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18th June 2021
The drugs, known as POLQ inhibitors, specifically kill cancer cells with mutations in the BRCA genes while leaving healthy cells unharmed.
And crucially, they can kill cancer cells that have become resistant to PARP inhibitors – an existing treatment for patients with BRCA mutations.
Researchers are already planning to test the new drug class in upcoming clinical trials. If the trials are successful, POLQ inhibitors could enter the clinic as a new approach to treating a range of cancers with BRCA mutations, such as breast, ovarian, pancreatic and prostate cancer.
Scientists at The Institute of Cancer Research, London, and the pharmaceutical company Artios, explored the potential of using POLQ inhibitors in treating cancer cells with defects in the BRCA genes.
Their study, published in Nature Communications, was funded by Artios, Cancer Research UK and Breast Cancer Now.
For some time now, scientists have known that genetically removing a protein known as POLQ killed cells with BRCA gene defects, although drugs that prevent POLQ from working had not been identified. In this new work, the researchers identified prototype drugs that not only stop POLQ from working, but which also kill cancer cells with BRCA gene mutations.
Both BRCA genes and POLQ are involved in repairing DNA. Cancer cells can survive without one or other of them, but if both are blocked or their genes switched off, cancer cells can no longer repair their DNA and they die.
Researchers found that when cells were treated with POLQ inhibitors, cancer cells with BRCA gene mutations were stripped of their ability to repair their DNA and died, but normal cells did not. By killing cancer cells with BRCA gene mutations, while leaving normal cells unharmed, POLQ inhibitors could offer a treatment for cancer with relatively few side effects.
Researchers also found that POLQ inhibitors work very well when used together in combination with PARP inhibitors.
The addition of POLQ inhibitors meant that PARP inhibitors were effective when used at a lower dose. And in laboratory tests in rats and in organoids – three-dimensional mini-tumours grown in the lab – POLQ inhibitors were able to shrink BRCA-mutant cancers that had stopped responding to PARP inhibitors because of a defect in a set of genes known as the ‘Shieldins’.
This suggests that POLQ inhibitors could offer an alternative treatment where PARP inhibitors are no longer working. Researchers believe that using a POLQ inhibitor in combination with a PARP inhibitor in patients with cancers that have faulty BRCA genes could prevent resistance from emerging in the first place.
Scientists at The Institute of Cancer Research (ICR), funded by Breast Cancer Now and Cancer Research UK, discovered how to genetically target PARP inhibitors against BRCA-mutant cancers and, with colleagues at The Royal Marsden NHS Foundation Trust, helped run clinical trials leading to the first PARP inhibitor being approved for use.
The next step will now be to test POLQ inhibitors in clinical trials led by Artios.
Study co-leader, Professor Chris Lord, Professor of Cancer Genomics at The Institute of Cancer Research, London, and Deputy Director of the Breast Cancer Now Toby Robins Research Centre at the ICR, said: “All cells have to be able to repair damage to their DNA to stay healthy – otherwise mutations build up and eventually kill them. We have identified a new class of precision medicine that strips cancers of their ability to repair their DNA. This new type of treatment has the potential to be effective against cancers which already have weaknesses in their ability to repair their DNA, through defects in their BRCA genes. And excitingly, the new drugs also seem to work against cancer cells that have stopped responding to an existing treatment called PARP inhibitors – potentially opening up a new way of overcoming drug resistance. I’m very keen to see how they perform in clinical trials.”
Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said: “It’s exciting that the new POLQ inhibitors should provide a different approach to treating cancers with BRCA gene defects – and particularly that this class of drugs should retain their activity in cancers that have developed resistance to PARP inhibitors. Most exciting of all is the potential of combining POLQ and PARP inhibitor drugs to prevent the evolution of BRCA-mutant cancers into more aggressive, drug-resistant forms – a major challenge that we see in the clinic.”
