June 2017
clinical initiatives, research and current updates in treatment
A Bandaid2 for heart failure Sarah Tollemache, Epic Pharmacy Greenslopes Heart failure (HF) is a complex syndrome affecting over 50% of the elderly population.1 Between 20 to 30% of patients with mild to moderate HF and 50% with severe HF die within a year.1 There are two main types of HF, the more common, left ventricular systolic dysfunction (HF‑LVSD), where patients have an ejection fraction of less than 40% and the less common, HF with preserved left ventricular ejection fraction (HFPEF). Treatment of HF-LVSD is focused on delaying disease progression, reducing cardiovascular risk and symptom relief. Standard evidence based guidelines have been developed for the management of HF-LVSD, however adherence to these guidelines is lower than expected. The mnemonic BANDAID2 has been developed to represent evidence based treatment of HF-LVSD and improve guideline adherence.1 BANDAID2
B A N D A I D
Beta-blocker Angiotensin converting enzyme inhibitor / Angiotensin receptor blocker Nitrate and hydralazine Diuretics Aldosterone antagonist Ivabradine Digoxin / devices
Beta-Blocker Beta-blockers are recommended for all patients with HF-LVSD. They have been shown to decrease both the combined risk of death and hospitalisation and the risk of death alone.2 The addition of a
beta-blocker provides greater symptom relief and improvement in both a patient’s clinical status and sense of well-being compared to increasing an ACEI dose.2 Prior to therapy initiation, the patient needs to be hemodynamically stable with minimal evidence of fluid retention as betablockers can exacerbate fluid retention.2 Beta-blockers should be initiated at the lowest possible dose to minimise the risk of common adverse effects such as the worsening of HF, hypotension and bradycardia. The dose can then be doubled at regular intervals of 2 to 4 weeks until a therapeutic dose is achieved.3 Only certain beta-blockers are recommended in the treatment of HF-LVSD and include bisoprolol, carvedilol, nebivolol and controlled release metoprolol.
Angiotensin-converting enzyme inhibitor (ACEI) / Angiotensin receptor blocker (ARB) ACEIs are considered first line therapy in HF-LVSD. They slow disease progression, decrease both the risk of hospitalisation and rate of reinfarction and improve survival.4 In addition, ACEIs have been found to reduce HF-LVSD symptoms, improve physical activity tolerance and quality of life.5 These benefits are seen in patients across all classes of HF-LVSD and there are no differences amongst various ACEIs and their effects on HF-LVSD symptoms and survival.5 If a patient is taking a diuretic prior to starting an ACEI, the diuretic may need to be withheld for 24 hours upon ACEI initiation.3 Certain ARBs (candesartan and valsartan) may be used as an alternative if ACEIs are not tolerated. ARBs have similar benefits to ACEIs, reducing the risk of all-cause mortality and HF-LVSD hospitalisations.6
Hydralazine and Isosorbide Dinitrate (H-ISDN) Hydralazine and isosorbide dinitrate (H-ISDN) complement each other by decreasing afterload and preload respectively.3 In patients already on digoxin and diuretics, high doses of the H-ISDN combination reduces the risk of all-cause mortality, improves exercise capacity and provides symptomatic relief.7 The H-ISDN combination however, has been found to be less effective than ACEIs and there is limited evidence available for combining H-ISDN and ACEIs.8 The H-ISDN combination should be reserved for cases of ACEI/ARB intolerance.8
Diuretics Diuretics, such as frusemide, are recommended in all HF-LVSD patients with fluid overload.2 Whilst diuretics have not been shown to directly prolong survival or alter disease progression, their appropriate use is vital in the success of concomitant medication i.e. beta-blockers.2 Care needs to be taken when initiating diuretics, due to the risk of adverse effects, such as dizziness and electrolyte disturbances. A mild increase in serum creatinine may be observed when diuretics are combined with ACEIs, however, it is not usually an indication to cease the ACEI, but to continue to monitor the patient (weight, electrolytes, kidney function) and adjust the diuretic dose if required.9
Aldosterone antagonist Prescribing an aldosterone antagonist, such as spironolactone, to patients already taking an ACEI, beta-blocker and other diuretics, reduces the risk of all-cause mortality.10 There is also evidence indicating aldosterone antagonists both decrease hospitalisation rates and improve ejection
fraction.10 Aldosterone antagonists can cause hyperkalemia, therefore, both electrolyte and renal function monitoring is recommended.3
Ivabradine In HF-LVSD patients, heart rate has been proven to be a predictor of adverse outcomes independent of all other measures of disease severity. An elevated heart rate is associated with increased cardiovascular morbidity and mortality11. By reducing the heart rate by approximately 10 beats / minute, ivabradine reduces both the risk of hospitalisation for worsening HF-LVSD and the combined risk of hospitalisation and death.11 It is of greatest benefit to patients with a left ventricular ejection fraction of less than 30% and a heart rate of more than 70 beats per minute.11 It is used in addition to optimal therapy and not as monotherapy.
