papers, commentaries, case reports, and literature published prior to the year 2000 were excluded from the search results. Original research published from 2000 was included in the review. The start date designated for the search was determined by the timeframe when prevention strategies were developed and researched (in the early 2000s). [9]

The quality of intervention research was then analysed using the Effective Public Health Practice Project assessment tool (EPHPP) for quantitative research, [16] and the Critical Appraisal Skills Programme tool (CASP) for qualitative research. [17] Consistent with the purpose of the appraisal tools to assess the effectiveness of public health programs and interventions, the quality of only intervention research studies that evaluate what works was assessed.  The EPHPP Quality Assessment Tool sections A to F (A. selection bias; B. study design; C. confounders; D. blinding; E. data collection methods; F. withdrawal and drop-outs) were coded strong, moderate, or weak according to the rating scale of the EPHPP dictionary. For qualitative studies, the CASP quality assessment tool was used to assess the clarity of study objectives, methodological quality, research design, data collection and analyses, ethical considerations, clarity of the statement of findings, and the value of the research. To assess the study quality of those using mixed-methods study design, the qualitative and quantitative components were assessed separately using both of the aforementioned tools.

Results

The search resulted in 50 articles. Of these, 32 were excluded as not being original research published after the year 2000, leaving a total of 18 original research papers. Of these, only 8 were intervention research studies, 10 were program descriptions, and there were no measurement research studies (Figure 1).

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of search results. This diagram shows the flow of information through the different phases of the systematic search. It depicts the number of articles found, included, and excluded, and the reasons for exclusions.

<<Insert Figure 1>>

Applying the quality appraisal criteria resulted in assessments of the eight intervention studies. Three were rated strong, one moderate, and four weak (Table 1).

Table 1: AIHT intervention quantitative studies assessed using EPHPP. 

Study	Selection bias	Study design	Confounders	Blinding	Data collection method	Withdrawal and drop-outs	Results
Barr et al. 2009a	Strong	Strong	Strong	Strong	Moderate	NA	Strong
Barr et al. 2009b	Strong	Strong	Strong	Strong	Strong	NA	Strong
Altman et al. 2011	Moderate	Moderate	Weak	Weak	Moderate	Weak	Weak
Dias et al. 2005	Strong	Strong	Strong	Strong	Moderate	N/A	Strong
Shephard et al. 2000	Weak	Weak	Weak	Weak	Weak	Strong	Weak
Stewart et al. 2011	Moderate	Weak	Weak	Weak	Moderate	Weak	Weak
Goulet et al. 2009 (quantitative component)	Moderate	Weak	Weak	Weak	Weak	Weak	Weak
Russell et al. 2008	Weak	Moderate	Weak	Moderate	Weak	Strong	Moderate

 

Table 2: Qualitative studies assessed using CASP. 

Study	Study objectives	Methodological quality	Research design	Data collection and analyses	Ethical considerations	Statement of findings	Value of the research
Goulet et al. 2008 (qualitative component)	Clearly stated	Appropriate	Appropriate	Poor	Ethically approved	Clearly stated	Valuable

Discussion

The review of the available literature indicates that there is little evidence about what works to prevent or treat AIHT, and more than half of the intervention studies were of poor quality.

Primary prevention studies

Two of the strong intervention studies were randomised controlled trials conducted by Barr et al. (2009a, 2009b). They were studies of a universal primary prevention program of AIHT that targeted parents of infants and newborns, and sought to prevent shaking from occurring through education. [10,11] The prevention program was called the Period of PURPLE Crying program (PURPLE^©) produced by the National Center of Shaken Baby Syndrome (Utah, USA). [4,5,8-12,14] PURPLE^© stands for Peak of crying, Unpredictable crying that has no apparent reason, Resists soothing, Pain-like face, Long-lasting crying for 30 to 40 minutes or longer, and Evening crying. [10,14] The program included a ten-minute DVD and an eleven-page coloured booklet, targeting all parents of newborns.  It was an evidence-based program delivered in three instalments that used 25 years of research on normal infant crying to educate parents on crying characteristics, coping strategies, and the dangers of shaking. [14]

The two studies by Barr et al. found that administration of the PURPLE^© materials had led to statistically significant improvements in maternal knowledge and behaviour relevant to shaking, compared to control material.  Compared to mothers that received the control materials, for mothers who received the PURPLE^© program, knowledge about normal infant crying was 5% higher in the first study and 6% higher in the second study. [10,11] Sharing information was shown to be higher in mothers who received the PURPLE^© program than those who received the controls; there was an 8% increase in sharing descriptions of crying, 13% increase in advice about walking away when frustrated, and 13% increase in warnings about the dangers of shaking. [10,11]

The strong intervention study by Dias et al. indicated that a universal hospital-based parent education program regarding the dangers of violent infant shaking, delivered prior to an infant’s discharge, significantly reduced the incidence of AIHT. All hospitals that provided maternity care in an eight-county region of western New York State were asked to provide parents with information describing the dangers of violent infant shaking and alternative responses to persistent infant crying. Program compliance was assessed by documenting the number of voluntary commitment statements signed by parents affirming their receipt and understanding of the materials, and returned by participating hospitals. Parents’ recall of the information was assessed by follow-up telephone interviews conducted with 10% of parents, seven months after the child’s birth. Finally, the regional incidence of AIHT was contrasted with the incidence during the six preceding years, and with statewide incidence rates during the study period. The study found a high voluntary compliance with the program, high recall of the information, and a decrease in AIHT by 47% amongst participating families during the six-year study, with no comparable decrease in the state. [9]

A weak retrospective descriptive study by Stewart et al., found that the three instalments of the PURPLE^© program were crucial to AIHT prevention.  Stewart et al. compared patients presenting with cases of AIHT that presented to the London Children’s hospital (London, UK) from 1991 to 2010. Pre-trained maternity nurses delivered the program to parents.  Stewart et al. found a 47% increase in the knowledge of nurses on crying, post-PURPLE^© training, and 78% said it would be easy to incorporate into their daily work schedule. Instalment one involved the DVD and booklet. Stewart et al. (2011) stated only 6.3% of families did not receive the program in the hospital, and needed to be educated during their home visits. [14] Instalment two was a reinforcement of the message delivered by a health nurse home visitor, paediatrician, family doctor, or other health practitioner at a public health clinic. It involved simply discussing with the parents the concepts taught in the program and giving parents a copy of the program if they had not collected one at the hospital.  Instalment three was a public education campaign. It provided information to the general public in an attempt to educate people in society more generally about inconsolable infant crying and the dangers of shaking. [10,11] Altman et al. conducted a weak intervention study showing that hospital-based parent education, delivered to all those with newborns, could significantly reduce the risk of sustaining an abusive head injury induced by shaking. [12] Further studies are required to gain evidence of the PURPLE^© program’s effects on reducing the incidence of AIHT in Australia.

Literature available on AIHT prevention programs other than PURPLE^© was extremely limited. A moderate-strength study conducted by Russell et al. (2008), compared types of AIHT prevention material. [13] The results showed that material delivered digitally via DVD, particularly material demonstrating alternative behaviours, was more successful in transferring awareness than interventions that involved only a brochure. DVDs significantly increased the potential for improving the population’s awareness of AIHT. This study was not specific for the period of PURPLE^© crying program DVD, and suggests that digital footage that is Australian-focused may be utilised equally as effectively. [13] Parents watched the DVD in the hospital before taking it home with their newborn. The nurse recommended to parents that they review the materials at home, and share the information with other caregivers of their baby. [10,11]

In a weak intervention study, Shephard et al. found the “Don’t Shake the Baby” education package was helpful to the majority of mothers; 49% said that they were less inclined to shake their babies after reading it, and 91% said they thought other parents should receive the same information. [18] The package involved brochures and cards with suggested coping strategies during inconsolable, frustrating crying, and information on the dangers of shaking; as well as television and radio public service announcements and posters containing information about AIHT. [18] These materials could be adapted to suit different language and cultural groups.

Goulet et al. analysed the adequacy and relevance of the Perinatal Shaken Baby Syndrome Prevention Program (PAIHTPP) based on parental and nurse feedback in another weak intervention study. [2] The PAIHTPP used educational cue-cards to increase knowledge about infant crying, triggering of caregiver frustration, and its potential progression to shaking, while suggesting coping strategies for frustration. [2] Findings indicated PAIHTPP to be relevant in all birthing institutions involved in the study. [2] The majority of birthing institutions reported increased knowledge about infant crying, anger, coping strategies, and AIHT. [2]

Other AIHT prevention programs that are available, which have not been evaluated, include programs specific for fathers, especially fathers in the military, prison and youth halfway houses, and programs specific for high school students. The programs are educational and contain appropriate language and imagery for the target audience. [19]

 Secondary prevention studies

Secondary prevention programs target specific subsets of the population considered to be at higher risk for child maltreatment. [8] It has been found that an increase in parental or caregiver stress correlates with an increase in AIHT incidence. [2,14,20] Therefore, parents and carers categorised as being under stress can be targeted for secondary prevention programs. Parents who may be under increased stress include single parents, young parents, those that are drug-dependent, alcohol-dependent, have impulse disorders, control problems, low socioeconomic status, or isolated parents. [14,20] Stewart et al. indicated that geographical areas that may be at higher risk for AIHT should be targeted for extra advertising campaigns, specifically those delivered in instalment three of the PURPLE^© program. [14] However, studies indicate that the focus of prevention should be primary and universal [10-13]; studies about secondary prevention programs were approximately 20 years old, and as such have not been included in this review. [21,22]

Tertiary prevention studies

Children who have been shaken and diagnosed with AIHT are targeted by tertiary prevention programs, which aim to prevent progression of injury and recurrence in the child affected and or other siblings. Diagnosis of AIHT is required before tertiary prevention can be implemented. Diagnosing AIHT is difficult due to its non-specific presenting symptoms and vague explanations made by perpetrators. [6] Reporting suspicion of shaking to departments of child protection can prevent further abuse to the child. [4,6]

According to research by King et al., the common clinical manifestations of AIHT are subdural effusion, retinal hemorrhages and cerebral oedema. [6] Cerebral oedema can be reduced through pharmacotherapy such as glucocorticoids, hyperosmotic agents, diuretics, and sedative-anesthetic agents to prevent progression of neurological damage. [15,23-25] Tertiary prevention through child protection case management is not specific to AIHT, but rather is managed like all traumatic brain injuries in children, through rehabilitation.

Conclusion
Literature on AIHT prevention is limited. Quality research in this area is needed because of the limited number of articles available, more than half of which are of limited quality. This review identified three qualitatively strong intervention studies, one moderate, and four weak, as well as ten program-description studies. These studies indicate that AIHT can be prevented through universal primary prevention techniques. These must be educational and ideally involve the use of a DVD in addition to written materials. Of the studied programs, the Period of PURPLE Crying Program^© has been shown to be the most effective. Tertiary prevention programs through case management by child protection agencies aim to restore child function and prevent progression of neural damage through rehabilitation, and to prevent reoccurrence by legal investigation of the perpetrator. However, further studies are required to assess its impact on AIHT incidence. In particular, evaluation is needed of the relevance of the American-developed Period of PURPLE Crying program^© in Australian settings.

This article is dedicated to Baby Joseph. Joseph did not receive any benefit from primary prevention efforts, and the effects of secondary and tertiary efforts to ameliorate the harm from his allegedly repeated shaking experiences have been limited and are ongoing.  His prognosis is guarded, and a return to his premorbid level of function is unlikely.  His case illustrates a great gulf between what is known about primary prevention and what is currently practised as primary prevention in most of Australia. Joseph’s situation is sadly and predictably, not unique. Primary prevention programs may lead to better baby outcomes into the future.

Acknowledgements
I wish to acknowledge public health researcher, Associate Professor Janya McCalman for mentoring me through the systematic review process and editing the paper. I wish to also thank rural generalist medical practitioner, Dr Bill Liley, who has mentored me through my medical degree, and who has a particular interest in preventing Shaken Baby Syndrome. Thanks also to the Commonwealth Government for funding my medical studies through a Remote Area Medical Undergraduate Scholarship.

Conflicts of interest
None declared.

References

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Aim: To evaluate the role of cricoid pressure in modern day anaesthetics. Methods: A literature review was conducted using the following databases: The Cochrane Database of Systematic Reviews, PubMed, Scopus, Ovid MEDLINE and EMBASE. Articles were found using following terms: cricoid pressure, aspiration, laryngoscopy, airway obstruction, anaesthesia, anaesthesiology, airway management, Sellick’s and rapid sequence intubation. Results: The literature review revealed a lack of high-level evidence supporting the use of cricoid pressure, however, observational studies have suggested a benefit in preventing gastric aspiration. The application of cricoid pressure is inconsistent and generally variable amongst clinicians. Sellick’s manoeuvre is occasionally associated with airway obstruction. Conclusion: When applied correctly, cricoid pressure may still have a role in preventing pulmonary aspiration of gastric contents. There is however a risk of airway obstruction and given the inconsistencies in technique, cricoid pressure should only be employed by trained individuals.