Study Co-Leader, Dr Graeme Smith, Chief Scientific Officer at Artios Pharma, Cambridge, said: “These exciting preclinical results provide a clear rationale for future clinical studies with a POLQ inhibitor. At Artios, we are on track to initiate our POLQ clinical programme before the year end to explore POLQ inhibition in the sensitive cancer types that this study has uncovered. Our planned POLQ inhibitor clinical studies will leverage these results, exploring combination treatment with PARP inhibitors and different types of DNA damaging agents.”
Citation
Zatreanu D et al. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat Commun 2021;12:3636
25th May 2021
Researchers say ‘stem cell memory T-cells’ appear critical in both destroying the cancer at the outset and for long term immune surveillance and exploiting this quality could improve the design and performance of CAR T therapies.
Researchers assessed the cells of patients involved in the CARPALL Phase I Study, which used a new CAR molecule known as CAT-19 developed between UCL Cancer Institute and UCL Great Ormond Street Institute of Child Health, for treatment in children with acute lymphoblastic leukaemia.
The team compared T-cells from patients who still had CAR T-cells detectable in the blood more than two years after their treatment, with individuals who had lost their cells in the one to two months post treatment.
Using a technique called ‘insertion site barcoding’, researchers were able to study the fate of different types of CAR T-cells in patients after they were given.
Corresponding author Professor Persis Amrolia, based at UCL Great Ormond Street Institute of Child Health and Consultant in Bone Marrow Transplant at GOSH, said: “Using this barcoding technique, we were able to see ‘stem cell memory T-cells’ play a central role both during the early anti-leukaemic response and in later immune surveillance, where the body recognises and destroys cancer cells.
“This suggests that this small sub-group of T-cells are critical to the long-term success of the therapy.”
Researchers say, this work indicates that the teams caring for patients could measure the types of CAR T-cells present after some someone has had their anti-leukaemia therapy, to gain an indication of whether they will be able to preserve their CAR T-cells into the future, avoiding relapse.
Professor Amrolia added: “This new insight may help us to improve our CAR T-cell therapy and work out which patients are at a higher risk of relapse and may benefit from a stem cell transplant after CAR T-cell therapy.”
Dr Biasco added: “It was extremely rewarding to see how the application of our new barcoding technology to study CAR T-cells is unveiling such important information about what happens to these cells after they are given to patients. We now plan to expand the technology we established at UCL and validate these findings in larger groups of patients.”
Co-author Dr Martin Pule said: “This research opens up new avenues to improve CAR design and manufacture, improving the performance of CAR T-cell therapy, to achieve a combination of early tumour clearance and long-term protection from relapses in patients with B cell leukaemia.”
Source: https://www.gosh.nhs.uk/news/new-insight-into-when-car-t-is-effective-against-childhood-leukaemia/
29th April 2021
The health care industry creates more than double the amount of greenhouse gas emissions than the entire aviation industry. Yet few are holding the sector accountable.
A recent webinar, “Towards a More Circular, Sustainable and Economic Health Care System in Europe,” offered an expert panel of key stakeholders, including representatives of the European Commission, European Parliament, European Committee of Regions, environmentalists, researchers, and industry to assess the health care waste problem, EU efforts to promote a circular economy, and offer a path forward for solutions.
The discussion is timely, as the EU’s Medical Device Regulation can have a profound impact on the way that hospitals across Europe can lower their carbon footprint while simultaneously reducing costs.
The following article includes edited versions of comments made by the authors at the 11 March 2020 webinar. The edits were made with permission of the authors to make the comments more suitable for printed format.
Q: Can you frame the scope of the environmental problem caused by the health sector?
A: Dorota Napierska, Chemicals Policy and Project Officer, Health Care Without Harm Europe:
If the health care sector were a country, it would be the fifth largest emitter of global emissions on the planet. The health care sector within the European Union is one of the most polluting after the US and China. Evidence shows that more than 70% of emissions are driven by the supply chain, and it is not really such a surprise if we realise how the health care is currently dependent on the use of disposables.
The production, use, and disposal of health care products is emblematic of the linear economy. Alternatives to counter these unsustainable practices will be shifting more to a circular health care economy model built on principles of resource conservation.
A change to more sustainable and very often reusable products and services brings not only environmental, but also significant financial benefits for hospitals, and medical device reprocessing and remanufacturing have proven to play an important role here.