Digoxin Digoxin is usually considered the last line of treatment, reserved for instances of atrial fibrillation and advanced HF-LVSD.12
It hasn’t been proven to reduce all-cause HF‑LVSD mortality, however, it has been shown to reduce HF-LVSD symptoms, improve exercise capacity and decrease HF‑LVSD hospitalisations. Patients with severely reduced ejection fraction benefit most from digoxin.12 Digoxin has a narrow therapeutic index, therefore requires careful dose titration and monitoring to prevent toxicity, especially in renal impairment.12
Devices Automatic Implantable Cardioverter Defibrillators (AICDs) and Cardiac Resynchronisation Therapy (CRT) are devices used in moderate to severe HF‑LVSD with arrhythmia.1 AICDs are a small implantable device that correct arrhythmias through cardioversion and defibrillation. CRT is a biventricular pacemaker which reduces the risk of all-cause mortality through heart rate resynchronisation and improving cardiac efficiency.1
Future treatments Neprilysin inhibitor
class of drug in the treatment of HF‑LVSD. To date, only one neprilysin inhibitor has gained TGA approval, in the form of a neprilysin inhibitor (sacubitril) and ARB (valsartan) combination. Neprilysin inhibitors control blood volume and lower blood pressure by inhibiting neprilysin mediated vasoconstriction and sodium retention.1 The combination has been shown to not only perform better than either treatment alone, but also be superior to first line treatments such as ACEIs, in reducing the risk of both hospitalisation and mortality.1 It’s adverse effect profile is similar to that of ACEIs or ARBs, with common side effects including hypotension, renal impairment, hyperkalaemia, headache and dizziness. HF-LVSD is a complex syndrome with substantial morbidity and mortality. Adherence to the current evidence based mnemonic BANDAID2 could dramatically improve patient outcomes. References are available on request.
Neprilysin inhibitors are a promising novel
Vaccination in Patients with Cancer Dr Shir Ley Tan, Icon Cancer Care Adelaide Infection is one of the most common lifethreatening complications of cancer and cancer treatment. Immunosuppression resulting from cancer and chemotherapy places patients at higher risk for contracting infections, as well as increasing the severity of infection. In the general population, vaccination is a simple yet important process used to prevent many infections. However, studies have indicated that immunosuppression reduces the effectiveness of the vaccines. Studies have reported the seroconversion rates of cancer patients range from 25% to 71%, compared with 67% to 88% in controls.1 Although vaccination appears to be less effective in cancer patients, it does have a role to confer protection to some patients and lessen the severity of infection in others. For a healthy immune system, it typically takes up to 2 weeks after vaccination for the adaptive immunity to respond to the exposed pathogen. Unfortunately, cancer patients may not be able to mount an adequate immune response within this time. Repeat vaccination or boosters may be crucial in prolonging and/or extending immunity. Immunisation with killed or inactivated vaccines does not represent a danger to immunosuppressed patients. The timing of vaccinations with respect to the treatment is important in achieving extended immunity and better outcomes for cancer patients. Ideally, vaccination should precede the commencement of chemotherapy by at least two weeks. Vaccination during chemotherapy or radiation therapy should be avoided because antibody responses
are suboptimal. However, this may not be feasible, given the need to start chemotherapy regimens in a timely manner. If vaccines are given during chemotherapy, they should not be considered valid doses unless protective antibodies are documented.4
Patients should be vaccinated at least 2 weeks before starting chemotherapy or in between cycles, with the former scenario likely more beneficial. Immunisation of close contacts of immunocompromised patients is highly recommended.4
Live-virus vaccines such as measlesmumps-rubella (MMR), Varicella Zoster and Bacille Calmette-Guerin (BCG), are contraindicated in immunosuppressed patients and should be deferred until immune function has returned to normal. Virus replication after administration of live, attenuated-virus vaccines can be enhanced in severely compromised persons resulting in serious or unusual adverse events.4,5 Patients with leukaemia, lymphoma or other malignancies whose disease is in remission and whose chemotherapy has been terminated for at least three months may receive live vaccines.6
Pneumococcal vaccine is recommended for all cancer patients, especially those with haematological malignancies (such as multiple myeloma (MM), Hodgkin’s disease and leukaemia) as they are at increased risk of invasive pneumococcal disease. To maximise effectiveness, the pneumococcal vaccine should be given four to six weeks (minimum 2 weeks) before the start of the chemotherapy regimen.2
The following sections outline some of the common inactivated vaccines and recommendations for their use in cancer patients.