Introduction

The first description of cricoid pressure (CP) was by Monro in 1774 when he used it to prevent gastric insufflation in near-drowned victims. But it was not until 1961 when Sellick utilised the manoeuvre to prevent regurgitation of gastric contents during the induction of anaesthesia that it came to the forefront of clinical anaesthesiology. [1] Consequently, over the last 50 years, CP has become an integral part of the rapid sequence induction (RSI) – an airway management technique employed in patients at high-risk of aspiration where administration of a sedative and muscle relaxant occurs virtually simultaneously. [2,3] However, more recently, there has been much dispute regarding the efficacy and evidence behind Sellick’s manoeuvre leading some anesthetists to even completely abandon it from their practice. [4]

This paper examines the evidence base for the use of cricoid pressure and whether it still has a role in the clinical milieu.

Clinical context    

The incidence of pulmonary aspiration of gastric contents has historically been reported as being low overall but it still remains a critical issue in modern anaesthetic practice, as shown by a survey in which 71% of respondents reported encountering at least once case during their careers. [5,6] Importantly, aspiration is associated with severe consequences in regards to morbidity and morality, with a 1999 Australian study reporting a death rate of 3.8%. [6,7]

The purpose of Sellick’s method is to decrease the likelihood of Mendelson’s syndrome, that is, aspiration pneumonitis – one of the recognised complications of general anaesthesia. The pathophysiology behind Mendelson’s syndrome lies in the concept that the unconscious patient has diminished protective airway reflexes placing them at an increased risk of aspiration. [8] This is supported by Vanner and Pryle who displayed an immediate loss of upper oesophageal tone after losing consciousness. [9] Consequently, physical compression of the oesophagus by placing pressure on the cricoid cartilage is expected to prevent the regurgitation of gastric contents.

Aim

To determine whether the application of cricoid pressure decreases the likelihood of gastric aspiration. To evaluate whether the benefits of cricoid pressure outweigh its adverse sequelae.

Search strategy

A search was undertaken of the medical literature using the following keywords and their alternative spellings: cricoid pressure, aspiration, laryngoscopy, airway obstruction, anaesthesia, anaesthesiology, airway management, Sellick’s and rapid sequence intubation. Results from all searches were refined with Boolean operators. The search was conducted in the following databases: The Cochrane Database of Systematic Reviews, PubMed, Scopus, Ovid MEDLINE and EMBASE. The search retrieved 571 papers. The reference lists of included studies were also manually reviewed to identify additional relevant literature. Papers including both human and cadaveric studies were included. The author determined which of the retrieved articles were to be included in the review and there were no explicit exclusion criteria.

Results

Evidence for efficacy

Sellick’s original articles supporting the use of CP in preventing aspiration are observational studies consisting of 26 and one patient(s) respectively. [1,10] His first article details a successful trial of his technique amongst cadavers by filling their stomach and placing them in a head down position while applying cricoid pressure. It was not until nearly a decade later that four more cadaver-based studies validated Sellick’s original findings. [9,11-13] Recently, a case report by Neelakanta further supported the use of cricoid pressure in preventing aspiration. [14] No randomised controlled trials have been conducted to assess the efficacy of CP in the prevention of pulmonary aspiration.

In regards to gastric insufflation, four historical studies have suggested that CP has a positive clinical outcome on decreasing the amount of gas in the stomach amongst patients being ventilated by a facemask. [15-18] It is important to note that that most recent of these studies was conducted in 1993 and consequently clinical protocols used at the time of the cited studies have changed compared to the present day and are inherently more conducive to decreasing aspiration risk, hence potentially undermining this suggested advantage. [19,20]

Anatomical and physiological debate

The crux of the cricoid pressure technique relies on the principle that the cricoid cartilage, oesophagus and vertebral bodies lie in a single axial plane. Subsequently, in theory, backward pressure on the cricoid cartilage against the posterior vertebral bodies should occlude the oesophagus. Studies of both computed tomography and magnetic resonance imaging have disputed this concept and demonstrated that the oesophagus is naturally displaced laterally in relation to the midline of vertebral bodies in 49% and 53% of individuals respectively. [21,22] With the application of CP, this lateral displacement is further exacerbated thus questioning the primary foundation of Sellick’s technique. [23] This phenomenon is not limited to just adults, but also seen in the paediatric population with younger children impacted more than those older. [24] Moreover, Rice et al. demonstrated that it is the hypopharynx and not the oesophagus that is situated behind the cricoid cartilage, and further, that the oesopahgus is inferior to the level of the cricoid ring; but interestingly concluded that the alimentary tract is still compressed adequately. [25]

Similar to the debate surrounding the anatomic foundations of CP, there have also been contrasting views regarding its physiological basis. Published papers have suggested that the application of cricoid pressure actually opposes its intended effect of preventing regurgitation by decreasing lower oesophageal sphincter tone. [26] While this has been shown to cause an increase in gastric distention during bag-mask ventilation, Skinner et al. suggested that the loss of tone has no significant impact on the risk of gastric reflux amongst healthy individuals. [19,27]

Technical pitfalls

Despite the case reports of CP preventing aspiration, the technique is far from perfect. Surveys revealed that up to 14% of anaesthetists had witnessed aspiration in the presence of cricoid pressure being applied. [28] A potential explanation for this may be the inconsistencies in CP technique between individuals. In his original report, Sellick did not specifically quantify the amount of force necessary to achieve an adequate compression of the alimentary tract other than describing it as “firm”. [1]  Consequently, the exact amount of force required to achieve the primary aim of preventing aspiration without compromising the ease of laryngoscopy and other complications has been greatly debated. A group of researchers first suggested that a force of 44 Newtons (N) needs to be applied, before Vanner recommended that 20 N be applied in the conscious patient before increasing to 40 N after the onset of anaesthesia. [29,30] In a more recent paper, the optimal amount of force was modified to 10 N and 30 N in the conscious and unconscious patient respectively. [31] Despite these rather precise theoretical recommendations, numerous studies have discovered that the CP forces applied by health professionals are discordant. [32-34] However, additional training was shown to improve staff technique. [33-37]

Adverse sequelae of CP

Whether stemming from the pitfalls in individual technique or not, CP has been associated with airway obstruction. Hartsilver & Vanner found that cricoid pressure applied according to the initial recommendations of Wraight et al. resulted in complete airway obstruction in 35% of patients. [29,38] This vastly declined to 2% when the recently suggested 30 N of force was applied; however, if this force is applied in an upward and backward direction as suggested by Vanner et al. [39] obstruction was seen in 56% of the population. [38] Another study reported 35% of their cohort as having airway obstruction evidenced by decrease in tidal volume on application of CP, of which 31% had complete obstruction. [40] However, it should be noted that the clinical utility of a decrease in tidal volume as a measure is questionable due to the application of CP during apnoea. Two further randomised controlled studies supported the association between CP and airway obstruction. [41,42] Additionally, the application of CP has been shown to impede laryngeal mask placement in patients who have failed RSI and require an airway resulting in a life-threatening situation as the patient cannot be adequately ventilated. [43,44] The experience is similar when attempting to place a laryngeal tube and laryngeal tube-suction II. [45] However, these difficulties were not encountered when using a cuffed oropharyngeal airway where no significant difference in tidal volume or peak inspiratory pressure was demonstrated when comparing “post-manoeuvre” measurements to baseline, regardless of whether CP was applied or not. [46] It has been reiterated that CP should be removed if any difficulty is encountered during intubation. [40]

The effect of Sellick’s manoeuvre on laryngoscopy has been the subject of much research and findings have varied. Vanner et al. propose that CP in either the classical form or in the modified upward and backward direction improves views at laryngoscopy compared to no CP, with the best views seen in the modified upward and backward group. [39] Furthermore, CP shows a greater improvement in views in the left lateral than supine position. [47] Nevertheless it should be noted that pressure on the thyroid cartilage resulted in superior views in 88% of patients compared to only 11% when pressure is applied to the cricoid cartilage. [48] In juxtaposition, Haslam et al. concluded that the relationship between CP and laryngoscopic views is complex in which low levels of force (< 30 N) may result in improved views but as the pressure increases there is an analogous increased risk of complete obstruction. [49] Similarly, Noguchi et al. determined that views are worsened with application of CP, however it is important to note that this was an observational study. [50]

Additionally, the application of cricoid pressure in the conscious patient has been shown to induce vomiting and cause oesophageal injury. [51] In their cadaveric studies, Vanner & Pryle reported oesophageal rupture occurring in 30% of the cadavers studied. [9] Another case report details experiencing this complication in a living patient. [52] Furthermore, by decreasing lower oesophageal sphincter tone, CP increases the likelihood of vomiting. [53,54] In contrast, Khan & ul Haq demonstrated a trend of decreased rates of nausea and vomiting in the postoperative period amid patients that had CP applied compared to the no CP group, but the results were not statistically significant. [55]

Discussion

Although there are studies that support the use of CP in preventing aspiration, it is important to consider that except for Neelankanta et al., they are relatively historical and cadaveric-based which questions its applicability in the modern clinical landscape and in living patients. [14] On the other hand, adverse consequences of CP have been described in both case reports and randomised trials. Furthermore, the debate surrounding the theoretical foundations of Sellick’s manoeuvre has cast doubts on its efficacy.

Cricoid pressure was once described as the “lynchpin of physical prevention [of aspiration]” and as a minimum of standard of care, thus implying that any randomised trials evaluating its efficacy would be unethical. [56] However, in light of recent evidence that has suggested several adverse sequelae of utilising Sellick’s manoeuvre, it may now be ethically acceptable to conduct a randomised study in order to better evaluate the value of CP. The impetus to perform further research is greater given that evidence supporting the use of cricoid pressure is of poor quality. The results of such a trial would be pivotal in either reaffirming or eradicating CP from the modern anaesthetic landscape.

Although many anaesthetists have already discontinued the use of CP from their practice, this may prove to have been somewhat hasty. While the evidence base exhibiting the benefits of cricoid pressure is scarce, it is important to consider the extremely low levels of aspiration-related death from anaesthesia since its introduction into the clinical domain. It is acknowledged that anaesthetic practice over that time period has undergone considerable change and whilst there are likely to be other factors also responsible for the low mortality rates, the true impact of Sellick’s manoeuvre cannot be quantified with any certainty.

Nevertheless, the body of evidence suggesting the cessation of cricoid pressure application needs to be considered carefully. This is especially the case when continued application of pressure results in airway obstruction and, subsequently, difficulty with ventilating the patient. Consequently, the risks and benefits need to be considered on an individual basis and CP should not be applied unless clinical judgment suggests otherwise.

Importantly, this paper has exhibited the substantial inconsistencies in cricoid pressure technique, which demands for better training of health professionals. The importance of this should not be underestimated as rectification of technique may result in both superior efficacy in preventing aspiration as well as a reduction in some of the reported adverse effects.

Conclusion

While there have been a number of reports of the adverse sequelae of applying cricoid pressure, of which complete airway obstruction is the most severe, it may still have a role in preventing aspiration and improving laryngoscopic views – especially at low forces, that is, below 30 N. Subsequently, its use in clinical practice should be evaluated on an individual basis by a risk-benefit analysis.

Overall, cricoid pressure is a pseudoaxiom that has been adopted as part of standard anaesthetic practice without solid evidence supporting its efficacy. In considering the currently available literature, its status as being universally accepted and applied during anaesthetic induction appears to be under threat. Further research is needed in order to more definitively determine whether cricoid pressure has a role to play in clinical practice.

Acknowledgements

None.

Conflict of interest declaration

None.

References

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Aim: Warfarin is the most frequently prescribed antithrombotic agent, available in Australia as brands Coumadin and Marevan. Although both are manufactured by Aspen Pharmaceuticals, there are differences in formulation. The product information states they cannot be used interchangeably. Two incident reports of warfarin brand interchange in our hospital prompted a literature review. We aimed to review published evidence on the pharmacokinetics and bioequivalence of different warfarin brands and make brand switching recommendations. Methods: Systematic review of the literature on warfarin bioequivalence and incidents reported by the Therapeutic Goods Administration (TGA).  Results and discussion: Fifteen studies explored different warfarin formulations. No significant differences were found in efficacy with brand switching in eight studies analysing participants who were healthy, had atrial fibrillation (AF), or a mechanical heart valve. Prospective observational studies demonstrated no significant difference in the International Normalised Ratio (INR) or adverse events, however, a retrospective observational study demonstrated an increase in complications. Of the four population studies, only one demonstrated elevated rates of haemorrhage or thrombosis. No studies directly compared Coumadin and Marevan. Three TGA case reports describe adverse events from brand switching. Conclusion: Studies of different warfarin formulations demonstrate bioequivalence in population studies, but with marked inter-individual variation, hence the recommendation is to continue the same brand of warfarin where possible. However, brand switching is preferable to withholding a dose of warfarin for inpatients, in the absence of the patient’s usual brand.  If substituting or brand switching, close monitoring with frequent INR testing is suggested.