Q: Does the EU’s MDR help to fix the problem?
A: Napierska: The real success and scaling up of reprocessing in the US started with strong regulation and strict guidelines. So, we are incredibly pleased with the adoption of the medical device regulation in Europe as it offers a path for hospitals to access environmentally preferable, more circular and lower cost reprocessed and remanufactured products.
In line with our global strategy, we believe that reprocessing and remanufacturing of medical devices can support hospitals on their way to maximise reuse, minimise waste, and save money. But this obviously needs support from national authorities, who must first make reprocessing and remanufacturing legal and possible.
Q: What does your research find regarding the environmental impact of using remanufactured single-use medical devices, compared to using a virgin or original device each time?
A: Anna Schulte, lead researcher of a detailed life cycle analysis study published recently in the journal, Sustainability, Fraunhofer Institute for Environmental Safety, and Energy Technology UMSICHT:
Medical device remanufacturing might be the most promising circular economy strategy for single-use medical devices because they cannot be easily just reused directly by hospitals and cannot simply be recycled.
Our research team proved environmental benefits associated with remanufactured electrophysiology catheters in 13 out of 16 impact categories evaluated. We found hospitals save more than 20% from the use of remanufactured EP devices compared to exclusive use of virgin devices. Global warming emissions were cut in half when using remanufactured catheters compared to the virgin product. For abiotic resource use, a saving of 28.8% was calculated.
Our study provides information for policy and other decision-makers as it shows the transformative potential from linear to circular use of catheters by applying a remanufacturing system. In a fully circular production system, the carbon footprint could be reduced about 34.5% compared to linear production.
If 750,000 electrophysiological catheters are used in Germany every year, for example, complete collection of catheters for remanufacturing would save about 450 tonnes of CO2 equivalents per-year, in contrast to linear manufacturing.
Q: What would you want Ministries of Health to know about your research?
A: Anna Schulte: A legal obligation to remanufacture medical devices with high remanufacturing potential could be a key to achieving the circular economy and lead to more sustainability in the health care system.
Circular value creation is both environmentally and economically beneficial compared to linear value creation. Remanufacturing of single-use medical devices is an excellent example because it has the potential to preserve the product at the highest value, to be circular and reduce environmental impacts compared to virgin production, and to reduce environmental impacts on a systemic level.
Q: Can you help readers to understand the EU’s new Medical Device Regulations, particularly Article 17 that govern the use single-use medical devices.
A: Erik Hansson, Deputy Head of Unit of Medical Devices and Health Technology Assessment, DG SANTE (Health and Food Safety), European Commission:
EU Member States may decide to allow reprocessing of single-use devices. If Member States permit reprocessing of single-use devices (SUDs), those devices must, like any other device, comply with the requirements of the EU Medical Device Regulation. Member States can however choose to derogate from these requirements with regard to devices that are reprocessed and used within a health institution provided the reprocessing is performed in accordance with Common Specifications adopted in August 2020.
Compliance with either of the above paths aims at ensuring that the safety and performance of the reprocessed device is equivalent to that of the original device.
Q: What are the options for EU Member State Ministries of Health and hospitals regarding the future of medical device reprocessing?
A: Erik Hansson: They could also decide whether they want to introduce even stricter conditions or requirements than what we have in the Common Specifications. So, Member States have a few options to decide what they wish to do with this new legal framework. The Member States have the obligation to notify us whether they will permit reprocessing of single-use devices, and how they want to do so – whether they wish to use the Common Specifications, whether to allow outsourcing to external reprocessors, and so on.
The Common Specifications contain requirements for organisation and risk management, for instance when contracting an external reprocessor; staff, premises, and equipment; monitoring of changes made by manufacturers; determination of the reprocessing process; technical documentation and so forth. The Common specifications also include requirements for the procedures and steps of the reprocessing cycle; the quality management system, annual audits and reporting of incidents; and traceability, for instance, tracking reprocessing cycles and keeping records.
Q: What is the Circular Economy Action Plan, and what else should health care entities know about the path toward a more circular economy?