Influenza Vaccine In comparison with non-cancer patients, patients with cancer and influenza usually suffer from more complications requiring hospitalisations and may lead to excess mortality.7,8 It is recommended that cancer patients obtain the influenza vaccine annually prior to the peak of the season. Patients who are receiving the influenza vaccine for the first time are recommended to receive 2 vaccine doses at least 4 weeks apart and 1 dose annually thereafter.9
Pneumococcal Vaccine
The current recommendations include the use of the more immunogenic pneumococcal conjugate vaccine (13vPCV) together with the pneumococcal polysaccharide 23-valent vaccine (23vPPV). The recommendations are as follow: ¬¬ For patients who have not previously received either 13vPCVor 23vPPV, a single dose of 13vPCV is recommended followed by a dose of 23vPPV at least 8 weeks later. ¬¬ For patients who have previously received one or more doses of 23vPPV, a single dose of 13vPCV should be given at least 12 months after the last 23vPPV dose was received. ¬¬ For patients who require additional doses of 23vPPV, the first such dose should be given no sooner than eight weeks after 13vPCV and at least five years after the most recent dose of 23vPPV.4 Continued on page 4.
What’s new Management of Inflammatory Bowel Disease with Biological Agents: Adalimumab, Infliximab and Vedolizumab Kate Siede, Epic Pharmacy Newcastle Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC) are chronic and progressive inflammatory conditions characterised by inflammation at various sites in the gastrointestinal tract (GIT) and are associated with an increased risk of colon cancer.1,2 CD causes inflammation of the full thickness of the bowel wall and can occur in any part of the GIT. UC causes inflammation in only the inner lining of the large bowel and rectum.3 The incidence and prevalence of IBD has markedly increased in recent years, and IBD is now considered to be one of the most prevalent gastrointestinal diseases.4 Although the precise aetiology of IBD remains unclear, evidence suggests that dysregulated immune responses to intestinal microbiota and other environmental factors play an important role in its development.5 It may be the interaction of these factors in patients with a multifactorial genetic predisposition that initiates an inflammatory cascade of excessive pro-inflammatory cytokine production in the GIT mucosa.1,3,6,7 Various immune cells infiltrate the mucosa and increasing evidence indicates that T lymphocytes, especially CD4+ T cells, play an important role in causing tissue damage by secreting excessive pro-inflammatory mediators, including cytokines, interleukins, and tumour necrosis factor (TNF).8 Current IBD therapies are aimed at various stages of the immuno-inflammatory cascade with the aim of therapy being to change the natural disease progression and its subsequent long term outcome, rather than just symptom control. This aim is reflected by the trend towards earlier use of potent immunomodulatory drugs rather than persisting with less potent drugs such as 5-aminosalicylates (e.g. sulfasalazine, mesalazine) and corticosteroids which have broad anti-inflammatory actions.2 Recent advances in the knowledge of IBD immunology and bioengineering have led to new therapeutic concepts that target almost every aspect of the inflammatory process. This article will focus on three commercially available biological agents funded on the Pharmaceutical benefits Scheme (PBS) for refractory moderate to severe IBD; adalimumab (Humira®), infliximab (Remicade® and the biosimilar, Inflectra®) and vedolizumab (Entyvio®).