Introduction

Warfarin is the most frequently prescribed antithrombotic agent in Australia. Indications include both prevention and treatment of thrombosis, prevention of strokes associated with atrial fibrillation (AF) as well as clotting on mechanical heart valves. [1]  Warfarin is also effective in the treatment of deep venous thrombosis and pulmonary embolism.  The benefits of warfarin need to be weighed against the risk of haemorrhage, a common complication seen in patients prescribed these anticoagulants. Every year 1.2 to 8.1% of patients on long-term warfarin therapy experience a major bleeding complication, attributable to its narrow therapeutic index, as well as susceptibility to other medications interfering with warfarin’s absorption, metabolism, and clearance. [2,3]

In Australia, there are two brands of warfarin: Coumadin and Marevan. Both brands are now manufactured by the same company, Aspen Pharmacare Australia Pty Ltd, and previously by Boots Healthcare Australia Pty Ltd. [1] Brands differ in tablet colour, markings and excipients, and were marketed before bioavailability testing was required. Prescribing bodies within Australia, including the Therapeutic Goods Administration (TGA) and the National Prescribing Service do not recommend interchanging warfarin brands, Coumadin and Marevan, due to the lack of information on bioequivalence. [1,4] It has been recommended that patients remain on the same brand of warfarin if possible, with more frequent International Normalised Ratio (INR) testing if switching brands. [5] The practice within hospitals in Victoria has been to prescribe Coumadin preferentially, with Marevan prescribed only if the patient has been previously stabilised on this brand. [6]

Two locally reported incidents involving brand switching led to a review of the literature to inform practice. One of the incidents involved a 52-year-old male patient who mistakenly received Coumadin, when Marevan was his usual brand. The nurse administering the nocte medications quickly discovered this incident. The patient’s INR was measured to be sub-therapeutic. The second patient was an 88-year-old female admitted to hospital after a fall and did not receive her regular prescribed Marevan dose, as staff were unable to source that brand after-hours. This patient had an elevated INR prior to the incident and warfarin was subsequently ceased. The two local incidents did not result in change of therapy or result in harm.

We aimed to review published evidence on the pharmacokinetics and bioequivalence of different warfarin brands and make brand switching recommendations.

Methods

Search strategy

A systematic review of the medical literature was performed by FC using PubMed (1996-Jan 2015). Author IW performed a cross-referencing search of Embase (1974-Jan 2015) to ensure the completeness of the literature review. The search terms included warfarin, bioequivalence, Coumadin, and Marevan. Additionally, the search included unpublished reports from the TGA Database of Adverse Events Notification (DAEN), which was searched by author LG for reports of unexpected therapeutic response from substitution of either Marevan or Coumadin. Search parameters on the DAEN: Date Range: 01/01/1971 to 21/05/2014 ‘Therapeutic response unexpected with drug substitution’; Medicine Names: Marevan, Coumadin, Warfarin Sodium. [7] Further unpublished information was included from the Danish Health and Medicines Authority (DHMA).

Eligibility Criteria for Studies

Studies that were considered for inclusion included randomised controlled trials (RCTs), crossover trials, retrospective studies, and case reports, published in English and on human participants, with any follow-up time. Systematic reviews and meta-analyses were analysed but not included. The bibliographies of all retrieved articles were manually checked.

Risk of bias

Risk of bias was assessed in each individual study (Table 1).

Summary measures

Summary measures used include confidence intervals, p-values, and area under the curve (AUC).

Results

Figure 1: Study flow diagram. 

The initial search identified 216 records. After duplicates were removed, 148 records were then screened for eligibility, resulting in 125 articles being excluded after review of the titles. A total of seven full-text papers were excluded for reasons stated in Figure 1.

Fifteen studies were included in the analysis, all published between 1971 and 2011. There were three studies in healthy subjects. There were twelve studies of outpatients taking warfarin, including five RCTs, two prospective observational studies, four retrospective studies and one ecological study. The literature search did not identify any studies in which Coumadin and Marevan (Boots or Aspen) were directly compared.

Pharmacokinetic studies in healthy subjects

Three studies in healthy patients demonstrated no difference in average peak plasma concentrations or AUC, but individual patient variability existed.  Müller et al. compared the bioavailability of four warfarin tablet formulations. [8] All products were administered as a single 10 mg oral dose to twelve healthy males, and no significant difference was found in the mean average peak plasma concentrations and AUC (for the plasma concentration time curve). Warfarin bioavailability in the four brands differed by less than 20% when compared to the reference product, Marevan, suggesting that all four types of warfarin could be safely interchanged, without any significant bleeding risk. [8] McGilveray et al. assessed the bioavailability of four warfarin products in eight healthy males. Of these, two sodium warfarin products gave AUC ratios of 97.3% and 100.5% and potassium warfarin of 86.6% relative to the reference products. Significant differences were noted in the time to reach peak concentration, as well as concentration at one hour with one of the products reaching its maximum concentration before this first measurement. [9] Wagner et al. found no significant difference in peak plasma concentration or average plasma concentrations measured at 4, 8, 12, 24, 48, 72, and 96 hours in three different brands of warfarin amongst a group of twelve healthy study subjects. However, there was a statistically significant difference in plasma concentration measured at one hour and in peak plasma concentration time, though it was minimal (p<0.005 and p<0.05 respectively). The three different brands had occurrences of peak plasma concentration at 2.3 hours, 3.6 hours, and 4.1 hours. [10] These studies demonstrate that in healthy males, when brand substitution of warfarin occurred, there was no significant difference in the overall peak concentration of plasma warfarin levels or AUC.

Crossover RCTs

Five RCTs with a crossover design measured the INR of patients with a history of AF or mechanical heart valves who were taking either a branded or generic version of warfarin, having achieved stable anticoagulation with long-term therapy prior to the study. After changing brand, all studies found no statistically significant difference in the average INR of both groups after at least nine weeks of follow-up.

Three studies, Neutel et al., [11] Handler et al., [12] and Weibert et al. [13] examined patients with AF. Neutal et al. demonstrated the bioequivalence of warfarin made by Dupont and Barr Laboratories in a randomised, blinded, crossover study, and showed that the average INR values differed by less than 2% in 55 patients with AF. [11] Handler et al. conducted a study with the objective of substituting warfarin (Dupont) and warfarin (Barr Laboratories) of the same dose and determining its safety and efficacy to confirm bioequivalence results found in other studies. Participants received either warfarin made by Dupont or Barr Laboratories for a period of 28 days and then switched over to the alternate drug for a further two 28-day periods. The mean change in INR measured after every 28 days was -0.17 in patients who began with warfarin (Dupont). After switching, the mean changes were -0.02 and -0.16 respectively. For those starting on warfarin (Barr Laboratories), the mean change from baseline in INR was +0.01, after switching it was -0.16 and -0.18. These differences were not statistically significant, and with the number of dose changes (0.70 ± 0.6 mg for brand A, 0.63 ± 0.9 mg for brand B, and 0.72 ± 0.8 mg for brand C, p=0.89) and mean dose for a stable INR (4.6 ± 2.2 mg, 5.3 ± 2.2 mg, and 5.3 ± 2.4 mg), warfarin (Dupont) was determined to be equivalent to warfarin (Barr Laboratories) in safety and efficacy. Eleven participants were excluded from the study due to dosage adjustments throughout the period, however, an intention-to-treat analysis showed the results fell within the Federal Drug Agency (FDA)’s INR variability values. Handler et al. therefore suggested that additional tests and surveillance are not needed when switching generic with branded warfarin. Weibert et al. performed an RCT crossover comparison of Coumadin and Apothecon warfarin in 19 patients with chronic and paroxysmal AF. [13] Participants already on anticoagulation therapy were randomly assigned to take either Coumadin or Apothecon warfarin for four weeks and then crossed over to receive the alternate for another four weeks.  Although seven participants in each group required dosage changes and experienced INR changes outside the desired range, there was no significant change in INR or dosage alteration in either group overall. Therefore, for chronic and paroxysmal AF patients, these brands were considered to be equivalent in anticoagulation action.

Lee et al. studied 35 patients with mechanical valves. [14] This study found no difference in pooled mean INR between Coumadin (Dupont) and warfarin (Lennon) (INR 2.28 and 2.27, respectively) and was within the range for bioequivalence (90% CI for the difference: 96.4 – 104.9). There were also no differences in the adverse event profiles of the two formulations. In a double-blinded crossover RCT, Pereira et al. also suggested that generic and branded warfarin may be used interchangeably. They studied seven patients, and switched them four times between generic Apo-warfarin and to Coumadin over 30 weeks. This study found no significant difference in mean INR results or number of dosage adjustments between patients who switched between the brands and a control group who stayed on Coumadin (p>0.69). They also found no patient and warfarin interaction (p>0.81). [15]

Observational studies

Observational studies were performed by Swenson et al., Milligan et al., and Richton-Hewett et al., observing patient groups switching from brand-name to generic warfarin. Swenson et al. prospectively studied 210 patients, with 105 controls remaining on Coumadin for the study period and 105 patients switching brands. The mean INR difference between the two groups before and after enrolment was not clinically significant (p=0.15). The number of dosage changes required was similar in both groups, with no thromboembolic or haemorrhagic adverse events or any emergency presentations associated with coagulation problems in either group. [16] Milligan et al. prospectively observed 182 participants switching from Coumadin to generic warfarin and demonstrated no significant variation in the parameters studied, including INR (p=0.3), adverse events, and frequency of INR monitoring. [17] One small retrospective study demonstrated an increase in complications with brand switching. Richton-Hewett et al. in 1980 assessed the effect of interchanging brand-name and generic warfarin with a retrospective chart review of 55 patients. [18] The 15 patients who switched to generic warfarin were significantly (p<0.001) more likely to have a prothrombin time (PT) outside of the therapeutic range and were also more likely to require a dosage change. Notably, one patient required a six-day hospital admission with epistaxis and an elevated PT.

Cohort studies

Regional changes in warfarin formulation afforded the opportunity to examine population-based changes in response to brand switching in three cohort studies and one ecological study. These studies demonstrated safety overall, but with some limitations. Halkin et al. observed 975 participants after a nationwide generic switch of warfarin formulations in Israel. [19] They found that INR values were lower and warfarin doses higher (p<0.01), consistent with decreased apparent warfarin sensitivity with the generic brand. Witt et al. found similar results in the United States in a retrospective cohort study of 2299 participants. Calculated INR values were similar, with the average INR decreasing by 0.13 after the switch and no significant differences found in outcomes of hospitalisation, Emergency Department (ED) visits, or bleeding and thromboembolism. However 39% of patients experienced a worsening in therapeutic INR control of more than 10%, whilst 33% experienced INR control that improved by greater than 10%. Witt et al. suggest that receiving long-term anticoagulation therapy with brand-name warfarin can be successfully switched to a generic warfarin, with overall INR levels similar or lower than before such a switch. [20]

A further population-based study was performed by Ghate et al. of 37,756 patients with AF and at least three warfarin prescriptions during the twelve-month follow-up period. The study population was identified via a database of patients receiving commercial health insurance benefits. [19] The patients stayed on Coumadin, generic warfarin, or switched their formulation. An increased risk of thrombotic events was observed in those who switched from Coumadin to generic warfarin compared to those who stayed on Coumadin (hazard ratio (HR)=1.81; 95% CI 1.42 to 2.31, p<0.001). Similarly, increased risk of thrombosis was seen in patients changing from generic warfarin to Coumadin (HR=1.76; 95% CI 1.35 to 2.30, p<0.001) and generic warfarin to another generic type (HR=1.89; 95% CI 1.57 to 2.29, p<0.001). In addition to this, all groups who switched were observed to have an increased risk of haemorrhage. In comparison to the group who remained on Coumadin, switching to the generic formulation was associated with a significantly higher risk of haemorrhagic events (HR=1.51; 95% CI 1.17 to 1.93, p=0.001). [21]

Paterson et al. conducted a population-based, cross-sectional, time series analysis of outpatients aged 66 or older in Ontario, Canada following the province’s switch to one of two generic warfarin formulations (Apo-warfarin and Taro-warfarin) from Coumadin. [22] Trends in warfarin prescribing, INR testing, and hospitalisations for major haemorrhage and stroke were analysed 40 months before, during the one month of, and the nine months after the mandated switch. No significant differences in the rate of INR testing was found (p=0.93), nor hospitalisation for haemorrhage (p=0.97), or cerebral thromboembolism (p=0.89). [22]

Case reports

Exploration of the TGA DAEN for unpublished Australian case reports revealed two adverse drug reactions involving change of warfarin brand, both of which occurred in 2007. They involved an increased INR when the patient changed from Marevan to Coumadin. One of these reports was complicated with a possible drug interaction with concomitant flucloxacillin. The severities of these two reports were not defined. A third report described a patient who experienced an INR decrease when changed from Coumadin to Marevan.

