Bicalutamide causes heart failure in an elderly patient with prostate cancer

1. Case

1.1. Presenting complaint

Mr FD is an 82-years-old male with prostate cancer who presented to a major metropolitan public hospital with a 2 weeks history of increasing shortness of breath on exer- tion (SOBOE), orthopnoea, swelling of ankle, and weakness.

1.2. Physical examination

Mr FD was found to have bibasal crepitations and edema of lower limbs.

1.3. Investigations

Routine biochemistry was requested and revealed a BNP of 3820 ng/L (Ref value <100 ng/L); troponin I was slightly elevated at 0.076 μg/L (Ref value <0.040 μg/L). A Chest X-ray was performed and car- diomegaly suggestive of congestive heart failure (CHF) was demonstrated. A request for transthoracic echocardiogram was made, and Mr FD was shown to have a left ventricular ejection fraction of 18% ± 5%. 1.4. Management Diuresis using oral frusemide 40 mg twice daily (increased from 20 mg initiated by GP) was instigated with good effect. The plan was to maintain Mr FD on this dose for a week, then reduce it to 40 mg in the morning thereafter. Bisoprolol 1.25 mg daily, ramipril 2.5 mg daily, and aspirin 100 mg daily were all started as part of CHF management. 1.5. Treatment response Mr FD responded well to the management strategy using heart failure medications. His chest was clear on discharge, and his leg oedema was improving bilaterally. 1.6. Discharge planning Mr FD was booked for a general medicine appointment and a follow up transthoracic echocardiogram 5 weeks post discharge; he has been discharged to the care of his regular GP 4 days after his hospital presentation. A referral to the outreach consultant pharmacist was also made to assess Mr FD’s medication management and compliance at home. 1.7. Follow-up The consultant pharmacist visited Mr FD 6 days post discharge and found he was on bicalutamide, among other medications (as listed in Table 1). It was established that Mr FD has been on bicaluta- mide 50 mg daily for his prostate cancer and was admitted to hospital on it. The medication was contin- ued while an inpatient, and he was discharged on it. From the time he presented to ED up until his dis- charge, bicalutamide was not suspected as a cause of Mr FD’s heart failure. However, the Naranjo adverse drug reaction probability scale score was +7, indicating that it is probable that Mr FD’s heart failure was caused by bicalutamide. Extensive history revealed that bicalutamide was initially started when prostate cancer was first diag- nosed in January 2009, but the patient ceased it after the first dispensing due to ‘side effects’ and feeling unwell, according to Mr FD. The second time bicaluta- mide was prescribed was for a different brand than that first dispensed, and this was in June 2009 (brand was Cosudex, dispensed from a different pharmacy). It is this second time that heart failure was formally diagnosed using relevant investigations, documented in the patient’s history, and treatment commenced.Following the home visit, bicalutamide was ceased. However, 21 months later, Mr FD was still on heart failure medications. He succumbed to prostate cancer in December 2011. 2. Discussion Bicalutamide is a nonsteroidal antiandrogen, which binds androgen receptors (AR) without activating gene expression [1,2]. It, thus, functions as an antago- nist at these receptors and prevents other androgens from binding to the receptors and initiating the gene expression cascade. This mechanism of action is respon- sible for bicalutamide’s potency in halting growth and causing apoptosis in androgen-dependent cells [3,4] and is what is aimed at when targeting cancer cells, hence its role in regressing prostate tumor. The dose of bicalutamide in prostate cancer is 50 mg daily, which does not need to be changed in patients with hepatic or renal impairments [5]. Mr FD used this dose both times bicalutamide was prescribed for him. Given the long half-life of 7–10 days with regular dosing [6], it offers the advantage of daily dosing and improved patient compliance and quality of life. Bicalutamide is commonly used with a LHRH agonist to offer maximum benefit in patients with advanced prostate cancer. If used as monotherapy, a higher dose of 150 mg daily is usually recommended [7]. Its place in therapy is still being determined, with further studies needed to compare it with other androgen antagonists, e.g. flutamide. However, it has proved to be a valuable addition in the fight against prostate cancer. Safety of bicalutamide is also under continuous scru- tiny. The most common adverse reactions associated with its use include gynecomastia, breast tenderness, hot flushes, dizziness, and anemia, all occurring at a rate of more than 10% [8]. Mr FD was fortunate to be spared all these common effects. However, there are more serious adverse drug reactions (ADRs), which tend to occur less frequently. Heart failure was twice as fre- quent in the bicalutamide group in clinical trials [9]. Yet, a cause–effect relationship was not comprehen- sively assessed, and nothing was reported during post marketing surveillance. It is an essential fact that Mr FD’s heart failure occurred after he commenced on bicalutamide; this establishes a temporal relationship. The patient in this case had no previous symptoms suggestive of heart failure, and his cardiovascular health was maintained up until the drug was initiated. Moreover, bicalutamide was initially used a few months earlier, and the patient had to cease it because of feeling unwell after starting on it. Although this feeling of being ‘unwell’ is not qualified and not described in details by Mr FD, it