Adalimumab and infliximab are both monoclonal antibodies (MAb’s) which bind to tumor necrosis factor alpha (TNF- ), preventing TNF- from attaching to the TNF-receptor and exerting its inflammatory activity.9-13 Adalimumab is available for use in severe CD to induce remission where conventional therapy (corticosteroids and immunomodulators; methotrexate, azathioprine or mercaptopurine) has failed following a 3 month trial. Adalimumab has demonstrated efficacy for induction and maintenance of remission in patients with moderate to severe CD and also as an effective treatment in case of failure or loss of response to infliximab. In addition, adalimumab has demonstrated steroidsparing properties and the ability to reduce hospitalisations and improve quality of life. Currently, infliximab is available for use in severe CD and in moderate to severe chronically active or frequently relapsing UC. In the setting of CD, infliximab and adalimumab appear to be similarly effective, so drug choice usually depends on clinician and patient preferences.2 Infliximab has demonstrated clinical benefit, reduction in signs and symptoms of disease and overall quality of life improvement.14 It has significantly improved IBD treatment outcomes by preventing progression of structural bowel damage, thereby reducing complications, steroid use and the need for surgery and hospitalisation.9,15 Significant adverse events including infections, and malignancies have been reported with use of anti-TNF therapy.11,17,18 Active sepsis is an absolute contraindication as this risks severe septicaemia. Reactivation or development of tuberculosis has been reported in rheumatoid arthritis patients given antiTNF therapy.11,18 Infliximab is a chimeric mouse-human recombinant MAb , which confers a higher risk for allergic events (than the completely human Mab, adalimumab).9 Infliximab infusion reactions (during or shortly after infusion) commonly occur and respond to slowing the infusion rate or treatment with antihistamines, paracetamol and sometimes corticosteroids.18 Anaphylactic reactions have also been reported. A delayed reaction in joint stiffness, fever, myalgia, and malaise may occur if there has been an interval of >1 year following a previous infliximab infusion and can be limited by pretreatment with a corticosteroid.18 Cutaneous reactions are common but rarely
necessitate stopping treatment. In 2014, adalimumab accounted for a significant number of injury reports received by the FDA. Among the serious injuries reported, almost a quarter of the cases indicated an infection, and more than 10% of the cases indicated cancer, including 197 reported cancer deaths. A third large group of adverse events involved hypersensitivity with more than 10,000 mostly non-serious injection site reactions were reported.19 In addition to these potential side effects the other main limitation of anti-TNF therapy is that a proportion of patients will be primary non-responders, possibly due to a different pathophysiological mechanism driving the disease.20 In these patients switching to another treatment modality such as an integrin antagonist may be required. Vedolizumab, an integrin antagonist, is a humanised MAb that exclusively targets the lymphocyte integrin alpha4beta7 ( 4 7). This interaction prevents the binding of gut homing T lymphocytes to mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1), thus reducing gastrointestinal inflammation.21 It is indicated in the treatment of moderate to severe UC and severe CD in adults who have failed at least one conventional therapy.22,23 Vedolizumab has demonstrated efficacy in induction and maintenance of clinical and endoscopic remission in UC patients, including patients not responding to initial glucocorticoid therapy and those whom have failed anti-TNF therapy.21,22 For CD, results are modest for induction and better for maintenance of clinical remission.23 In clinical trials, vedolizumab appears to have been well tolerated with few serious side effects.21 Recently collated clinical trial adverse events (AE) data demonstrated that drug related AE were similar for UC and CD (including headache, nasopharyngitis, nausea, arthralgia, upper respiratory infection and fatigue). Serious infections and drug-related serious AE occurred in 4% and 2% of UC patients and in 7% and 5% of CD patients respectively. Malignancies were observed in 1% of patients. There were six deaths among 1822 patients, three in the UC group (respiratory failure, acute stroke and pulmonary embolism) and three in the CD group (septicaemia, traumatic intracranial haemorrhage and suicide). While this data supports the relative safety of vedolizumab in severe CD and UC long term safety is yet to be published. References are available on request.