Other case reports have documented adverse events after switching to generic warfarin. The DHMA has made a precautionary decision to cease switching Marevan to generic warfarin Orion after similar adverse drug reaction reports of elevated INR levels. It is important to note that they have not observed any problems with the generic brand and have not ruled out alternate reasons for the changes in INR. [23] In Oklahoma City, two cases saw subtherapeutic INR levels after a switch from Coumadin to generic warfarin despite the Food and Drug Administration asserting bioequivalence. Both reports conclude that INR levels should be closely monitored if switching is unavoidable. [24]

Discussion

This systematic review of the literature identified a number of studies exploring different warfarin brands, using different methodologies and with a variety of measures of bioequivalence in both healthy subjects and patients. However, the brands raising concern in our hospital, Coumadin and Marevan, have not been directly compared. This review demonstrates that there are conflicting findings in individual versus population studies. Overall, there were no significant differences in plasma drug levels or in efficacy as measured by INR with brand switching on an individual patient level. However, population studies demonstrated an increased risk of thrombosis and haemorrhage with brand switching.

Given the widespread use of warfarin, there are a very low number of reports of issues after brand switching both locally and in the published literature. This may be due to under-recognition and under-reporting of adverse reactions. [7] It may also be that brand switching of warfarin rarely occurs and, if it is occurring, then it may be happening without significant adverse events. In Australia, it is recommended that switching warfarin brands should be avoided. Differences in the excipients between the different brands theoretically may affect bioavailability, however, no comparative trials of the Aspen brands have been published. Another important issue in switching brands is the potential for confusion in patients due to different strengths and colours of the medications, potentially resulting in incorrect dosage.

This review demonstrates that when brand switching does occur in a supervised manner, such as that of a clinical trial, the risks are minimal. For hospital inpatients, we would therefore suggest that giving the alternate brand of warfarin is preferable to withholding a dose. Either a return to the patient’s usual brand or a permanent switch to the preferred brand could then be considered. Increased vigilance in following up the INR would be mandatory, due to both the change in formulation and the fact that hospital inpatients are unwell, and that in itself can affect the INR.

The majority of warfarin use, however, is in the community rather than in hospitals. Switching a patient’s warfarin brand should be considered on a case-by-case basis. There should be a compelling reason for brand switching, and the patient’s ability to comprehend the different dosing between brands should be considered. Most importantly, there should be capacity, both by the patient and the pathology provider, to increase monitoring of INR until clinical stability is established on the new brand.

The strengths of this review are that a variety of methods have been used to address the question of safety of switching warfarin brands, which improves the quality of the evidence. With recent updated information available, paired with case examples, it allows a comprehensive expansion on previous reviews exploring similar topics. However, there are several important limitations. The RCTs reviewed all had small sample sizes, with the largest having only 113 participants. [13] This limits the generalisability of these results. Additionally, RCTs may overstate the safety of brand switching due to selection bias, for example,  (1) patients on anticoagulation who agree to enter a trial may manage their anticoagulation better than the general population, (2) well-controlled patients are more likely to participate in a trial, or (3) compliance with medication and dietary restrictions increases during the period of the trial. Studies focusing on pharmacokinetics and bioequivalence may not be adequate to assess clinical outcomes. There are also biases in population studies. For example, factors such as changes to the environment affecting the whole region and contributing to the outcome may not be recognised. Ecological studies cannot be used to prove or explore associations between determinants of disease. There are limitations in the use of a retrospective dataset, such as health insurance claims, in which it cannot be confirmed whether individuals actually took the warfarin dispensed by the pharmacy. Additionally, if the dataset was created for an alternate purpose, such as discharge coding to determine reimbursement, inconsistent definitions, or coding practices may mean the data is of too poor quality to use in a study. There may also be inadequate information about the confounders and data quality. Differential loss to follow-up can introduce bias in retrospective and prospective cohort studies. Across all studies, publication bias and selective reporting within the studies may influence the cumulative evidence.

Conclusion

Studies of different brands of warfarin demonstrate that brand switching is generally safe, although some population studies have demonstrated that INR control may worsen for a period, and that risk of both thrombosis and haemorrhage may increase. Based on the studies reviewed, we support the recommendation to continue with the same brand of warfarin, if possible. However, in the inpatient hospital setting, brand switching is preferable to withholding a dose of warfarin in the absence of the preferred brand, with appropriate INR testing afterwards. We therefore recommend that in an in-patient situation, substitution with an alternate brand of warfarin should occur if one brand is unavailable and INR is monitored daily until stability is assured. In the community, brand switching should be considered on a case-by-case basis with increased INR monitoring until clinical stability is reached. Phasing out formulations of warfarin so only one brand is available, with support from the local regulatory drug agency, including advisory information and support for patients and clinicians, would resolve the confusion.

Conflicts of Interest

None declared.

References

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[2] Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant therapy. Chest. 1998;114:511S-523S.

[3] Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ,  Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest. 2012;141:1412S3.

[4] Adverse Drug Reactions Advisory Committee, Coumadin and Marevan are not interchangeable, Australian Adverse Drug Reactions Bulletin, June 1999;18:2.

[5] Fry FK, PBAC, Boots. Warfarin tablets, Aust Prescr 1997;20:33.

[6] Dooley M. Recommendations for warfarin in Victorian public hospitals [letter]. Aust Prescr 2003;26:27-9.

[7] Adverse Drug Reaction Reports. Received via personal communication with the Therapeutic Goods Administration. 4th April 2014.

[8] Müller FO, Steyn JM, Hundt HK, Luus HG (1988 Dec 3) Warfarin bio-availability. A comparison of 4 products. S Afr Med J, 74, pp. 1.

[9] McGilveray IJ, Midha KK, Cooper JK: Bioavailability of Canadian tablet formulations of Warfarin Sodium and Potassium. Can J Pharm Sci. 1978;13:9-11.

[10] Wagner JG, Welling PG, Lee KP and Walker JE: In vivo and in vitro availability of commercial Warfarin tablets. J Pharm Sci. 1971;60:666-677.

[11] Neutel JM, Smith DHG. A randomized crossover study to compare the efficacy and tolerability of Barr warfarin sodium to the currently available Coumadin. Cardiovasc Rev Rep. 1998;19:49–59.

[12] Handler J, Nguyen TT, Rush S, Pham NT. A blinded, randomized, crossover study comparing the efficacy and safety of generic warfarin sodium to Coumadin. Prev Cardiol. 1998;4;13–20.

[13] Weibert RT, Yeager BF, Wittkowsky AK, Bussey HI, Wilson DB, Godwin JE et al. A randomized, crossover comparison of warfarin products in the treatment of atrial fibrillation. Ann Pharmacother. 2000;34:981–8.

[14] Lee HL, Kan CD, Yang YJ. Efficacy and tolerability of the switch from a branded to a generic warfarin sodium product: an observer-blinded, randomized, crossover study. Clin Ther. 2005;27:309–19.

[15] Pereira JA, Holbrook AM, Dolovich L, Goldsmith C, Thabane L, Douketic JD et al. Are brand-name and generic warfarin interchangeable? Multiple n-of-1 randomized, crossover trials. Ann Pharmacother. 2005 Jul-Aug; 39:1188-93.

[16] Swenson CN, Fundak G. Observational cohort study of switching warfarin sodium products in a managed care organization. Am J Health Syst Pharm. 2000;57:452-455.

[17] Milligan PE, Banet GA, Waterman AD, Gatchel SK, Gage BF. Substitution of Generic Warfarin for Coumadin in an HMO Setting. Ann Pharmacother. 2002;36: 764-768.

[18] Richton-Hewett S, Foster E, Apstein CS: Medical and economic consequences of a blinded oral anticoagulant brand change at a municipal hospital. Arch Intern Med. 1998;148:806-808.

[19] Ghate SR, Biskupiak JE, Ye X, Hagan M, Kwong WJ, Fox ES, et al. Hemorrhagic and thrombotic events associated with generic substitution of warfarin in patients with atrial fibrillation: a retrospective analysis. Ann Pharmacother. 2011;45: 701-12.

[20] Halkin H, Shapiro J, Kurnik D, Loebstein R, Shalev V, Kokia E. Increased warfarin doses and decreased international normalized ratio response after nationwide generic switching. Clin Pharmacol Ther. 2003;74:215-221.

[21] Witt DM, Tillman DJ, Evans CM, Plotkin TV, Sadler MA. Evaluation of the clinical and economic impact of a brand name-to-generic warfarin sodium conversion program. Pharmacotherapy. 2003;23:360-368.

[22] Paterson JM, Naglie G, Laupacis A, Stukel T. Clinical consequences of generic warfarin substitution. JAMA. 2006;296:1969-1972.

[23] Danish Health and Medicines Authority. Warfarin Orion must not replace Marevan and Waran. Danish Pharmacovigilance. 2015[cited 2015 July 4]. Available from: https://sundhedsstyrelsen.dk/en/news/2015/danish-pharmacovigilance-update,-april-2015.

[24] Hope KA1, Havrda DE. Subtherapeutic INR values associated with a switch to generic warfarin. Ann Pharmacother. 2001 Feb;35:183-7.

Table 1: Summary of studies

Reference Year	Country	Trial design*	Participants	Number of subjects	Follow up (weeks)	Mean age (years)	Males (%)	Brands	Outcomes	Limitations and bias
Müller8 1988	South Africa	RCT	Healthy males	12	1.14 (8 days)	22	100	Warfarin (Petersen), Warfarin (Lennon), Coumadin (Boots), Marevan (Allen & Hanburys)	Test products differed less than 20% from Marevan	Single blind – experimenter’s bias Small study size Only male participants
McGilveray9 1978	Canada	Crossover trial	Healthy males	8	None	25-42 (range)	100	Sodium warfarin Potassium warfarin (Manufacturers not stated)	No difference in average peak plasma concentrations. Significant difference in the time required to reach peak concentrations. Two sodium warfarin products gave AUCs of 97.3% and 100.5%. The potassium warfarin gave a lower value of 86.6% relative to the reference products	No mention of blinding – performance bias No mention of randomisation – selection bias Small study size Only male participants
Wagner10 1971	US	Crossover trial	Healthy subjects	12	1	25	83	Warfarin (3 different manufacturers not identified)	No overall significant difference in average peak plasma concentrations or average time taken to reach peak plasma concentration. A small statistically significant difference in plasma concentration measured at 1 hour and in peak plasma concentration time (p<0.005 and p<0.05 respectively)	No mention of blinding – performance bias No mention of randomisation – selection bias Small study size Study performed more than 44 years ago
Neutel 11 1998		SB crossover RCT	Outpatients Atrial Fibrillation	39	9	70	100	Coumadin (Dupont) Warfarin (Barr Laboratories)	Changes in INR after switching were not significant (p>0.05); no differences in adverse effect profiles	AF participants – detection bias Only male participants Small study size
Handler 12 1998	US	DB crossover RCT	Outpatients Atrial Fibrillation	57	12	69	65	Coumadin (Dupont) Warfarin (Barr Laboratories)	No significant differences in INR (p=0.40), dose adjustments, adverse events	AF participants – detection bias Small study size Funded by generic manufacturer
Weibert13 2000	US	DB crossover RCT	Outpatients Atrial fibrillation	113	14	70	75	Coumadin (DuPont) Warfarin (Apothecon)	No significant differences in daily dose (0.5 mg/d), average INR difference (< 0.08), adverse events	AF participants – detection bias Small study size Single blind of investigators not patients – performance bias Increased regularity of INR monitoring, which may have detected more variability than normal Funded by generic manufacturer
Lee14 2005	Taiwan	SB crossover RCT	Mechanical heart valves	35	12	52	71	Coumadin (Dupont) Warfarin (Lennon)	Dose changes were rare; no significant differences in pooled INRs between Coumadin (Dupont) and warfarin (Lennon) (INR 2.28 and 2.27, respectively). The 90% CI for the difference was 96.4 – 104.9	HV participants – detection bias Observer blinded Small study size
Pereira15 2005	US	DB crossover RCT	Outpatients Various indications	7	30	63	43	Coumadin (Bristol-Myers Squibb) Warfarin (Apotex)	No significant differences in mean INR measurements or variation (p>0.69). No patient and warfarin interaction found (p>0.81)	Small study size Patients underwent dosage adjustments if INR was out of target range
Swenson16 2000	US	Prospective observational cohort study	Outpatients Various indications	210	20	78	50	Coumadin (Dupont) Warfarin (Barr Laboratories)	No significant differences in INR between groups (p=0.15); no adverse effects or events	Non-randomised assignment – selection bias Confounding
Milligan17 2002	US	Prospective observational study	Outpatients Various indications	182	78	75	57	Coumadin (Bristol-Myers Squibb) Warfarin (Barr Laboratories)	No significant differences in INR (p=0.3), dose adjustments, adverse events	Funded by an insurance company Non-randomised assignment – selection bias Confounding
Richton-Hewett18 1998	US	Retrospective cohort study	Outpatients Various indications	55	30	56	47	Coumadin (Du Pont) Panwarfarin (Abbott Laboratories)	Higher rate of INR out of range (p<0.001), dose changes (p<0.05), clinic utilisation (p<0.03) with generic group; no significant differences in morbidity/mortality	Non-randomised assignment – selection bias Non-blinded staff – experimenter’s bias Confounding Small study size
Halkin19 2003	Israel	Retrospective observational study	Outpatients Various indications	975	52	70	47	Coumadin Sodium (Taro Pharmaceutical Industries) Coumadin Sodium clathrate (Taro, new formulation)	After the switch, INR values were lower and warfarin doses prescribed were higher (p<0.01)	Non-randomised assignment – selection bias Confounding Data from administrative database
Witt20 2003	US	Retrospective cohort study	Outpatients Various indications	2299	26	69	54	Coumadin Warfarin (Barr Laboratories)	INR values below therapeutic range with generic (p<0.0001); overall average INR decreased by 0.13 after switch; no significant differences in hospitalisations, ED use, outcomes (bleeding or thromboembolism)	Non-randomised assignment – selection bias Confounding Fatal adverse effects not included in study as post-conversion questionnaire required
Ghate21 2011	US	Historical cohort analysis	Atrial fibrillation	37 756	52	71	58	Generic warfarin Coumadin (DuPont/Bristol-Myers Squibb)	Increase in thrombotic events in those groups who had switched Coumadin to generic warfarin (HR=1.81; 95% CI 1.42 to 2.31, p<0.001) Generic warfarin to Coumadin (HR=1.76; 95% CI 1.35 to 2.30, p<0.001) Generic warfarin to another generic (HR=1.89; 95% CI 1.57 to 2.29, p<0.001) Increase in haemorrhagic events in those groups who had switched to generic (HR=1.51; 95% CI 1.17 to 1.93, p=0.001)	Non-randomised assignment – selection bias Information from insurance claims database with no available information about INR monitoring, adherence to therapy and missed follow-up appointments Confounding
Paterson23 2006	Canada	Ecological study	Outpatients Various indications	36 724	200	>65 years old	Not specified	Coumadin (Bristol-Myers Squibb) Warfarin (Apo-warfarin and Taro-warfarin)	No significant differences in INR testing (p=0.93) or hospitalisation for haemorrhage (p=0.97) or thromboembolism (p=0.89)	Funded by the government Focussed on major clinical events needing hospitalisation but excluded other outcomes with less reliable code, for example, DVT Cross-sectional – cannot determine causation Administrative health data used