A: Paola Migliorini, Deputy Head of Unit, DG ENV, the European Commission:
The Circular Economy Action Plan announces a set of initiatives for 2021 to ensure that all products on the EU market, including those used in the health sector, are sustainable by design, so that sustainability becomes the norm. And for that we need a product policy framework.
Many products break down too quickly, or cannot be easily reused, repaired, recycled, remanufactured, or refurbished. In health care, many are made for single use only. At least 80% of the products’ environmental impacts are determined at the design phase, so it is especially important to ensure that the design is optimal and allows for refurbishment and remanufacturing. We also need to address false green claims to ensure that there is no confusion when a product can claim to be “green”, and that there are clear lines of information for producers and consumers alike.
Currently there is no comprehensive set of requirements that ensures sustainability and the circularity in products, and we need to clearly act on that.
Under the Circular Economy Action Plan, we also want to take the lead on global efforts towards a circular economy. In February, we launched the Global Alliance on Circular Economy and Resource Efficiency to mobilise partners across the globe towards the development of a circular economy going beyond EU borders.
Q: Is the European Union ready to do the heavy lifting to create meaningful change for the future of the planet?
A: Sirpa Pietikäinen, Finnish Member of the European Parliament, representing the European People’s Party. She is a member of the Economic and Monetary Affairs Committee and a substitute member of the Environment, and the Public Health and Food Safety (ENVI) Committee:
We would need four planets’ worth of resources by 2050 if we do not make drastic changes. So, the first and most important signal from the EU Parliament is that you need to have the right ambition level.
If you do not remember anything else that I have said, please remember that by 2050, all sectors, including the health sector, would need to produce the same or better welfare, the same or better income for your company, and the same or better quality for the customers and patients than today, but with one-tenth of the resources.
We must do this to stay within planetary boundaries that are absolute and non-negotiable. All products marketed in the EU should be durable, upgradable, reusable, repairable, and then recyclable at the highest level as parts of an equipment or as materials.
Q: Do you see a connection between the COVID pandemic, climate change, and the EU’s move toward a circular economy?
A: Tjisse Stelpstra, Regional Minister, Province of Drenthe NL, Member, European Committee of Regions:
The COVID crisis is very urgent, and we must act on it without hesitation. Those working in health care know, maybe better than others, that this crisis is about health, it is about life. Let us hope it is a temporary crisis. There is no doubt that this crisis has had great effects on the world economy, and a recovery from this crisis is needed. But there is also another crisis, and it is also about health, and it is also about life, and that is the climate crisis. Where covid seems like an acute illness, the climate crisis is an insidious disease which more and more manifests itself as acute.
Q: What can be done locally and regionally to help transform to a circular economy?
A: Tjisse Stelpstra: Local and regional authorities have an important role. They can help us to not only build a circular economy, but to intensify a circular society more broadly. I think that is what we need. Let us use this reality as a great opportunity for cooperation. There will also be skepticism and ignorance, and that is why we all – especially governments – have a lot of work to do. We must convince our citizens, our companies, our industries, and our clients about the importance of this transition to a circular economy and show them it is not only making the world better environmentally, but it is also the next step to more welfare.
So, I am an optimist, I am hopeful. COVID has shown us that we are resilient – in no time, we made a change to a digital economy, so I hope that we can in no time make the change to a circular society.
Q: Tell us about the National Health System’s (UK) interest in the use of remanufactured single-use devices.
A: Alan Wain, Chief Operating Officer for NHS Supply Chain Coordination, National Health System, England:
Remanufacturing is quite sophisticated. Most of these devices cannot simply be put through a sterilizer; you have got to take them apart; you have got to reprocess them put them back together and make sure they are clinically safe to use again.
Just to put remanufacturing into context, if we examine our strategy to net-zero carbon emissions, the NHS needs to take out something like 16.5 million tonnes of carbon dioxide equivalent per year just from the supply chains.