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What’s New Olaparib
Brigitte Janse van Rensburg and Jordan Hamlet, Epic Pharmacy Toowoomba Olaparib (Lynparza®) is an oral poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor. It has been shown to significantly increase progression free survival when prescribed as maintenance treatment in adults with Breast Cancer 1 (BRCA1) or Breast Cancer 2 (BRCA2) mutated high‑grade serous ovarian, fallopian tube or primary peritoneal cancer, who have previously responded to platinum-based chemotherapy regimens.1,2 PARP is a key enzyme that repairs single-stranded DNA breaks, enabling continued cell division and tumour growth.2 It’s inhibition leads to double-stranded DNA breaks which require functional BRCA genes to be repaired. This accumulation of DNA damage in BRCA1 and BRCA2 mutated cancer cells results in the disruption of cellular homeostasis and cell death.1
Olaparib is dosed orally at 400mg (eight 50mg capsules) twice daily, beginning within 8 weeks of the final chemotherapy dose. It is best taken either two hours before or one hour after food, as food increases its absorption.3 The capsules should be swallowed whole and not opened, crushed or chewed. Common adverse effects are generally of mild or moderate severity and include nausea, vomiting, fatigue, diarrhoea, headache and decreased appetite .1,3 Haematological toxicities, such as anaemia are also common. These adverse effects do no usually lead to treatment discontinuation. Olaparib is a cytotoxic medication and appropriate precautions should be adhered to. References are available on request.
Management of Inflammatory Bowel Disease with Biological Agents: Adalimumab, Infliximab and Vedolizumab Continued from page 3 In summary, the ideal therapeutic strategies for patients with IBD aim to induce and maintain long-term remission. All currently available biological agents infliximab, adalimumab and vedolizumab have significantly improved treatment outcomes for patients with moderate to severe IBD however there is still significant potential risk from drug related AEs. It is hoped as research continues to reveal the complex underlying immunological mechanisms associated with IBD more specifically targeted treatment modalities with fewer side effects will be identified. References are available on request.
Vaccination in Patients with Cancer Continued from page 2
Tetanus toxoid, diphtheria toxoid and pertussis vaccines Tetanus and diphtheria booster immunisations should be considered for all patients with cancer. Adults who have not been vaccinated with the acellular pertussis vaccine should receive the vaccine containing tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (dTpa).4
Hepatitis B Vaccine Hepatitis B vaccine is not required for previously vaccinated patients undergoing chemotherapy alone, as immunogenicity is sustained throughout treatment, unless hepatitis B antigen is undetectable by titer.10
Meningococcal Vaccine Due to the life threatening nature of Neisseria meningitides infection, the meningococcal vaccine is an important
consideration in certain high-risk patient groups such as in cases of functional or anatomical asplenia, and haematopoetic stem cell transplant. There are currently no specific recommendations for patients with cancer. Meningococcal vaccination is advocated when an indication arises. Consideration should be given to the appropriate formulation and vaccine schedule based on the patient’s age and underlying illness.4,11
Special Consideration: Patients on Immune Checkpoint Inhibitors Data is lacking on the recommendations for vaccinations in cancer patients receiving checkpoint inhibitors such as pembrolizumab, nivolumab and ipilimumab. No controlled clinical trials have been conducted to investigate the combination of influenza vaccines with immune checkpoint inhibitors.
However, extreme caution is recommended in patients receiving both ipilimumab and nivolumab, as serious adverse events have been reported in patients who had received concomitant influenza vaccine prior to or during treatment with this combination therapy.12 Decision on whether or not to immunise a patient lies in the hands of the clinicians who will consider the risk versus benefit on a case by case basis. In summary, childhood vaccination has led to the elimination of many preventable diseases in the general population. Likewise, the same approach has shown to be beneficial in the haematology and oncology population. Immunisation can reduce the incidence and severity of infections, and optimal timing of vaccine administration can further increase the chance of successful protection. Avoidance of live vaccines in crucial in this group of patients. References are available on request.
If you have any queries regarding Circuit content and authors please contact the Epic Pharmacy Practice Unit by email: circuit.editor@epicpharmacy.com.au Every effort has been made to ensure this newsletter is free from error or omission.
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