indicates that bicalutamide caused enough discomfort to warrant the patient ceasing it despite knowing it is for a newly diagnosed potentially fatal prostate cancer. Formal heart failure diagnosis was made on rechal- lenge, i.e. on the second attempt at using bicalutamide; this is a very strong indication that bicalutamide has been the cause of heart failure in this patient. It was associated with ‘side effects’ the first time it was used and had to be ceased and was also associated with congestive heart failure the second time it was used and had to be ceased. Use of leuprorelin cannot be totally ruled out as a confounding factor in this case. However, the timeline of events strongly links Mr FD’s heart failure to bicalu- tamide, rather than any other medication he was using. Another possible confounder could be the recent ces- sation of amlodipine for hypertension; it was ceased 10 months before CHF diagnosis was made. Examining his dispensing history, Mr FD seems to have been very compliant with 5 mg daily of amlodi- pine for about two and half years before the diagnosis of his heart failure. There were no other cardiovascular risk factors or cardiovascular drugs used before amlodi- pine was commenced. Chronic uncontrolled hyperten- sion may be a factor in developing heart failure. However, this is unlikely in this case, mainly due to the relative recency of his hypertension and appropri- ate control. Hospital records confirm that a few years prior to his diagnosis of heart failure, Mr FD had no hypertension. The Naranjo ADR probability scale [10] indeed gave this case a score of 7, indicating that it is probable that bicalutamide was the cause of heart failure in Mr FD. The Naranjo scale is a validated tool that is widely utilized to assess the cause–effect relationship between a drug and an alleged adverse event. It takes into account factors such as the temporal rela- tionship, other possible causes, and prior exposure to the drug. Bicalutamide does not simply increase the risk of cardiovascular disease due to hormonal changes, as suggested by some [11]. Apart from an overall hormo- nal imbalance that increases the risk of cardiovascular morbidity [12], there seems to be a direct injurious action that bicalutamide mediates. In one study, bicalutamide significantly increased NTproBNP from baseline to 3 and 6 months [13]. The median value at baseline, 3, and 6 months was 55, 101, and 118 ng/L, respectively. This is consistent with the assertion that bicalutamide can indeed cause cardio- toxicity, even though through unknown mechanisms. The increase in BNP in that study was very modest, compared to the case of Mr FD, which was 3820 ng/L, perhaps indicating a more extensive damage. The use of goserelin, a GnRH agonist similar to the leuprorelin Mr FD was using, did not sustain an increase in NTproBNP levels at 6 months [13]. This again dismisses any confounding role leuprorelin may have played in the case of Mr FD. The Androgen–Androgen Receptor (A-AR) system has a protective role against angiotensin II (AngII)- induced vascular remodeling [14]. Vascular remodeling is an underlying mechanism in the vasodilatory failure that contributes significantly to left ventricular dys- function [15,16]. Inactivating the A-AR system in mice is also known to cause AngII-induced cardiac fibrosis [17]. Thus, by blocking such A-AR system activation, through its antagonistic effect at these receptors, bica- lutamide may be responsible for vascular remodeling and cardiac fibrosis that ultimately compromises left ventricular function. The administration of the vasoactive peptide AngII to A-AR gene knockout mice caused increased medial thickening of the coronary and thoracic aortic arteries, as well as perivascular fibrosis [14]. This thickening of the thoracic aorta would increase aortic pressure and thus be responsible for increasing afterload, which may contribute to the pathogenesis of heart failure. Furthermore, blocking the A-AR system has been associated with increased intima–media thickness of the common carotid artery of middle-aged and elderly men [18,19]. Common carotid artery diameter is asso- ciated with left ventricular mass through ventricular– arterial coupling [20] and is predictive of congestive heart failure [20,21]. Using bicalutamide to antagonize the A-AR system would result in such pathophysiologi- cal processes. On the other hand, bicalutamide seems to be effec- tive at lowering nitric oxide (NO) availability by generat- ing reactive oxygen species, thus causing hypertrophic changes [14]. The importance of NO in preventing vas- cular remodeling is well established [15]. Mr FD indeed showed cardiac hypertrophy on presentation, which may indicate he was subjected to such pathogenic process while on bicalutamide. AR activation also suppresses TGF-B Smad signaling pathway and prevents vascular fibrosis [14], but bicalutamide seems to antagonize this, by blocking AR receptors Figure 1. Figure 1. Vascular changes leading to bicalutamide-induced heart failure. A therapeutic target in the treatment of androgen- independent prostate cancer is the inhibition of endothelin-1, the functions of which are mediated by ETA receptors [22]. On the other hand, androgen depri- vation increases ETA receptor expression [23], meaning that the use of bicalutamide induces ETA–mediated ET-1 functions. This may explain why treating androgen- dependent prostate cancer increases the risk of develop- ing androgen-independent prostate cancers through selective pressure that leads to mutant androgen recep- tors [24]. The use of androgen antagonists, such as bicalutamide, in these androgen-independent