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Did you miss any clinical highlights from 2013?

To get you up to date, Harriet Adcock, The Journal’s news editor, asked specialist pharmacists about the most important clinical developments of the past 12 months

Frustrations around funding decisions and absent or unwelcome top-down guidance were common themes among the various clinical specialisms in 2013. New commissioning structures within the NHS, particularly in England, also presented challenges for clinicians. But alongside the frustrations, there were interesting developments, particularly in Scotland where the profession is set to have a more clinical focus. In addition, many specialists remain excited about developments in their field.

Cardiology: return to grassroots

It was a quiet year in cardiology, experts agreed, with the implementation of novel oral anticoagulants remaining the primary focus. “Their use has prompted much discussion within cardiology, both in terms of their place in therapy and the agent of choice. Perhaps their greatest legacy will be the increased awareness of the risk of stroke in atrial fibrillation and how that risk is assessed and managed,” said Steve McGlynn, specialist principal pharmacist (cardiology) at NHS Greater Glasgow and Clyde.

Blood clot (Sebastian Kaulitzski/Dreamstime.com)

Arterial blood clots are among cardiovascular risks associated with diclofenac, similar to those of selective COX-2 inhibitors

Mr McGlynn also highlighted the use of antiplatelet agents in acute coronary syndromes as having a significant effect on clinical practice in 2013. “Although less controversial in Europe, the use of ticagrelor [Brilique] has generated much debate in the US, with concerns over the variability of clinical trial results across the globe,” he said.

Helen Williams, consultant pharmacist for cardiovascular disease at NHS Southwark Clinical Commissioning Group, noted publication of the Department of Health’s cardiovascular disease (CVD) outcomes strategy, with 10 core recommendations for the NHS. These included reducing premature mortality rates for CVD, supporting better identification of those at high risk of CVD and improving primary care management.

“This will drive the direction of CVD care for the next decade and has a clear focus on implementation of prevention strategies and up-skilling primary care in CVD management. From my perspective, this means returning to the grassroots of cardiovascular care — primary and secondary prevention, including addressing lifestyle issues and implementing core cardiovascular drugs which we are all familiar with — aspirin, statins, ACE inhibitors and beta-blockers,” she said.

The demise of diclofenac was highlighted by Sotiris Antoniou, consultant pharmacist (cardiovascular medicine) at Barts Health NHS Trust: “The European Medicines Agency concluded that the risk of cardiovascular side effects with diclofenac (so often the non-steroidal anti-inflammatory drug of choice for formularies) was on a par with that observed with selective COX-2 inhibitors, and [that the drug] is also contraindicated in people with ischaemic heart disease.”

One new cardiovascular drug was launched onto the market in 2013 — lomitapide (Lojuxta) — a potent lipid-lowering agent for use in homozygous familial hyperlipidaemia (FH). “An expensive option, the agent may find a use to reduce the need for apheresis in a very small population — fewer than 100 individuals are thought to have homozygous FH in the UK,” said Mrs Williams.

Respiratory: take a deep breath

The urgent and emergency care system was put under pressure in 2013, and people with respiratory disease contributed significantly to the strain, according to Anna Murphy, consultant pharmacist, University Hospitals of Leicester NHS Trust. “Clinical commissioning groups have focused on initiatives aimed to reduce hospital admissions and improve the quality and frequency of primary care reviews.”Alongside this, community pharmacy services are being encouraged to support people with respiratory disease, Mrs Murphy said.

In terms of drug developments, 2013 saw the EU approval of Ultibro — a novel long-acting muscarinic antagonist (LAMA) — glycopyronnium — in combination with a long-acting beta-2 agonist (LABA) — indacaterol — set to be launched for chronic obstructive pulmonary disease. And in the past few weeks, EU approval has also been granted for a new once-daily inhaled corticosteroid/LABA combination — Relvar Ellipta (fluticasone furoate/vilanterol) — delivered via a new dry powder device and licensed for both asthma and COPD.