 

Psoriasis is a chronic, immune-mediated inflammatory dermatosis with many comorbidities, particularly psoriatic arthritis, metabolic syndrome, and depression. Psoriasis has a significant impact on quality of life, especially for those with severe disease. It is therefore important for the physician to evaluate patient preferences and choices when considering an optimal treatment approach and therapeutic regimen for the individual patient. Currently, the physician can select from multiple treatment options. Lifestyle modifications should be considered for all patients to minimise triggering factors. Topical therapy, particularly corticosteroids and vitamin D creams, are first-line for most patients with chronic plaque psoriasis. Other conventional therapies for psoriasis include phototherapy and systemic agents. Over the past decade, advances in the understanding of psoriasis pathogenesis have allowed the emergence of newer biologic agents that have significantly improved disease outcomes for patients with moderate-to-severe psoriasis. These include tumour necrosis factor alpha (TNFα) inhibitors, such as infliximab, adalimumab, and etanercept; an interleukin-12/interleukin-23 (IL-12/IL-23) inhibitor, namely ustekinumab; and the latest class of biologics, IL-17 inhibitors, such as secukinumab. New oral molecule inhibitors, such as phosphodiesterase-4 inhibitors and Janus kinase (JAK) inhibitors are currently being trialled in severe psoriasis.

Introduction

Psoriasis is a chronic, recurrent, immune-mediated inflammatory dermatosis with wide-ranging systemic effects. It affects approximately 2-3% of the population worldwide, with an estimated prevalence of 2.3-6.6% in Australia, where it is reported to be almost twice as prevalent in men as in women. [1] Psoriasis is currently understood as a multifactorial disorder with immune dysregulation, genetic susceptibility, and internal and environmental factors contributing to the disease onset. [1,2] The most common form of psoriasis is chronic plaque psoriasis, where salmon-pink plaques with silvery scales develop over the scalp, extensor surfaces, elbows, and knees, (due to the Koebner phenomenon). Sometimes it develops over the entire body surface and patients can become erythrodermic. Other subtypes of psoriasis are well described, such as guttate, flexural, pustular, and erythrodermic psoriasis.

Psoriasis is associated with several comorbidities, including psoriatic arthritis (PsA), cardiovascular disease, metabolic syndrome, hypertension, diabetes mellitus, dyslipidaemia, malignancies (skin cancers and lymphomas), inflammatory bowel disease, and psychiatric illness, including depression and anxiety. [1,3,4] It can have a significant impact on the patient’s quality of life (QOL) and cause considerable psychosocial distress and disability.

The management of psoriasis, therefore, necessitates that the physician develop a holistic approach towards the patient. It is important for the patient to develop an understanding of the disease to allow discussion of therapeutic strategies with the physician and for the patient to express his/her treatment preferences. Common goals of therapy in psoriasis include complete remission of skin disease, optimising QOL, preserving functional status, and minimising or controlling comorbidities, particularly diseases of the joints.

Over the past decade, increasing understanding of the molecular and immunological mechanisms of psoriasis pathogenesis and the advent of newer monoclonal antibodies that demonstrate immense efficacy in treating psoriasis have dramatically expanded the treatment strategies that the physician can employ to treat an individual patient’s condition. This paper will review and examine the various treatment modalities that are currently available to treat psoriasis, as well as highlight several upcoming novel agents for psoriasis treatment. It will focus on the Australian patient context, which will be relevant and practical to the Australian medical student.

Methods

A computerised search strategy was performed using MEDLINE and EMBASE up to November 2015. The search was limited to human studies of adults published in the English language and included reference lists of papers published.

Severity and impact of disease

Severity of disease can be measured using the Psoriasis Area and Severity Index (PASI) or body surface area (BSA) affected by psoriatic lesions. Mild disease is considered with lesions covering <10% of BSA or PASI ≤ 10. [5] PASI is one of the most commonly used measures of a clinically meaningful improvement. Clinical trials often use PASI 75 as a primary outcome, where the percentage of patients having at least 75% reduction in baseline PASI is evaluated. [6] Dermatology Life Quality Index (DLQI) is a quantitative measure examining the patient’s perspective of the disease impact on his/her life. [7]

The impact of psoriasis on the patient’s QOL cannot be underestimated. Various studies have assessed and evaluated DLQI and the clinical severity of psoriasis. QOL of psoriasis patients, in general, is strongly reduced and there is a linear, positive correlation between DLQI and BSA. [8] Patients suffer in many aspects of their lives, most frequently in social and emotional areas. [9] With the use of biologics, patients report satisfaction with their treatment, and DLQI and PASI decline and remain low for prolonged periods, with improvement in QOL. [10,11] It is important for the physician to evaluate patient preferences, choices regarding dosing frequency, and satisfaction with prior treatments in order to determine appropriate treatment regimens for the individual patient.

Considerations to treatment approach

Currently, the physician can select from a range of treatment strategies for psoriasis, from topical therapy and phototherapy to systemic oral agents and novel biologics,. However, there are currently no consensus guidelines that provide a specific treatment algorithm. [12] Treatment regimens should hence be considered and individualised to each patient.

There are several factors that have to be considered by the physician in selecting an appropriate treatment regimen. The physician has to consider the patient’s ability to apply and comply with topical therapy, which can be influenced by factors, such as the patient’s age (young or elderly patients), presence of lesions over inaccessible areas, and the ease of application of topical therapy. [13,14] Extensive psoriasis-afflicted areas, such as in moderate or severe disease affecting large body surface areas, may be better treated with UV therapy, systemic therapy, or biologics, as compared to topical therapy, which may be a less practical treatment option. [14] The presence of PsA may suggest use of systemic therapies or biologics, which can be efficacious against both skin and joint diseases. [14]

Lifestyle modifications

Obesity has a strong known association with psoriasis severity. [4] Lifestyle weight loss intervention, by dieting or exercise, has been shown to reduce severity of psoriasis by a PASI score of 2.5, compared to a non-intervention group. [4] It is postulated that weight loss and the consequent decrease in adipose tissue decreases inflammatory cytokines, contributing to the improvement in severity of psoriasis. [4] Other modifiable lifestyle factors, such as stress, smoking, and trauma (in cases of the Koebner phenomenon) are also well-documented triggers of psoriasis. [1] Active steps can be taken by the patient, supported by their physician, to modify such factors to help decrease psoriasis flares and disease severity.

Topical therapies

Topical therapies are the first-line treatment for most patients with psoriasis, as most patients tend to have mild or limited disease. [13,14] It is common practice for patients to be on combination therapies, such as multiple topical agents, or topical therapies with a systemic or biologic therapy. [13]

Topical corticosteroids, such as hydrocortisone, mometasone and clobetasol, are the most frequently used treatments for psoriasis and remain the mainstay of therapy, having anti-inflammatory and anti-proliferative activity. [14,15] Topical steroids are classified based on potency and the selection of the steroid class depends on the location and sensitivity of the lesion to topical steroids. [14] High potency preparations are required for scalp and palmoplantar lesions and low potency preparations are used for facial and genital lesions. Ointments are considered the most efficient delivery systems, being more occlusive than creams or lotions. [14] Side effects of topical steroids include skin atrophy, telangiectasia, and easy bruising. [14]

Topical vitamin D3 analogues, calcipotriol and calcipotriene, have anti-proliferative properties and provide significant improvement after a three-month course of therapy. [14] Calcipotriene is one of the most commonly used non-corticosteroid treatments for psoriasis. [15] Topical vitamin D3 analogues can cause perilesional skin erythema and irritation. [14] Recent studies have demonstrated that a combination of topical steroids and calcipotriene is more effective and safer than either agent alone. [16]

Other topical therapies may be used with corticosteroids or vitamin D analogues. Tar is sometimes used as an adjunct therapy, having some anti-inflammatory and anti-pruritic properties. [14] It is, however, messy to use and can cause skin irritation and folliculitis, especially in higher concentrations. [14] Dithranol, an anthracene derivative, is postulated to work by inhibiting keratinocyte proliferation and has been shown to produce prolonged, sustained remission of psoriasis. [14,17] It can cause skin irritation and staining. [14] Topical retinoids, such as tazarotene, may also be used in localised psoriasis. Compounded creams with salicyclic acid have been used for thickened scales, as salicyclic acid has anti-inflammatory and desquamative effects and increases corticosteroid penetration. [2]

Phototherapy

Phototherapy is a second-line treatment modality that is often used in eczema and other pruritic dermatoses, and has been shown to be safe and effective. [18] Narrow-band ultraviolet B radiation (NB-UVB) and psoralen and ultraviolet A radiation (PUVA) are the current phototherapy treatments used in psoriasis. UVB radiation primarily acts on epidermal and epidermodermal junction components, while UVA radiation affects epidermal and dermal components. [18] Phototherapy has both immediate and delayed effects on the skin. Immediate effects include formation of DNA photoproducts and damage, which cause apoptosis of resident skin cells and inflammatory cells, while delayed effects include local and systemic immune suppression, leading to suppression of disease activity. [18] As a monotherapy, PUVA has been demonstrated to be more effective than NB-UVB, with respect to achieving PASI 75. [19] Although short-term adverse effects are shown to be mild with a low withdrawal rate, use of PUVA has been consistently shown to be associated with increased risk of skin cancer. [19,20] Phototherapy with NB-UVB, now more commonly used in Australia instead of PUVA, can be an appropriate treatment for moderate-to-severe psoriasis and may be combined with other systemic therapies, such as methotrexate, that, overall, may be more efficacious than monotherapy. [12]

Systemic therapies

Various systemic immunosuppressants have been used for decades in the treatment of psoriasis. Used in other diseases, such as rheumatological diseases and inflammatory bowel disease, their long-term safety and side effect profiles are well documented and understood. Approximately 20-30% of patients suffer from moderate-to-severe disease and often require systemic therapies, in addition to conventional therapies. [3] Data of head-to-head studies on these systemic therapies, however, are lacking and insufficient. [21]

Methotrexate is a systemic drug that has been proven to have great efficacy as a monotherapeutic option in the treatment of psoriasis, though it can be considered with other agents or phototherapy to maximise its effectiveness. [12] It has long-term potential in causing hepatotoxicity, bone marrow suppression, and lung fibrosis.