cases has disappointing outcomes for prostate cancer patients [25]. These ET-1 functions include vasoconstriction and proliferative effects on smooth muscle cells [26,27]. Moreover, in one study [28], the use of flutamide, which is of the same class as bicalutamide, enhanced the pressor effect of ET-1 in rats. Furthermore, another study demonstrated that bicalutamide directly increases the secretion of ET-1 [29], thus exerting a direct effect mediated by ET-1 binding of ETA receptors. On the other hand, when ETB receptors are blocked, the clearance of ET-1 is reduced, resulting in less NO production [30]. This, again, may explain the role of bicalutamide in vascular remodeling as it lowers NO availability. Bicalutamide may have a direct nonselective antagonistic effect on ET receptors. Further studies are needed to specifically examine this. When bicalutamide blocks AR and initiates apopto- sis, cancerous cells bypass androgen dependency by overexpressing Bcl-2 proteins, thus inhibiting apoptosis [24]. This is one mechanism of turning androgen- dependent prostate cancer into androgen-independent [24]. However, Bcl-2 proteins are not entirely anti-apop- totic, some Bcl-2 proteins are indeed pro-apoptotic [31]. There are implications in heart failure for the expression of Bcl-2. Bicalutamide, somehow at a molecular level, leads to cardiovascular effects through its drive to over- express Bcl-2 when blocking AR. Its ability to promote proliferation of smooth muscle cells may be mediated, at least partially, by overexpressing the Bcl-2 gene that has been shown to cause myocyte proliferation in mice [32]. Whether this also involves cardiomyocyte prolifera- tion, and cardiac hyperplasia, is unclear. On the other hand, bicalutamide has been shown to directly inhibit cyclin-A expression, possibly by inhibiting FGF-8 mRNA expression and FGF-8 protein secretion [33]. Cyclin-A enhanced cardiac function in ischemic heart fail- ure and indeed induced myocardial regeneration [34]. The hemodynamic benefits included maximizing preload and significantly increasing cardiac output. In one study, the ejection fraction in swine increased by 18% [35]. This is in addition to an active repair process in those myocytes that have been injured [36]. The ability of bicalutamide to inhi- bit cyclin-A clearly reflects its cardiotoxic impact, where it directly affects the myocardium and cardiac function. An important clinical implication of the role of bica- lutamide in heart failure relates to the efficacy of phar- macotherapy. For example, the vascular remodeling induced by angiotensin converting enzyme (ACE) and AngII [37,38] may be further mediated by the use of bicalutamide. This is because the A-AR system has a protective role against this remodeling, which bicaluta- mide compromises. This may render agents such as the AngIIR blockers, e.g. irbesartan, and ACE inhibitors, e.g. ramipril, less effective. The vascular remodeling process that bicalutamide allows to proceed, either by inhibit- ing the A-AR system [14] or a postulated antagonistic action at ET receptors, counteracts the partial correction ACE inhibitors produce [37] Figure 2. Clinicians will need to be more vigilant of cardiovas- cular risk factors when assessing patients for suitability of bicalutamide. The risk of developing heart failure may be an exclusion criterion for its use, but this is a hard call to make. Mr FD developed heart failure but what ultimately ended his struggle was prostate cancer. Whether his heart failure altered the course of disease progression or complicated end of life management is an unknown. Further studies are needed. The use of bicalutamide has improved the care of patients with prostate cancer, but dismissing its direct effect on the cardiovascular system could be a grave mistake. It appears that bicalutamide can be the prob- able cause of heart failure in some patients, and clin- icians need to be well aware of this probability. More studies are required to investigate the molecular mechanisms mediated by the drug and to examine their role in causing cardiotoxicity, so we have a better understanding of its safety profile. 3. Conclusion This paper describes Mr FD who was diagnosed with heart failure on rechallenge with bicalutamide. The Naranjo probability scale strongly suggests that bicalu- tamide was indeed the probable cause of heart failure in this patient. The contribution of bicalutamide-caused heart failure cannot be ruled out in the patient’s death. Further studies are required to ascertain the underlying processes that mediate such pathogenesis, but evi- dence thus far points to possible direct cardiotoxic effects, mediated by apoptosis molecules, ET-1, cyclin- A, and BCl-2. The risk of developing or exacerbating heart failure should be considered in patients on bicalutamide. Figure 2. Possible molecular effects of bicalutamide. It decreases Cyclin-A, and increases Bcl-2 and ET-1. Increases in ET-1 via the ETA receptors lead to decreases in nitric oxide (NO), which in turn contributes to vasoconstriction and vascular remodeling. Declaration of interest The author has no relevant affiliations or financial involve- ment with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, con- sultancies, honoraria, stock ownership or options, expert tes- timony, grants or patents received or pending, or royalties. References Papers of special note have been highlighted as: • of interest •• of considerable interest 1. Furr BJA, Tucker H. The preclinical development of bica- lutamide: pharmacodynamics and mechanism of action. Urology. 1996;47:13–35. 2. 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