Another notable clinical development occurred when the National Institute for Health and Care Excellence rethought draft recommendations and agreed that omalizumab (Xolair) can be used to treat severe, persistent asthma.
Potential safety risks associated with inhaled medicines, in particular inhaled corticosteroids (ICSs) and LAMAs, were highlighted last year. Pneumonia is the main concern with ICSs and cardiovascular events with LAMAs, explained Mrs Murphy. “The debate continues. In the meantime, any prescriber should be vigilant and aware of the risks,” she said.

Infections: bad year for macrolides

Rotavirus vaccine (Luk Cox/Dreamstime.com)Publication of the chief medical officer’s report in March calling for antimicrobial resistance to be listed alongside terrorism on the national risk register was the major news story of the year, according to Kieran Hand, consultant pharmacist (anti-infectives) at University Hospital Southampton NHS Foundation Trust. This was followed in September by the UK five-year antimicrobial resistance strategy, which included action on antibiotic stewardship. “On a positive note, research was published showing a reduction in prescribing of cephalosporin and quinolone antibiotics in primary and secondary care coinciding with a drop in resistance to these antibiotic classes,” said Dr Hand.

Vaccination also featured prominently following an outbreak of measles in Swansea and a national measles, mumps and rubella catch-up programme. Rotavirus vaccine was introduced to routine vaccinations and a nasal influenza vaccination for two-year-olds began in September, along with shingles vaccination for the over 70s.

It was a bad year for macrolides, said Dr Hand. “The debate continues to rage over the cardiovascular safety of both azithromycin (see research here) and clarithromycin (see research here) as well as evidence of increased risk of acute kidney injury and hypotension thought to be due to an interaction between clarithromycin and calcium channel blockers.”

Dr Hand also highlighted the withdrawal of oral ketoconazole following a reappraisal of its risk-benefit ratio and updated guidance from Public Health England which set out recommendations on the place in treatment of fidaxomicin for Clostridium difficile infections.

The dosing of nitrofurantoin in renal failure provoked controversy, said Dr Hand, with the Medicines and Healthcare products Regulatory Agency warning not to use the drug if creatinine clearance is <60ml/min.

Another notable development in the field of infectious disease was the launch of Stribild, a four-drug combination tablet licensed for HIV. It is the first single tablet regimen to contain an integrase inhibitor (elvitegravir), explained Heather Leake Date, consultant pharmacist at Brighton and Sussex University Hospitals NHS Trust. It also contains cobicistat (a CYP3A inhibitor), emtricitabine and tenofovir disoproxil.

Toby Capstick, advanced clinical pharmacist (respiratory medicine) at Leeds Teaching Hospitals NHS Trust, highlighted Voractiv (rifampicin/isoniazid/pyrazinamide/ethambutol) as an “incredibly important advance” for patients with tuberculosis. It allows patients to take fewer tablets per day. The improved simplicity over other dosing regimens aids patient education, especially for those with limited English, said Mr Capstick.

He highlighted an issue with BNF dosing recommendations. “The BNF does not advise using Voractiv in patients >70kg as this exceeds the BNF maximum dose for isoniazid and risks peripheral neuropathy. However, this dose is recommended in the summary of product characteristics and by the World Health Organization and is used widely in clinical practice,” he said.

Rheumatology: waiting for oral biologic

Tofacitinib (Xeljanz), a Janus kinase (JAK) inhibitor developed by Pfizer, offered perhaps the most exciting addition to the armoury against rheumatoid arthritis since the first tumour necrosis factor inhibitors were developed in the 1990s, said Ian Scott, rheumatology pharmacist at Peterborough City Hospital. The drug was approved in the US towards the end of 2012. “However, in early 2013 rather surprisingly and, in the eyes of many in the world of rheumatology, rather disappointingly, the European Medicines Agency refused to give it approval,” said Mr Scott. The EMA cited concerns over the medicine’s risk-benefit ratio. Pfizer is planning to resubmit data, continued Mr Scott, but no date has been set and the UK still awaits the first widely available oral biologic for rheumatoid arthritis.