One of the biggest contributors [of emissions in the NHS] is down our supply chains, our suppliers’ own carbon footprints, and that that accounts for about 4.5 million tonnes. Of that, 157,000 tonnes could be removed by using remanufactured or reprocessed devices, and another 202,000 tonnes from reused and refurbished devices.
To achieve our objectives, the NHS needs to be working with our strategic suppliers to achieve a major, seismic shift in carbon footprint reduction. We have been working with Vanguard as a strategic supplier, and we are doing a lot of engagement around the NHS for uptake of remanufactured devices.
It starts with the collection of the original device and sending it off to Vanguard’s remanufacturing unit to remanufacture them for reuse by the NHS. The next step is to get a bigger uptake of these devices within the NHS. There is, now, a small amount of uptake, but the ambition is to get to a much larger footprint wherein 40–50% of the devices being used are remanufactured.
Remanufacturing is an important part of our strategy – though it is not the only part of our strategy – and we are looking forward to working with our strategic suppliers to drive down the carbon footprint across the whole NHS.
Q: What is at stake with the upcoming implementation date for the EU’s Medical Device Regulation?
A: Dan Vukelich, President and CEO, Association of Medical Device Reprocessors:
The provisions in Article 17 of the MDR represent one of the greatest opportunities for hospitals in Europe to lower costs, reduce waste, and reduce greenhouse gas emissions.
Unfortunately, medical device remanufacturing is currently not available in most EU Member States. So AMDR is urging Member States to act quickly to promote this circular economy solution for health. The practice has grown substantially in many countries. In 2019, our members served over 7600 hospitals and surgical centres worldwide, enabling them to participate in a circular economy for hundreds of types of medical devices labelled for single use.
As confirmed by the science presented, devices that are remanufactured have a substantially lower carbon footprint and use less resources.
Additionally, remanufacturing eliminated nearly 7 million kilos of medical waste from landfills and incinerators. This environmental contribution comes at no extra cost. In fact, medical remanufacturing has enabled health care systems to save over 446 million euros in 2019. This will potentially change when the MDR comes into force.
Q: What EU Member States have opted-in to the MDR so far?
A: Dan Vukelich: So far, the Netherlands and Belgium have allowed remanufactured products and notified the commission. I expect Germany soon, and I would hope before the May deadline that we are going to have some others that will report favourably towards allowing these products.
So, I hope each of us, from our individual standpoints, will encourage the European Commission and the European Parliament to continue down that path of promoting a circular economy and including health care within their scope. As we have learned from Anna Schulte’s research and from the example that Alan Wain and others have brought up, reprocessed and remanufactured medical devices are an immediate solution.
22nd February 2021
The report – ‘Heart Failure: A call to action’ – makes ten recommendations, including an increase in the number of specialist heart failure nurses – from one to four for every 100,000 people – to meet the growing demand from a rising number of heart failure cases.
Current recommendations, originally published in 2002, suggest one heart failure specialist nurse (HFSN) per 100,000 population, a target that is currently met by 84% of heart failure services. There is evidence that services are overstretched however, with only one in three HFSNs managing to see more than 65% of patients within two weeks of discharge. Despite an increased prevalence of heart disease, and considerable advances in therapies, the recommendation has remained unchanged.
The report points to the growing prevalence of heart failure. Before the COVID-19 pandemic, around 200,000 new cases were being diagnosed every year, with over 900,000 people in the UK affected. The report warns that COVID-19 could result in a significant increase in the disease, highlighting concerns that two-thirds of patients with heart failure are not seeking care during the pandemic as well as significant delays in treatment.
Louise Clayton, Advanced Nurse Practitioner and Co-Chair of the Alliance for Heart Failure said, “Early input by heart failure specialists, including nurses, has been shown to improve patient outcomes and reduce mortality. Around eight in ten patients admitted with heart failure are now identified and seen by specialists during their admission, with around half seen by a specialist nurse.
“There is huge variation between hospitals though. In 2018, only six out of ten achieved specialist review rates of over 80%. This postcode lottery for patients must be eradicated.
“The shortage of specialist heart failure nurses was an issue long before the Covid-19 pandemic, but its impact means this needs to be addressed more urgently than ever.”