Cyclosporine, a calcineurin inhibitor, is similarly very efficacious in the treatment of moderate-to-severe psoriasis as monotherapy by inducing immunosuppression. [22] It can sometimes be used in combination with methotrexate or tumour necrosis factor (TNF) inhibitors. [3] Cyclosporine is associated with hypertension and impaired renal function.

Acitretin is a vitamin A derivative that is often used for palmoplantar, pustular, and erythrodermic psoriasis, but has lower efficacy in chronic plaque psoriasis. [22] Unlike methotrexate and cyclosporine, acitretin is not immunosuppressive. [22] Acitretin can cause hyperlipidaemia, hepatitis, and alopecia.

Biologics

The traditional systemic therapies, such as methotrexate, have been the mainstay of therapy, particularly in moderate-to-severe psoriasis. However, some patients suffer loss of efficacy, adverse effects, cumulative organ-specific toxicity and inadequacy or inability to clear resistant lesions with the use of these conventional therapies. [3] With rapid advances in the understanding of psoriasis pathogenesis, newer biologic agents, such as monoclonal antibodies targeting TNFα and interleukin-12/interleukin-23 (IL-12/IL-23), have emerged over the past decade. These agents have broadened treatment options for patients with moderate-to-severe psoriasis and have demonstrated high efficacy and favourable safety profiles, improving disease outcomes.

TNFα inhibitors

TNFα inhibitors represent the first wave of biologics in the therapeutic strategy for treatment of psoriasis. TNFα inhibitors that are US Food and Drug Administration (FDA)-approved and Australian Pharmaceutical Benefits Scheme (PBS)-approved for use in psoriasis include etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade). All three agents have been shown in various trials to produce significant benefits to psoriasis outcomes in terms of PASI and DLQI. [23-26] Etanercept has been shown to produce 59% PASI 75, versus taking placebo, at week 12, with improvement in DLQI. [23] A twice-weekly regimen has been demonstrated to be more beneficial than a once-weekly regimen, producing a more rapid and greater response in the PRISTINE trial. [27] Infliximab produced 81% PASI 75 and 88% clearance at week 10. [25] Infliximab has been shown to be superior to etanercept, in terms of efficacy, at 24 weeks. [28] Adalimumab has demonstrated improvement in self-reported work productivity, total productivity impairment, and total activity impairment. [26]

There are currently limited direct, long-term, head-to-head trials comparing the efficacy of the three TNFα inhibitors in treating psoriasis. [21] Use of these TNFα inhibitors, in particular infliximab and adalimumab, has been associated with a higher risk of serious infections, compared to non-methotrexate and non-biologic therapies. [29]

IL-12/IL-23 inhibitors

Molecular studies in recent years have shed light on the immuno-pathogenesis of psoriasis. IL-12 is a cytokine involved in stimulating naïve T cells to differentiate into CD4 cells and natural killer cells (NK cells) and upregulating production of interferon-γ (IFNγ). [30] IL-23 is a heterodimeric cytokine consisting of IL-23p19 and IL-12/23p40 subunits. [28] Recent evidence suggests that IL-12 antagonism inhibits T helper cell type 1 (Th1) development or responsiveness, while IL-23 antagonism impairs survival, expansion, or function of IL-17-producing T cells (Th17). [30] IL-23 has been proven to be a necessary upstream mediator to the Th17 pathway, as it activates Th17 cells to produce IL-17. [30] IL-23 is thought to be significantly important in psoriatic inflammation and specific inhibition of IL-23 is speculated to have profound therapeutic value.

This is clearly seen in the use and subsequent FDA-approval of ustekinumab (Stelara) in 2009 for use in psoriasis and PsA, where it demonstrated 81% achievement of PASI 75, versus 2% by placebo, at week 12. [31] It was found to be superior to etanercept. [32] More than 80% of patients were able to maintain PASI 75 for more than 3 years, without evidence of cumulative damage, in the POENIX 1 trial. [33]

IL-17 inhibitors

Along with IL-12 and IL-23, molecular studies have brought attention to a central pathogenic pathway in psoriasis, where interleukin-17A (IL-17A) is regarded as the most critical T-cell-derived cytokine in altering growth and differentiation of skin cells. [3,6] IL-17A acts on endothelial cells, fibroblasts, chondrocytes, osteoblasts, monocytes, synovial cells, and keratinocytes. [6] The main physiological function of IL-17A is protection from infections by recruiting inflammatory cells to local sites of infection. [6] However, in psoriasis, there is hyperproliferation of keratinocytes driven by these cytokines from T cells. The psoriatic plaque typically shows infiltration of activated T cells, especially Th1 and Th17 cells that produce large amounts of IL-17, interferon-α (IFNα), and TNFα. [6] Hence, IL-17A is considered as a potential therapeutic target that may reduce the inflammation seen in psoriasis.

The results of phase II trials using IL-17 inhibitors support the hypothesis that IL-17 is indeed an essential target in treatment of chronic plaque psoriasis. [34] Targeting the IL-17 pathway may result in additional systemic benefits, particularly to arthritis and cardiovascular risk. [34] These novel agents acting on the IL-17 pathway have shown promising results in the therapeutic management of psoriasis.

Secukinumab (Cosentyx) was the first IL-17 inhibitor and was approved by the FDA in January 2015 for use in psoriasis treatment. It is also approved for PBS-subsidised treatment for chronic plaque psoriasis. Secukinumab neutralises IL-17A and had achieved 63% PASI 50 at week 12 in phase I trials. [35] Subsequent phase II and III clinical trials showed more than 80% of patients achieve PASI 75 at week 12. [36] Phase III trials have demonstrated that patients taking secukinumab are less likely to experience loss of response and showed superior PASI outcomes, compared to placebo, etanercept, and ustekinumab groups. [36-38]

Two other IL-17 inhibitors, brodalumab and ixekizumab, are in the last stages of development before they are approved for use. Ixekizumab is similar to secukinumab, as it inhibits IL-17. Phase II trials have shown significant scores of PASI 75 in 76.7%, 82.8% and 82.1% of patients receiving 25mg, 75mg, and 150mg, respectively, of ixekizumab at week 12, with significant and sustained reduction in DLQI scores. [39] Interestingly, use of ixekizumab has resulted in a reduction in inflammatory infiltrate, with modulation and normalisation of psoriasis disease-related genes. [6] Brodalumab inhibits the receptor subunit IL-17RA. Phase II trials have showed improvements, with a PASI scores of 85.9% and 86.3% using 210mg and 140mg, respectively, at 12 weeks, with significantly lower DLQI. [40] Both ixukizumab and brodalumab are currently in phase III trials to investigate their safety and efficacy.

Adverse effects of the three IL-17 inhibitors are reported in their respective trials. They are generally well-tolerated, but may show various drug reactions, such as nasopharyngitis, arthralgia, injection-site erythema, headache, and pruritus. [6] There are theoretical concerns that suppressing IL-17, which is a pro-inflammatory cytokine that activates innate immune responses against extracellular organisms, will increase the risk of neutropaenia with the decreased attraction of neutrophils. [3,6,34] However, these trials have not found that bacterial or fungal infections pose a significant problem. [6] It should be noted that most of these trials are short in duration and long-term efficacy, safety, and tolerability are not yet fully established. [34] Further longitudinal studies will be required to follow these trial patients.

Novel molecule inhibitors

New oral molecule inhibitors that are awaiting PBS approval include apremilast and tofacitinib. Apremilast, a phosphodiesterase-4 inhibitor, is a new oral agent approved in 2014, which has been shown to be effective against moderate-to-severe plaque psoriasis. [41] An oral inhibitor of the JAK/STAT signalling pathway, tofacitinib, is being trialled and will soon receive PBS-approval for subsidy. [42,43]

Biologic therapies for patient use in Australia

Given their hefty cost, these biologic agents are heavily subsidised under the PBS and strict qualifying criteria are applied to prescribe them in Australia. To qualify for the five currently approved biologic agents (adalimumab, etanercept, infliximab, secukinumab, and ustekinumab), patients must have failed to achieve an adequate response to at least three of the four treatments of: phototherapy, methotrexate, cyclosporine, or acitretin. [44] The biologic agent must be used as systemic monotherapy and the patient must subsequently be assessed to have demonstrated an adequate response to this current treatment by having a PASI score of greater than 15 in order to be eligible for continuing treatment. [44]

Future directions

We need to further explore and deepen our understanding of the pathogenic pathways in psoriasis to uncover components that can be potential therapeutic targets. Further understanding of the impact of psoriasis on other systemic co-morbidities is required, such as evaluating and quantifying the risk of cardiovascular disease. We will need to have more long-term, head-to-head trials to allow comparison of efficacy and safety of these novel biologics. We need further evaluations of combination regimens using traditional and biologic therapies to increase efficacy of treatment, decrease cumulative dose, and minimise side effects. This ultimately allows us to establish combined, multi-modal therapies for the individual patient to produce complete remission of skin disease and optimal QOL and functional status. Our healthcare system should explore various strategies aimed to reduce the cost of biologics and improve their accessibility to patients.

Conclusion

Advances that have been made into understanding psoriasis have led to emerging, promising, and effective treatments. As we witness an ever-expanding treatment armamentarium with novel agents, further work is still required to examine their efficacies and evaluate their use in combination regimens. Future understanding of disease pathogenesis, stratification of disease, outcome measures, and novel therapeutics will allow physicians to optimise disease and functional outcomes for patients.

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[11] Chaptini C,Quinn S, Marshman G. Durable dermatology life quality index improvements in patients on biologics associated with psoriasis areas and severity index: a longitudinal study. Australas J Dermatol.

[12] Soliman A, Nofal E, Nofal A, Desouky FE, Asal M. Combination therapy of methotrexate plus NBUVB phototherapy is more effective than methotrexate monotherapy in the treatment of chronic plaque psoriasis. J Dermatolog Treat. 2015;26(6):528-34.

[13] Van de Kerkhof PC. An update on topical therapies for mild-moderate psoriasis. Dermatol Clin. 2015;33(1):73-7.

[14] Simpson KR, Lowe NJ. Trends in topical psoriasis therapy. Int J Dermatol. 1994;33(5):333-6.

[15] Feldman SR, Fleischer AB, Cooper JZ. New topical treatments change the pattern of treatment of psoriasis: dermatologists remain the primary providers of this care. Int J Dermatol. 2000;39(1):41-4.

[16] Ma L,Yang Q, Yang H, Wang G, Zheng M, Hao F, et al. Calcipotriol plus betamethasone dipropionate gel compared with calcipotriol scalp solution in the treatment of scalp psoriasis: a randomized, controlled trial investigating efficacy and safety in a Chinese population. Int J Dermatol. 2016;55(1):106-13.

[17] Hollywood KA,Winder CL, Dunn WB, Xu Y, Broadhurst D, Griffiths CE, et al. Exploring the mode of action of dithranol therapy for psoriasis: a metabolomic analysis using HaCaT cells. Mol Biosyst. 2015;11(8):2198-209.

[18] Situm M,Bulat V, Majcen K, Dzapo A, Jezovita J. Benefits of controlled ultraviolet radiation in the treatment of dermatological diseases. Coll Antropol. 2014;38(4):1249-53.

[19] Almutawa F, Alnomair N, Wang Y, Hamzavi I, Lim HW. Systematic review of UV-based therapy for psoriasis. Am J Clin Dermatol. 2013;14(2):87-109.

[20] Archier E, Devaux S, Castela E, Gallini A, Aubin F, Le Maitre M, et al. Carcinogenic risks of psoralen UV-A therapy and narrowband UV-B therapy in chronic plaque psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol. 2012;26(S3):22-31.

[21] Nast A, Jacobs A, Rosumeck S, Werner RN. Efficacy and safety of systemic long-term treatments for moderate-to-severe psoriasis – a systemic review and meta-analysis. J Invest Dermatol. 2015.

[22] Mahmood T, Zaghi D, Menter A. Emerging oral drugs for psoriasis. Expert Opin Emerg Dr. 2015;20(2):209-20.

[23] Tyring S, Bagel J, Lynde C, Klekotka P, Thompson EH, Gandra SR, et al. Patient-reported outcomes in moderate-to-severe plaque psoriasis with scalp involvement: results from a randomized, double-blind, placebo-controlled study of etanercept. J Eur Acad Dermatol Venereol. 2013;27(1):125-8.

[24] Gottlieb AB, Langley RG, Strober BE, Papp KA, Klekotka P, Creamer K, et al. A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis. Br J Dermatol. 2012;167(3):649-57.

[25] Yang HZ, Wang K, Jin HZ, Gao TW, Xiao SX, Xu JH, et al. Infliximab monotherapy for Chinese patients with moderate to severe plaque psoriasis: a randomized, double-blind, placebo-controlled multicentre trial. Chin Med J (Engl). 2012;125(11):1845-51.

[26] Kimball AB, Yu AP, Signorovitch J, Xie J, Tsaneva M, Gupta SR, et al. The effects of adalimumab treatment and psoriasis severity on self-reported work productivity and activity impairment for patients with moderate to severe psoriasis. J Am Acad Dermatol. 2012;66(2):e67-76.