On a more positive note, the first infliximab biosimilars for rheumatology Remsima (manufactured by Celltrion) and Inflectra (from Hospira) have been authorised by the EMA. “The hope is that this development will increase competition, help drive down prices and, therefore, increase the availability of the biologics in these times of austerity,” he said.

Abatacept was approved by both NICE and the Scottish Medicines Consortium. The drug offers an alternative to anti-TNFs, which remain the mainstay of biologic treatment in rheumatology, said Mr Scott, who also highlighted new guidelines from the European League Against Rheumatism, which now include combination treatment as an option for first-line therapy.

Paediatrics: codeine chaos

In paediatrics, the big story of 2013 was the MHRA advice not to use codeine in children, said Steve Tomlin, consultant pharmacist — children’s services, Evelina London Children’s Hospital. “This has caused utter chaos in the paediatric world with no other preparation being routinely used for moderate pain in children as an add on to paracetamol and ibuprofen.” Dihydrocodeine, tramadol and morphine are all being used across the UK to varying extents with all having potential problems, he added.

New commissioning structures are especially challenging for clinicians working with children, said Mr Tomlin, with much of their practice commissioned under specialist arrangements. “Cost effectiveness evidence is now required (understandably) for drugs that have a very small cohort of use. This is challenging for pharmacists and clinicians alike… . However, it serves to highlight the fact that more children need to be in trials in order to establish a far better evidence base.”

Cancer: no big hits

Transition to a single national cancer drugs fund and the move to commission all chemotherapy centrally via NHS England were perhaps the biggest developments in oncology in England. “This will hopefully have the impact of reducing postcode prescribing but initially this has highlighted differences in baseline commissioning of cancer medicines that area team cancer pharmacists are working hard to identify and resolve,” said Simon Purcell, lead haematology pharmacist, Wirral University Teaching Hospital NHS Foundation Trust. “Eventually the aim is to have nationally approved treatment algorithms and protocols for cancer treatments,” he explained.

Clinically there have been numerous developments despite there being no NICE-approved drugs for cancer indications in 2013, said Mr Purcell. “Abiraterone [launched in 2011] and enzalutamide [launched in 2013], both oral hormonal agents, in men with prostate cancer have been welcome additions in a disease that hadn’t seen much development for a number of years,” he said.
Steve Williamson, consultant cancer pharmacist, Northumbria & North Cumbria NHS Trusts, also highlighted the introduction of subcutaneous Herceptin and the MHRA safety alert on ondansetron dosing as affecting chemotherapy services. And, although there were no “big hits” in terms of new medicines, Mr Williamson noted the introduction of pertuzamab, bosutinib, pomalidomide and regorafenib (see Panel).