The Alliance for Heart Failure report’s ten recommendations, which build on those made by the All-Party Parliamentary Group on heart disease in 2016, also include:
The Alliance for Heart Failure report ‘Heart Failure: A call to action’ was published on 22 February 2021.
30th November 2020
The precise reasons why obesity enhances the risk of a more severe outcome in COVID-19 remains unclear. Nevertheless, obesity is associated with several other additional risk factors such as cardiometabolic, thromboembolic and pulmonary disease and it is likely that it is this combination of factors that raises the overall risk. For example, obese patients have higher levels of pro-inflammatory cytokines and oxidative stress which can impact on both the innate and adaptive immune system, all of which may contribute to a worse prognosis. Metabolic surgery in obese patients leads to improvements in cardiovascular risk factors and the amelioration of the pro-inflammatory state linked with obesity.
In a retrospective study of patients testing positive for COVID-19, researchers from the Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Ohio, US, set out to examine the relationship between prior metabolic surgery and the severity of COVID-19 in severely obese patients. A total of 33 individuals who had prior metabolic surgery (the surgical group) were identified and were matched 1:10 to non-surgical patients to create a cohort with a body mass index (BMI) greater than or equal to 40kg/m2 at the time of testing. The pre-specified endpoints examined were: admission to intensive care, need for mechanical ventilation, dialysis during their hospital stay and mortality.
Findings
Data on a total of 363 patients, including the 33 who had prior metabolic surgery were available for analysis. The surgical group had a mean age of 46.1 years (78% female) with a mean BMI of 37.2±7.1 compared to 46.7± 6.4kg/m2 in the control group. A subsequent univariate analysis showed that 18.2% of those in the surgery group and 42.1% in the control group were admitted to hospital because of their infection with COVID-19. A prior history of metabolic surgery was associated with a statistically lower odds of being admitted to hospital (odds ratio = 0.31, 95% CI 0.11 – 0.88, p = 0.028). Furthermore, none of the surgical group patients experienced one of the four pre-specified endpoints. In contrast, 13% of those in the control group were admitted to intensive care, 6.7% required mechanical ventilation, 1.5% dialysis and 2.4% died. The authors suggested that prior metabolic surgery was associated with a lower severity of COVID-19 infection but recognised that these observations were based on a small sample size and they were also unable to account for their findings.
They concluded by calling for more research to understand the mechanistic role of both obesity and intentional weight loss on COVID-19 infection.
Reference
Aminian A et al. Association of prior metabolic and bariatric surgery with severity of coronavirus disease 2019 (COVID-19) in patients with obesity. Surg Obes Relat Dis 2020. https://doi.org/10.1016/j.soard.2020.10.026
Mutations in RNA viruses can arise through copying errors, genomic variability when two viral lineages infect the same host and finally because of host-induced RNA-editing systems. Any mutations that have a deleterious effect on the virus will be quickly removed from the population although those which provide an advantage are retained. Researchers have been closely monitoring mutations in COVID-19 because any such changes could affect the ability of the virus to replicate and may even increase transmissibility.
A study by a team from the Genetics Institute, University college, London, have been cataloguing mutations in the virus and assessing whether or not these mutations have the potential to increase the transmissibility of COVID-19. They assessed the difference in transmissibility by estimating the relative fractions of descendants produced by a particular genotype. The rational for this approach was based on the notion that the worldwide distribution of the virus is likely to introduce a high level of genetic diversity which might increase the potential for greater transmissibility.
Findings
The researchers analysed 46,723 SARS-CoV-2 genome assemblies although none of these were found to deviate by more than 32 single-nucleotide polymorphisms from the reference genome, Wuhan-Hi-1. The team estimated a mutation rate of 9.8 x 10-4 substitutions per site per year and this finding is in line with work on other coronaviruses. The team also explored viral homoplasies, i.e., nucleotide changes that have not arisen through simple inheritance and identified a total of 185 such cases. However, none of these were associated with an increased risk of viral transmission or, interestingly, a reduced risk of transmission and all were effectively neutral changes.