[27] Kemeny L, Amaya M, Cetkovska P, Rajatanavin N, Lee W-R, Szumski A, et al. Effect of etanercept therapy on psoriasis symptoms in patients from Latin America, Central Europe, and Asia: a subset analysis of the PRISTINE trial. BMC Dermatol. 2015;15:9.

[28] Sandoval LF, Pierce A, Feldman SR. Systemic therapies for psoriasis: an evidence-based update. Am J Clin Dermatol. 2014;15(3):165-80.

[29] Kalb RE,Fiorentino DF, Lebwohl MG, Toole J, Poulin Y, Cohen AD, et al. Risk of serious infection with biologic and systemic treatment of psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). JAMA Dermatol. 2015;151(9):961-9.

[30] Adriane AL, Gottlieb AB. Specific targeting of interleukin-23p19 as effective treatment for psoriasis. J Am Acad Dermatol. 2014;70(3):555-61.

[31] Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, Wang Y, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007;356(6):580-92.

[32] Gospodarevskaya E, Picot J, Cooper K, Loveman E, Takeda A. Ustekinumab for the treatment of moderate to severe psoriasis. Health Technol Assess. 2009;13(S3):61-6.

[33] Kimball AB, Gordon KB, Fakharzadeh S, Yeilding N, Szapary PO, Schenkel B, et al. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the POENIX 1 trial through up to 3 years. Br J Dermatol. 2012;166(4):861-72.

[34] Brown G, Malakouti M, Wang E, Koo JY, Levin E. Anti-IL-17 phase II data for psoriasis: a review. J Dermatolog Treat. 2015;26(1):32-6.

[35] Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis and uveitis. Sci Transl Med. 2010;2(52):52ra72.

[36] Lopez-Ferrer A, Vilarrasa E, Puig L. Secukinumab (AIN457) for the treatment of psoriasis. Expert Rev Clin Immunol. 2015;11(11):1177-88.

[37] Warren R, Guettner A, Morita A, Gisondi P, Cooper S. Secukinumab efficacy in subjects with moderate to severe plaque psoriasis: pooled subgroup analyses by patient age of 4 phase 3 clinical studies. J Am Acad Dermatol. 2014;70(5,S1):AB186.

[38] Garnock-Jones KP. Secukinumab: a review in moderate to severe plaque psoriasis. Am J Clin Dermatol. 2015;16(4):323-30.

[39] Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366(13):1190-9.

[40] Papp KA, Leonardi C, Menter A, Ortonne JP, Krueger JG, Kricorian G, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012;366(13):1181-9.

[41] Kang EJ and Kavanaugh A. Psoriatic arthritis: latest treatments and their place in therapy. Ther Adv Chronic Dis. 2015;6(6):196-203.

[42] Papp KA, Menter A, Strober B, Langley RG, Buonanno MS, Wolk R. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a phase 2b randomized placebo-controlled dose-ranging study.Br J Dermatol. 2012;167(3):668-77.

[43] Menter A, Papp KA, Tan H, Tyring S, Wolk R, Buonanno M. Efficacy of tofacitinib, an oral Janus kinase inhibitor, on clinical signs of moderate-to-severe plaque psoriasis in different body regions.J Drugs Dermatol. 2014;13(3):252-6.

[44] Pharmaceutical Benefits Scheme [Internet]. Commonwealth of Australia: Australian Government Department of Health; 2015. Etanercept [updated 2015; cited 2015 Dec 3]. Available from: http://www.pbs.gov.au/medicine/item/1954W-3445H-3448L-5734T-6367D-8637N-8638P-8778B-8779C-9035M-9036N-9037P-9429G.

 

The selective oestrogen receptor modulator (SERM), tamoxifen, is pivotal in treating oestrogen receptor positive (ER+) breast cancers—the most common subtype of breast cancer.  As the first targeted therapy for breast cancer, tamoxifen remains the gold standard of adjuvant endocrine therapy.  However, this important drug has its limitations: its efficacy is frequently hampered by the phenomenon of tamoxifen resistance.

This article provides an overview of ER+ breast cancer biology relevant to understanding the complexities of tamoxifen resistance.  The principal aim is to review the current literature on the mechanisms underpinning tamoxifen resistance and emerging strategies to overcome this challenge, with a focus on those with the greatest translational potential.

Numerous molecular mechanisms of tamoxifen resistance have been proposed and investigated.  Well-studied, clinically relevant mechanisms include growth factor receptor signalling, kinase pathway aberrations, cell-cycle dysregulation and epigenetic involvement.  Other areas of relevance include the development of new generation SERMs and preclinical studies with novel agents.  There is also increasing research into the roles of ER coregulator proteins and cancer stem cells.

Altogether, these areas of interest represent promising opportunities in overcoming the challenge of tamoxifen resistance and ameliorating current breast cancer therapies.

Introduction

Breast cancer is one of the most commonly diagnosed cancers in Australian women. [1] Importantly, breast cancer is a heterogenous disease.  It exhibits a wide spectrum of clinical, histopathological and molecular features, which impact prognosis, survival, and response to treatment.  In 1896, Sir George Beatson made a landmark discovery: bilateral oophorectomy resulted in tumour remission in a significant proportion of women with metastatic breast cancer. [2] This finding gave birth to the theory that the ovarian hormone, oestrogen, is involved in stimulating the growth of some breast cancers.  Indeed, on a molecular level, 70-75% of invasive breast cancers are oestrogen receptor positive (ER+) and proliferate in response to oestrogen, [3] as Beatson deduced.

Patients with ER+ tumours tend to have good prognoses and long-term survival, with a 5-year survival rate of 80-85% in the curative setting.  In comparison, ER negative (ER-) cancers are associated with earlier relapses and a lower 5-year survival rate. [3] These discrepancies are partly attributable to availability of effective endocrine therapies, and demonstrate the marked efficacy of such targeted therapies.

Methods

A broad literature review was undertaken on Ovid MEDLINE and PubMed using combinations of the search terms ‘tamoxifen resistance OR endocrine resistance’; ‘mechanism’; and ‘breast cancer’.  Limits were set to include articles written in English published since 2000.  The search was then further refined to clinical trials published since 2010.

Background

Endocrine therapy

Beatson’s findings led to the naissance of endocrine therapies: drugs that either inhibit oestrogen synthesis or block the oestrogen receptor (ER).  Indeed, these therapies have revolutionised breast cancer management.   There are three main classes of endocrine therapies (Table 1) used as adjuvants to surgery, radiotherapy, and chemotherapy in treating ER+ breast cancers.

Tamoxifen, in particular, has changed the landscape of breast cancer treatment since its discovery over three decades ago. In 1998, a meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group confirmed that adjuvant tamoxifen treatment substantially improved 10-year survival rates in women with ER+ breast tumours. [4] It has achieved a 39% reduction in disease recurrence and 31% reduction in mortality in early-stage ER+ cancers. [5]

Despite newer drugs, such as aromatase inhibitors (AIs) and selective oestrogen receptor degraders (SERDs), tamoxifen remains the cornerstone of endocrine therapy.  Current American Society of Clinical Oncology guidelines outline tamoxifen as first-line adjuvant endocrine therapy in pre-menopausal women and, alongside aromatase inhibitors, in postmenopausal women. [6] Until recently, tamoxifen was also recommended for systemic therapy for metastatic hormone-dependent breast cancers. [7] However, AIs are increasingly being used due to the issue of tamoxifen resistance. [8]

Table 1. Endocrine therapies currently used for ER+ breast cancer.

Class	Example	Mechanism of action
Selective oestrogen receptor modulators (SERMs)	Tamoxifen	Partial ER agonist and antagonist Binds ER, modulates downstream gene transcription and function
Aromatase inhibitors (AIs)	Steroidal: Anastrozole Letrozole Non-steroidal: Exemestane	Blocks peripheral conversion of adrenal androgens to oestrogen Only successful in women without ovarian function
Selective oestrogen receptor degraders (SERDs)	Fulvestrant	Binds to ER, leads to degradation of receptor

 

Tamoxifen resistance

Approximately 30% of patients with ER+ tumours fail to respond to tamoxifen from the initiation of therapy, [9,10] which is termed de novo or intrinsic resistance. [11] Another 30-40% of patients receiving adjuvant tamoxifen eventually develop disease progression or recurrence within three to five years; this is known as acquired resistance. [10,12]

Understanding tamoxifen resistance is a major focus of current breast cancer research.  Before undertaking a literature review on current strategies to overcome tamoxifen resistance, it is necessary to touch on basic ER biology in breast cancer.

Oestrogen receptor biology

There are two ER isoforms, ERα and ERβ, [13] and both are present in normal breast tissue. ERα is clearly associated with breast carcinogenesis and progression, and is the subtype best measured in assays. In contrast, the role of ERβ in breast cancer is still unclear. [13] Use of the term ER hereon refers to ERα, unless otherwise specified.

The classical pathway of ER signalling involves oestrogen binding to the ligand-binding domain of ER.  The ligand-activated ER then binds to oestrogen response elements via essential transcription factors that regulate target gene expression. [14] In breast cancer, oestrogen-mediated activation of the ER pathway leads to another chain of events resulting in altered gene transcription, ultimately producing proteins that drive cell division, differentiation, proliferation, and angiogenesis.  Subsequently, this leads to tumour growth and progression. [15] Furthermore, coregulator proteins modulate ER transcriptional activities.  These proteins either activate or repress transcription of ER-responsive genes and are known as coactivators and corepressors, respectively. [16]

Mechanisms to overcome tamoxifen resistance

Growth factor receptor signalling

Growth factors are involved in regulating the ER signalling pathway. [17] These include membrane receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) and human epidermal receptor (IGFR) (Figure 1). [17,18] If upregulated, these growth factor pathways can provide ER+ breast cancers with stimuli for growth, proliferation, and survival, even when the ER pathway has been inhibited, thus behaving as ER-independent drivers of tumour growth.

Figure 1: Pathways upregulated in tamoxifen resistance in ER+ breast cancers and associated drug targets.  1. Oestrogen activates the ER.  Oestrogen-bound ER activates ER target gene transcription, which is influenced by ER coregulator proteins and enzymes, such as histone deacetylases.  2. Oestrogen-bound ER also activates growth factor receptors (IGFR, EGFR, HER2).  3. This activates key molecules in the PI3K/Akt/mTOR downstream pathway.  In turn, this leads to increased cell growth, survival, and proliferation.  There is bidirectional crosstalk among the PI3K/Akt/mTOR pathway, EGFR/HER2 and ER.  4. Cyclin D1 is an ER transcriptional target gene that activates CDK4 and CDK6, leading to cell proliferation. 5. Histone deacetylation and 6. ER coregulator proteins modify ER target gene transcription, which also leads to cell growth, survival and proliferation. Gefitinib inhibits EGFR; everolimus and temsirolimus inhibit mTOR activation, palbociclib; palbocilib is a selective CDK4 and CDK6 inhibitor; and vorinostat inhibits histone deacetylation. (Abbreviations: ER, oestrogen receptor; IGFR, insulin-like growth factor receptor; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; PI3K, phosphatidylinositol-3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; CDK, cyclin-dependent kinase)

There is a growing body of evidence that increased growth factor signalling contributes to endocrine therapy resistance.  The EGFR/HER2 pathway has been strongly implicated. In fact, preclinical and clinical studies demonstrate that tumours overexpressing EGFR or HER2 are less likely to benefit from endocrine therapy. [19] HER2+/ER+ tumours have poorer prognoses, compared to HER2-/ER+ tumours. [3] In xenograft models, HER2 overexpression leads to tamoxifen-stimulated growth, a potential mechanism conferring intrinsic resistance. Direct interactions between ER and HER2 protect HER2+ cancer cells from tamoxifen-induced apoptosis. [17,20] Consequently, blocking this pathway with the HER2 antibody, trastuzumab, restores tamoxifen sensitivity in resistant cells. [21]

The EGFR/HER2 pathway is also involved in acquired tamoxifen resistance.  In vitro, long-term tamoxifen treatment leads to stronger EGFR and HER2 expression at the time of drug resistance. A marked increase in EGFR expression is seen in xenograft ER+ tumours with acquired resistance. [12] It has also been shown that EGFR downstream elements that stimulate proliferation and cell survival are overactive in tamoxifen resistant cells. Gefitinib is a selective inhibitor of the tyrosine kinase domain of the EGFR (Figure 1).  Adding gefitinib to tamoxifen has been shown to significantly delay the onset of resistance, in vitro. [22]

 Based on these promising findings, several phase II clinical trials have combined endocrine and targeted inhibitor therapies.  Recent preliminary studies confirm that adding gefitinib to tamoxifen is beneficial compared to placebo, and the combination warrants further clinical investigation. [23]

Kinase pathways

The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) /mammalian target of rapamycin (mTOR) pathway is an important downstream target in ER+ breast cancer (Figure 1).  It has a key role in breast carcinogenesis, and has been linked to endocrine therapy resistance.  The mTOR protein controls cellular processes such as growth, survival, and proliferation. Activating mutations in PI3K are known to be oncogenic. [24] Indeed, PIK3CA gene mutations are amongst the commonest somatic mutations in breast cancer and are more frequently identified in ER+ breast cancers than ER- cancers. [25,26]

Crosstalk between ER and the PI3K/Akt/mTOR pathway increases oestrogen-induced transcriptional activity, contributing to tamoxifen resistance. [27] In vitro, the PI3K pathway is activated in response to oestrogen depletion, leading to acquired hormone-resistant breast cancer cells. [28] The drug temsirolimus prohibits mTOR activation, thus acting as an mTOR inhibitor (Figure 1).  Temsirolimus can restore tamoxifen sensitivity in breast cancer cells. Phase II clinical trials demonstrate the beneficial effects of adding another similarly acting mTOR inhibitor, everolimus, to tamoxifen in patients with metastatic disease that is resistant to AIs. [29] Likewise, clinical trials of everolimus in combination with endocrine therapies (exemestane and letrozole) have led to the first mTOR-inhibitor being approved for postmenopausal women with advanced ER+/HER2- breast cancer. [29,30] Altogether, this points strongly at the role of mTOR inhibitors in overcoming endocrine resistance.