29 new medicines in 2013

  • Bosutinib, a protein kinase inhibitor, for chronic myelogenous leukaemia (Bosulif; Pfizer).
  • Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, for type 2 diabetes (Invokana; Janssen).
  • Colestilan granules and tablets for hyperphosphataemia in patients with chronic kidney disease (BindRen; Mitsubishi Pharma Europe).
  • Dapoxetine, a selective serotonin-reuptake inhibitor, for premature ejaculation (Priligy; Menarini).
  • Enzalutamide, an androgen receptor signalling inhibitor, for metastatic castration-resistant prostate cancer (Xtandi; Astellas).
  • Ingenol mebutate for non-hyperkeratotic, non-hypertrophic actinic keratosis in adults (Picato; Leo Pharma). 
  • Infliximab biosimilars (Remsima; Celltrion and Inflectra; Hospira) for a number of autoimmune conditions, including rheumatoid arthritis, crohn’s disease and psoriasis.
  • Insulin degludec, a once-daily basal insulin, for type 1 and type 2 diabetes (Tresiba; Novo Nordisk). 
  • Linaclotide, a guanylate cyclase C receptor agonist for moderate-to-severe irritable bowel syndrome with constipation (Constella; Almirall).
  • Lisdexamfetamine, a centrally acting sympathomimetic, for attention deficit-hyperactivity disorder (Elvanse; Shire). 
  • Lixisenatide, a glucagon-like peptide-1 agonist for type 2 diabetes (Lyxumia; Sanofi).
  • Lomitapide, a selective inhibitor of the microsomal triglyceride transfer protein for homozygous familial hypercholesterolaemia (Lojuxta; Aegerion).
  • Lubiprostone, a locally acting activator of the chloride channel CIC-2, for chronic idiopathic constipation (Amitiza; Sucampo).
  • Mirabegron, a selective agonist of the beta 3-adrenoceptor for urgency incontinence and other symptoms of overactive bladder syndrome (Betmiga; Astellas).
  • Nalmefene, a ligand of the opioid receptors to treat alcohol dependence (Selincro; Lundbeck).
  • Ocriplasmin, a recombinant truncated form of human plasmin with proteolytic activity for vitreomacular traction (Jetrea; Alcon Laboratories).
  • Pertuzumab, a recombinant humanised monoclonal antibody that blocks coupling of the human epidermal growth factor 2 receptor with other HER receptors, for HER 2-positive breast cancer (Perjeta; Roche).
  • Pixantrone, a cytotoxic alkylating agent for non-Hodgkin B-cell lymphoma (Pixuvri; CTI Life Sciences).
  • Pomalidomide, an immunomodulator for relapsed and refractory multiple myeloma (Imnovid; Celgene). 
  • Ponatinib, a tyrosine kinase inhibitor with activity against the BCR-ABL protein for certain types of chronic myeloid and acute lymphoblastic leukaemias (Iclusig; Ariad Pharma). 
  • Regorafenib, an inhibitor of multiple protein kinases for metastatic colorectal cancer (Stivarga; Bayer).
  • Relvar Ellipta, a once-daily combination inhaler (fluticasone furoate plus vilanterol, a selective long-acting beta-2 receptor agonist), for asthma or chronic obstructive pulmonary disease (GlaxoSmithKline).
  • Stribild, a four-drug combination tablet licensed for HIV, containing elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil (Gilead).
  • Tafamidis, a stabiliser of transthyretin for transthyretin amyloidosis (Vyndaqel; Pfizer).
  • Ultibro, a novel long-acting muscarinic antagonist — glycopyronnium — in combination with long-acting beta-2 agonist indacaterol for COPD (Novartis).
  • Vismodegib, a small molecule inhibitor of the hedgehog pathway for advanced skin cancer (Erivedge; Roche).
  • Voractiv (rifampicin/isoniazid/pyrazinamide/ethambutol) for Mycobacterium tuberculosis (Sandoz).
  • Zoely, a combined oral contraceptive (estradiol plus nomegestral acetate; Merck Sharp & Dohme).

Pain: frustrations with NICE

“Members of the UK Clinical Pharmacy Association pain management group have spent a year banging their collective heads against a NICE-built wall,” Lee Wilson, consultant pharmacist at Bassetlaw Hospital, Worksop, said. He highlighted a draft clinical guideline on osteoarthritis management that signals the end of paracetamol as baseline medication for thousands of sufferers (and that the Scottish Intercollegiate Guidelines Network assessed what appeared to be the same evidence and drew different conclusions). But he has not lost hope, citing NICE’s neuropathic pain guideline, issued in November, which was completely rewritten between consultation and publication.

Dermatology: facial erythema drug

Rod Tucker, a pharmacist with a special interest in dermatology, gave special mention to the launch of Picato (ingenol mebutate) for the management of actinic keratosis of the face, hands and scalp. The product needs to be used for only three days so there is likely to be better adherence than to currently available treatments such as diclofenac gel 3 per cent, which needs to be used for up to three months, he explained.