Commenting on these findings, the authors noted that COVID-19 has only acquired moderate generic diversity since its jump to humans and concluded that there is currently no a priori reason to suspect that any lineage might arise with an increased potential for transmissibility.
Reference
Van Dorp Let al. No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2 Nat Commun 2020;11:5986.
27th November 2020
While the precise cause of CSU remains unclear, contemporary European guidelines advocate the use of second-generation antihistamines as a first-line treatment for the condition. Although these drugs can be effective, for patients in which symptom control remains inadequate, the guidance recommends up-dosing to four times the recommended dose as a second-line treatment option.
This latter commendation is based on expert opinion and for this study, a team from the Allergology Department, Complexo Hospital, A Coruna, Spain, set out to review the available evidence to support this approach. They included studies published in English or Spanish with patients at least 12 years of age with CSU on regular (as opposed to “on-demand”) therapy with a second-generation antihistamine. Other inclusion criteria were that the study should have a single antihistamine (rather than a combination), a placebo arm and using the drug at a higher than recommended dosage.
Findings
In total and after removal of duplicates and exclusions, only 14 articles were analysed in detail including 20 to 439 patients. Six studies focused on fexofenadine (up-dosing to 720 mg), 2 on cetirizine, levocetirizine, rupatadine, desloratadine and 1 trial with either ebastine or bilastine. Furthermore, only 5 of these trials were placebo controlled and all studies lasted between 2 and 8 weeks except for one fexofenadine trial which lasted 16 weeks. A higher dose of fexofenadine produced a dose-dependent significant response and controlled CSU in the majority of patients. Commenting on their findings, the authors noted that of the 14 trials, only 6 were of high quality and that the high level of heterogeneity in sample size, design, duration etc, which made it very difficult to make comparisons. Interestingly, they also note that despite current guideline recommendations, most studies did not find a significant impact on symptom control from up-dosing.
The authors concluded that while up-dosing appears both effective and safe, there is a lack of evidence to support this approach and called for further studies to validate the recommendations in guidelines.
Reference
Iriarte SP T et al. Up-dosing antihistamines inn chronic spontaneous urticaria: efficacy and safety. A systematic review of the literature. J Investig Allergol Clin Immunol 2020 doi: 10.18176/jiaci.0649
24th November 2020
Guidance on the use of statins as a means of reducing this risk recommends that any decisions are made jointly by patients and clinicians, especially given the wide range of cardiovascular risk factors, comorbidity burden and life expectancy of patients within this age range. While the benefits of statin therapy are well established, what remains unclear is the time-frame over which these benefits occur. In other words, how long is the “time to benefit” (TTB) from statins.
In an analysis, researchers from the Division of Geriatrics and Gerontology, University of California, US, conducted a meta-analysis of the major randomised clinical trials to determine the TTB, which served as the primary outcome and which they defined as the time from starting a statin to the first MACE. The team only included trials which had more than 1000 participants, aged at least 55 years and older. Given that the focus was primary prevention, researchers also limited the search to those trials in which less than 15% of participants had pre-existing cardiovascular disease.
Findings
A search of all the major databases, identified 8 randomised trials including 65,383 patients (66.3% male) and with less than 10% of participants having existing cardiovascular disease. The analysis showed how the benefit of statin therapy increased with the duration of the study so that, for example, after 1 year, 0.3 MACEs were prevented for every 100 people treated with statins and this increased to 2.5 MACEs after 5 years. They calculated that 2.5 years were required to prevent 1 MACE for every 100 patients given statins. Thus statin treatment was only likely to benefit patients aged 50 to 75 years where they had a life expectancy of at least 2.5 years. Interestingly, only one statin trial found that therapy reduced overall mortality.
The authors concluded that their results reinforce the importance of individualised statin treatment-related decision making.
Reference
Yourman LC et al. Evaluation of time to benefit of statins for primary prevention of cardiovascular events in adults aged 50 to 75 years. A Meta-analysis. JAMA Intern Med 2020 doi:10.1001/jamainternmed.2020.6084
20th November 2020
Oral iron is always oxidised to the Fe3+ state, irrespective of how it is taken and requires an acidic environment for adequate absorption. Vitamin C creates a more acidic environment and can prevent the oxidation of iron to the ferric form. However, whether the common practice of advising that vitamin C is taken alongside iron supplements to enhance iron absorption is beneficial has never been tested.