Histone deacetylases

Epigenetic mechanisms, such as histone acetylation and hypoacetylation, modify gene expression. Both histone acetylation and hypoacetylation can contribute to oncogenesis, depending on the target gene.  Histone deacetylases (HDACs) are the primary enzymes involved in histone hypoacetylation, and have been associated with breast cancer. Importantly, studies have shown that HDACs interact with the ER signalling pathway (Figure 1), but the precise mechanism remains to be elucidated. [31] Epigenetic modulation of ER signalling by HDAC inhibition is another promising strategy to combat tamoxifen resistance. The drug vorinostat binds to the active site of HDACs, to inhibit their action (Figure 1).  In vitro, vorinostat downregulates ER transcription and potentiates apoptotic cell death in ER+ cells. [32] In Phase II clinical studies, the combination of vorinostat and tamoxifen appears well tolerated and provides encouraging results for reversing hormone resistance. [33]

Cyclins and cyclin-dependent kinases

Cyclins and cyclin-dependent kinases (CDKs) are involved in cell-cycle regulation.  The cyclin D1 gene is a direct transcriptional target of ER signalling.  Cyclin D1 activates cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), thus inactivating the retinoblastoma tumour suppressor protein.  In turn, this promotes cell-cycle entry and proliferation. [34] In vitro, endocrine therapy-resistant breast cancer models exhibit an uncoupling of ER signalling and cell cycle progression: cyclin D1 activity is maintained despite effective blockade of ER with tamoxifen.  There is evidence suggesting that resistant cancers remain dependent on cyclin D1-CDK4 to drive proliferation. [35] Palbociclib is a selective CDK4 and CDK6 inhibitor (Figure 1) [34] that has been studied as a potential reverser of endocrine resistance. In vitro studies and phase II trials of palbociclib as a synergistic therapy with letrozole in resistant tumours demonstrated that this combination is associated with longer progression-free survival. [36-38] A recent phase III trial involving patients with advanced endocrine therapy-resistant ER+ tumours concluded that palbociclib combined with fulvestrant was more effective than fulvestrant alone. [39] Though these studies do not focus on tamoxifen resistance per se, the results suggest a promising role for this drug in improving treatment outcomes for ER+ cancers.

Alternative endocrine therapies

Aromatase inhibitors (Table 1) are now standard treatment options for postmenopausal women with ER+ tumours.  It is commonly accepted that third generation AIs have equivalent or superior efficacy to tamoxifen in postmenopausal women. [8,40-42] Furthermore, AIs appear to be effective in some postmenopausal patients with acquired tamoxifen resistance. [43] However, AI resistance is proving to be as significant a problem as tamoxifen resistance.   There is increasing research into the mechanisms behind AI resistance and trials combining targeted therapies with AIs. [44]

The SERD, fulvestrant, binds to the ER, degrades the receptor and inhibits its signalling pathways (Table 1).  Unlike tamoxifen, it does not have agonist effects but has comparable efficacy to tamoxifen in postmenopausal women. [45] Importantly, it is not cross-resistant to tamoxifen and is as effective as anastrozole in treating postmenopausal women with acquired tamoxifen resistance. [46, 47]  However, the efficacy of fulvestrant is dose-dependent [48] and more studies are needed to optimise treatments. Nevertheless, novel ER antagonists are a growing area in the pursuit to overcome endocrine resistance.

One such novel antagonist is TAS-108, a synthetic ER ligand with pure antagonistic activity that promotes corepressor recruitment without preventing DNA-binding activity.  In preclinical studies, TAS-108 successfully inhibits tamoxifen-resistant tumour growth. [49] Phase II trials in postmenopausal patients show that it leads to observable clinical benefits in a proportion of patients.  Additionally, it is well tolerated and not associated with significant changes in hormone levels or bone metabolism markers, as is the case with tamoxifen. [50]

New generation SERMs

Another strategy hinges on the development of new SERMs to inhibit ER signalling pathways.  Two classes of alternative SERMs have been developed: tamoxifen-like compounds (idoxifene, toremifene, and droloxifine) and fixed-ring compounds (raloxifene, arzoxifene, and EM-800). [51,52]

As a class, new generation SERMs have greater binding affinity for ER and reduced agonist activity, compared to tamoxifen.  Preclinical studies (in vitro and in vivo) have demonstrated that some alternative SERMs are more effective than tamoxifen in inhibiting ER+ tumour growth, including tamoxifen-resistant tumours. [53-55] However, this efficacy is yet to be recapitulated in clinical trials. [56] The prospect of clinically useful alternative SERMs is clouded by the fact that most known SERMs display a high level of cross-resistance with tamoxifen. [57] Indubitably, further research is required.

Novel agents in preclinical investigation

VEGF inhibitors

Angiogenesis is a hallmark of tumour growth and invasion. This process is modulated by the vascular endothelial growth factor (VEGF) family of growth factors and their associated receptors. Oestrogen enhances angiogenesis via VEGF release. [58] This oestrogen-dependent production of VEGF can be ablated by tamoxifen in tamoxifen-sensitive breast cancer cells. However, in tamoxifen-resistant cells, the VEGF/vascular endothelial growth factor receptor 2 (VEGFR2) signalling loop remains active, despite anti-oestrogenic treatment. [59]

High VEGF/VEGFR2 expression with concomitant elevated p38 mitogen-activated protein kinase activity is associated with poor outcomes in tamoxifen-treated cancers. Inhibition of p38 increases the inhibitory effect of tamoxifen in tamoxifen-resistant cells. [59] In murine xenograft models of tamoxifen-resistant ER+ tumours, low doses of the small-molecule VEGFR2 antagonist, brivanib alaninate, combined with tamoxifen, retards tumour growth and maximises therapeutic efficacy. [60] It remains to be seen whether this approach is effective in the clinic.

Src inhibitors

Src is a membrane-associated non-receptor tyrosine kinase belonging to the Src family kinase group (SFK). [61] Through their involvement in regulating signals from transmembrane receptor-associated tyrosine kinases and in activating intracellular target proteins, [62] SFKs modulate cell survival, proliferation, differentiation and angiogenesis. [63] Src also coordinates ER signalling and plays a role in its non-genomic effects. [63] Studies demonstrate associations between endocrine resistance, elevated Src activity and more aggressive tumour phenotypes. [64,65] Blocking interactions between ER and Src inhibits downstream cellular pathways, leading to decreased cell growth. [66] In vitro, Src inhibitors, which target the peptide substrate site of Src, partially restore response to tamoxifen in resistant cells [67] and reduce their invasive ability. [65] The combination of Src and EGFR inhibition has been shown to result in further growth inhibition in tamoxifen-resistant breast cancer cells. [65] These preclinical results suggest a promising role for Src inhibitors in overcoming tamoxifen resistance.

Notch inhibitors

Notch receptors belong to a signalling pathway involved in cell-to-cell communication and regulation of differentiation, proliferation, and apoptosis. [68] Elevated Notch-1 is associated with poor prognosis in breast cancer. In cell models of ER+ breast cancer, small interfering RNA-mediated Notch inhibition potentiates the effects of tamoxifen. When added to tamoxifen in murine xenograft models, such Notch inhibition leads to regression of ER+ tumours. [69]

Other areas of interest

Oestrogen receptor transcription factors and coregulator proteins

ER activity is influenced by ER transcription factors and coregulatory proteins.  The ER pioneer transcription factor, forkhead box protein A1 (FOXA1), and transcription factor GATA3 regulate binding between ER and chromatin, which is vital for tamoxifen’s activity on ER. [70] Indeed, FOXA1 has been identified as a positive prognostic marker of ER+ breast cancer and an indicator of endocrine therapy response. [71] GATA3 has received attention, as it is one of three genes mutated in over 10% of breast cancers, however, it is yet to be clearly linked with endocrine response. [72]

ER coregulators have long been known to play a part in tamoxifen’s function. When tamoxifen binds to ER in the breast, the resulting receptor conformation favours corepressor recruitment, consequently blocking the proliferative actions of ER signalling.  In contrast, oestrogen-bound ER favours coactivator recruitment. [73]

Increased coactivator and decreased corepressor expression is frequently seen in breast tumourigenesis. [74] Coactivator gene AIB1 is amplified in 50% of primary breast tumours and correlates with ER-positivity. [75] AIB1 overexpression is also associated with poorer outcomes in patients receiving tamoxifen, pointing at a link to tamoxifen-resistant tumours. [76] Experimental overexpression of the coactivator, nuclear receptor coactivator 1 (NCOA1), increases tamoxifen’s agonist activity. [77] This bolsters the belief that coactivator overexpression contributes to endocrine resistance by enhancing the unfavourable ER agonist activity of tamoxifen.

Conversely, downregulation of the corepressor, nuclear receptor corepressor (NCOR), is observed in xenograft models with acquired tamoxifen resistance. [78] An imbalance in coactivator and corepressor gene expression may impair tamoxifen activity by eliminating its antagonistic effect. [74] Indeed, coregulators appear to be an exciting future drug target.

Cancer stem cells

The cancer stem cell (CSC) hypothesis has established another area of investigation.  Tumour-initiating CSCs drive cancer progression and metastasis and may be partly responsible for resistance. In the normal breast, stem cells possess an ER- phenotype.  It is postulated that a remaining pool of ER- CSCs in tumour areas continue to develop over growth-arrested ER+ cells.  In essence, this converts the bulk of tumour cells from ER+ to ER-. [79] Most current therapies fail to eliminate CSCs, thus potentiating such growth.

Tamoxifen-resistant cells have a larger CSC population than sensitive cells. [80] Furthermore, several groups have identified dysregulated stem cell signalling mechanisms and overexpressed stem cell markers in tamoxifen-resistant cells and tumours that have failed endocrine therapy. [80,81] Significantly, in preclinical studies, downregulation or inhibition of these pathways sensitises resistant cells or decreases progenitor populations. [80,81] Therefore, CSCs hold great potential as putative targets for treating tamoxifen-resistant breast cancers.

Future

It is a fundamental tenet of oncology that no single drug will “cure” cancer.  Likewise, no single drug will overcome tamoxifen resistance.  It is resoundingly clear that there is no single mechanism underlying tamoxifen resistance. Rather, it involves complex molecular interactions and crosstalk between pathways. The key to overcoming resistance lies in the development of combination therapies.  Many promising clinical trials in this area centre on combining tamoxifen with drugs targeting postulated molecular pathways that modulate ER effects.  Other approaches aim to build on the principles of tamoxifen therapy by optimising its pharmacology and elucidating methods to increase its favourable antagonist actions.

Moreover, multiple mechanisms may contribute to resistance in an individual patient.  This ties in with another principle of modern oncology: the importance of personalised medicine.  The concomitant challenge lies in identifying prognostic biomarkers of intrinsic resistance before commencing therapy, and those of acquired resistance as early as possible.  The advent of next generation sequencing has already enabled the identification of some genetic and molecular signatures.  Hand-in-hand with this, comes the potential need for rebiopsy to detect changes in tumour biology following directed therapies, an area which requires careful consideration. Undoubtedly, in the future, clinically useful biomarkers will facilitate personalised, targeted therapies to overcome the issue of tamoxifen resistance.

Conclusion

There are numerous approaches to addressing tamoxifen resistance.  Altogether, this plethora of information sheds light on the clinical conundrum.  More importantly, it draws us closer to a multi-faceted strategy; the clinical trials highlighted above are testament to this. With greater research and collaboration, areas currently in the basic scientific or preclinical pipeline may be translated to clinical trials.  This will provide clinicians and patients further hope in combating the phenomenon of tamoxifen resistance with more effective therapeutic options.

Conflicts of Interest

None declared.

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