Dr Tucker also highlighted brimonidine tartrate 0.3 per cent topical gel, which was approved in the US in August as a treatment for facial erythema in rosacea. “[This] should come to the UK in the near future.” He pointed out that treatments such as topical metronidazole gel are used for papulopustular rosacea but that there are no effective permanent treatments for facial erythema.

Psychiatry: parity of esteem

There were two new drugs of note in the field of psychiatry — nalmefene and lisdexamfetamine, according to Steve Bazire, consultant pharmacist, Hellesdon Hospital, Norfolk and Suffolk NHS Foundation Trust. Nalmefene (Selincro) is used on an as needed basis to reduce alcohol intake. “Clinical commissioning groups are having difficulty understanding that reduction of alcohol intake has enormous health benefits and does not require complete abstention to obtain these health benefits,” said Professor Bazire.

Lisdexamfetamine (Elvanse) is a once-a-day dexamfetamine and seems to be effective in methylphenidate non-responders. “It is very effective and likely to become a standard treatment for attention deficit-hyperactivity disorder,” said Professor Bazire.

Cost containment measures in primary care are impacting on the clinical care of patients and contributing to the gradual loss of the pharmaceutical industry from the mental health field, argued Professor Bazire. More positively, the parity of esteem initiative (ie, looking after the physical health of people with mental health problems at the same level as people without mental health problems) has gathered pace in 2013.

In Scotland, moving to phase 2 of the Scottish Patient Safety Programme in mental health and publication of national standards for physical health monitoring with clozapine are also highlighted as significant developments. And, in Wales, implementation of “Together for mental health — a strategy for mental health and wellbeing in Wales” is helping to improve support for people with mental ill-health.

Diabetes: bolting on new therapies

The introduction of new drugs for type II diabetes continues to increase the opportunities to individualise care, but a lack of updated clinical guidelines is hampering progress, according to Victoria Ruszala, highly specialist pharmacist, North Bristol NHS Trust. She highlighted the imminent launch of the next sodium-glucose co-transporter 2 (SGL2) inhibitor to come to market — canagliflozin (Invokana) — which received its European marketing authorisation in November. It follows the first-in-class SGL2 inhibitor dapagliflozin (Forxiga), which was the subject of a NICE technology appraisal in June 2013. “NICE has said that dapagliflozin can be used second line… . But no one really knows where these therapies will fit because we don’t have an updated guideline,” explained Ms Ruszala. “NICE is helping, but bolting new therapies onto old guidelines is not ideal,” she added.

Lixisenatide (Lyxumia), the third glucagon-like peptide-1 (GLP-1) receptor agonist to come to market, is notable because of its cost, said Ms Ruszala. “It doesn’t offer any overriding benefits over the other GLP-1s but it is by far the cheapest of the three therapies,” she said. “It is once daily, like liraglutide, and can be used with insulin, like exenatide, so it has a licence that combines advantages of the other two,” she pointed out, adding that despite it being the newest GLP-1, many commissioners are using it first-line because spend on GLP-1s is so huge.

Another notable development in the diabetes field was the launch of insulin degludec (Tresiba), an ultra long-acting once-daily basal insulin for type 1 and type 2 diabetes patients. “Insulin degludec was launched into a market that is trying to minimise prescribing of long-acting insulins and is prohibitively expensive,” said Ms Ruszala. “Locally, we are using insulin degludec for type I patients with problems with nocturnal hypoglycaemia because it’s marginally cheaper than a pump,” she added.

“Diabetes in 2013 has been about trying to pull everything together,” said Ms Ruszala. “Having so many drugs makes it difficult for the prescriber to get it right.”

Conclusion

For pharmacy, 2013 brought a host of clinical developments, with a steady stream of new medicines and the continued roll out of clinical services. The Journal will continue to report similar developments in the year ahead.

Citation: The Pharmaceutical Journal URI: 11132580

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