As a result, for this study a team from the Department of Haematology, Huashan Hospital, Shanghai, China, undertook a randomised, open-label trial in adult patients with newly diagnosed iron-deficiency anaemia (IDA). Participants were given 100mg oral iron tablets plus 200mg of vitamin C or 100 mg of iron alone every 8 hours for a total of 3 months and the authors assessed treatment compliance by determining the number of iron and vitamin tablets returned at the end of the study. Included patients had a haemoglobin level less than 13g/dl for men or less than 12g/dl for women. Although treatment continued for 3 months, the primary outcome measure, the change from baseline in haemoglobin levels, was assessed after two weeks. Secondary outcomes included the increase in serum ferritin after 8 weeks and the haemoglobin level after 4 and 8 weeks.
Findings
A total of 440 patients with a mean age of 38.3 years (96.8% women) were randomised and treatment compliance was 98.2%. The mean baseline haemoglobin level was 8.76g/dl in both groups and serum ferritin, 5.89 in the vitamin C group and 6.34 in the iron only group. After two weeks, the change from baseline in haemoglobin levels was 2.00g/dl in the vitamin C group and 1.84g/dl in the iron only group which was not significant. Similarly, the mean change in serum ferritin levels were 35.75ng/ml vs 34.48ng/ml (vitamin C vs iron only). Furthermore, there were no differences in haemoglobin levels after 2, 4, 6 or 8 weeks. The authors concluded that it is unnecessary to add in vitamin C to the iron regime for patients with IDA.
Reference
Li N et al. The efficacy and safety of vitamin D for iron supplementation in adult patients with iron deficiency anaemia: A randomised clinical trial. JAMA Network Open 2020;3(11):e2023644. doi:10.1001/jamanetworkopen.2020.23644 (R
Thus any intervention that is able to reduce disability by reducing a subsequent ischaemic stroke is a major objective of immediate therapy. Although the use of aspirin in combination with clopidogrel has been shown to reduce the risk of further stroke and myocardial infarction, to date, evidence for a beneficial effect from adding ticagrelor to aspirin in terms of a reduction in the burden of disability after a stroke is lacking.
In an analysis, researchers from the Department of Neurology and Stroke Center, University of Paris, France, sought to examine whether combing both drugs reduced the 30-day risk of disabling stroke or death. Disability was measured using the modified Rankin Scale (mRS) which ranges from 0 to 6, in which 0-1 represents no disability, 2-5 increasing disability and 6, death. Patients were enrolled if they were 40 years of age and older, with a non-cardioembolic acute ischaemic stroke and a stroke scale score of 5 or less (higher scores indicate more severe stroke). They were randomised to ticagrelor or matching placebo 1:1 and a loading dose of 180mg was given as soon as possible after randomisation, followed by a daily dose of 180mg (90mg twice daily). In addition, all patients received 300 to 325 mg of aspirin on the first day, followed by 75 to 100mg until day 30. The main outcome measure was the time to the occurrence of disabling stroke or death within 30 days, measured by the mRS scale.
Findings
A total of 11,016 patients with a mean age of 68.1 years (42.6% female) were included in the study. A primary end point with a mRS > 1 at day 30 (that is. disabling stroke or death) occurred in 221 (4.0%) of patients taking ticagrelor and in 260 (4.7%) of those taking placebo. This provided a number needed to treat of 133. In other words, treating 133 patients with ticagrelor and aspirin for 30 days, avoided 1 disabling stroke or death at day 30. Furthermore, disability burden (based on the mRS scale) was reduced by 23%.
Reference
Amarenco P et al. Ticagrelor added to aspirin in acute ischemic stroke
or transient ischemic attack in prevention of disabling stroke: A randomized clinical trial. JAMA Neurol doi:10.1001/jamaneurol.2020.4396
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