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1st March 2023
Rucaparib improves progression-free survival in metastatic, castration-resistant prostate cancer with BRAC alteration compared to usual care.
Rucaparib in men with metastatic, castration-resistant prostate cancer and BRAC alteration improved progression-free survival compared to physician’s choice of treatment according to the findings of a randomised trial by the TRITON3 investigators.
The five-year survival of men diagnosed with metastatic prostate cancer has been estimated to be around 28%. Moreover, the presence of inherited mutations in DNA-repair genes such as BRCA2, increase the risk of the cancer being lethal with one analysis finding that such mutations were detected in nearly 12% of metastatic prostate cancers.
In fact, the presence of BRAC 1 and 2 mutations are associated with poor survival outcomes in men with prostate cancer.
The enzyme poly(ADP-ribose) polymerase facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Furthermore, use of PARP inhibitors to selectively kill a tumour, represents a new concept in cancer treatment.
In a phase 2 trial (TRITON2), the use of oral rucaparib, which is a PARP inhibitor, showed that the drug had anti-tumour activity in men with metastatic, castration-resistant prostate cancer and a deleterious BRAC alteration.
In the current study, researchers sought to be build on the success of TRITON2. They undertook a phase 3 trial in men with metastatic, castration-resistant prostate cancer and a BRCA1, BRCA2, or ataxia telangiectasia mutated (ATM) alteration, whose disease had progressed after use of a second-generation androgen-receptor pathway inhibitor.
Participants were randomised 2:1 to oral rucaparib (600 mg twice daily) or a physician’s choice control which was docetaxel or abiraterone acetate or enzalutamide.
The primary outcome as the median duration of imaging-based progression-free survival according to independent review.
A total of 405 men with a median age of 70.5 years were randomised to rucaparib (270) or control. In the rucaparib arm, 201 patients had a BRAC alteration.
After 62 months, the median duration of progression-free survival in those with a BRAC alteration was 11.2 months compared to 6.4 months in the control arm (Hazard ratio, HR = 0.50, 95% CI 0.36 – 0.69, p < 0.001).
Similarly, among the intention-to-treat group, survival was also significantly longer (HR = 0.61, 95% CI 0.47 – 0.80, p < 0.001). However, in an exploratory analysis, the median duration of progression-free survival in the ATM subgroup was not significantly lower (HR = 0.95, 95% CI 0.59 – 1.52).
Citation
Fizazi K et al. Rucaparib or Physician’s Choice in Metastatic Prostate Cancer. N Eng J Med 2023.
Aspirin use for the prevention of myocardial infarction (MI) appears to be reduced by concomitant statin use in patients without atherosclerotic cardiovascular disease (ASCVD) without affecting the risk of a major bleed according to a meta-analysis by US researchers.
In 2019, US guidance suggested that aspirin should be used infrequently in the routine primary prevention of ASCVD because of lack of net benefit. More recently, the US Preventative Services Task Force has endorsed these earlier recommendations for primary prevention in adults aged between 40 and 59 with a 10% or higher, 10-year risk of CVD. While historically, aspirin was considered to reduce the risk of an MI, in the context of use with other strategies such as statins, one analysis concluded that the effect of aspirin on myocardial infarction risk was significantly attenuated, whereas its major bleeding and haemorrhagic stroke complications were retained.
For the current meta-analysis, researchers wanted to examine the impact on aspirin use with and without statins, specifically in those without ASCVD but at different levels of risk. The team included a range of risk levels from very low (< 5%) through to very high (> 30%). They included trials where patients were prescribed aspirin and followed for at least 12 months and the team determined the absolute risks for cardiovascular outcomes, major bleeding and mortality over 5 years.
Aspirin use with and without statins
In a total of 16 trials with 171,215 patients with a median age of 64 years (46% women), the use of aspirin alone was associated with a 15% lower risk of a myocardial infarction (risk ratio, RR = 0.85, 95% CI 0.77 – 0.95) although the drug did not reduce mortality. However, the drug lead to a higher risk of major bleeding (RR = 1.48, 95% CI 1.32 – 1.66, p < 0.001).
When considering the absolute benefits, the researched calculated that aspirin monotherapy in patients with a very low ASCVD risk, was likely to lead to 3 fewer myocardial infarctions (MIs) per 10,000 patients but 21 more major bleeds. In contrast, when taken in conjunction with a statin, there would be only 1 less MI but 20 more major bleeds. At the other extreme of ASCVD risk (i.e., > 30%), monotherapy might lead to 49 fewer MIs (but 98 major bleeds) but in combination with a statin, there would be 37 fewer MI’s but 94 major bleeds.
The authors concluded that among adults who did not have ASCVD, statin use with aspirin, appeared to attenuate to some extent aspirin’s clinical benefit but without influencing the bleeding risk, suggesting that the risk of a major bleed from taking aspirin exceeded its benefits across all levels of ASCVD risk.
Citation
Khan SU et al. Aspirin With or Without Statin in Individuals Without Atherosclerotic Cardiovascular Disease Across Risk Categories. JACC Adv 2023
A study of men with prostate cancer has revealed how just over half had three or more poorly controlled cardiovascular risk factors.
In men with prostate cancer, an international research group has found that just over half had three or more cardiovascular risk factors which are poorly controlled, highlighting a gap in care that requires attention.
It is recognised that men with prostate cancer (PC) have an elevated cardiovascular risk, with one study of nearly 2,500 male cancer patients, finding that two-thirds were deemed to be at high risk.
Other research has revealed that cardiovascular causes of death can be greater than those of the cancer itself. For instance, a study of 752,092 men with PC identified that while 17% died because of their cancer, 83% died of other causes, of which, 23% were cardiac-related.
Despite evidence that men with PC have a higher risk of cardiovascular-related death, which particular risk factors are present and how well these are controlled is unclear.
In the current study, researchers used data from the RADICAL-PC trial, a longitudinal prospective cohort study of men with PC.
Information of demographics and clinical factors were collected from participant’s medical records although individuals also completed several lifestyle questionnaires and were assessed for frailty.
Poor risk factor control for cardiovascular disease was defined in terms of low-density lipoprotein levels, physical activity, blood pressure control and a waist: hip ratio > 0.90.
A total of 2,811 men with a mean age of 68.3 years were included in the study and of whom, 91% had non-metastatic PC, with just over a third (38%) in receipt of androgen deprivation therapy.
In addition, 23% of participants had pre-existing cardiovascular disease and virtually all (98%) had at least one poorly controlled cardiovascular risk factor. In fact, 51% of men had > 3 risk factors that were poorly controlled.
The researchers found that men with > 3 poorly controlled risk factors were generally older, had advanced cancer and were receiving androgen deprivation therapy.
In multivariable analysis, there were four factors linked to having > 3 poorly controlled risk factors.
Not taking a statin (odds ratio, OR = 2.55, 95% CI 2.00 – 3.26), physical frailty (OR = 2.37), the need for blood pressure medication (OR = 2.36) and finally increasing age (OR per 10-year increase = 1.34).
The authors concluded that poor cardiovascular risk factor control in men with prostate cancer is common and requires improved interventions to target the problem.
Citation
Klimis H et al. The burden of uncontrolled cardiovascular risk factors in men with prostate cancer. A RADICAL-PC analysis. J Am Coll Cardiol CardioOnc 2023.
Increases in the level of N-terminal B-type natriuretic peptide (NT-proBNP) over time are associated with a higher risk of incident heart failure and death among those initially without the disease according to the findings of a study by US researchers.
NT-proBNP levels serve as an important biomarker for patients with chronic heart failure. In fact, higher levels of the protein upon admission to hospital with COVID-19, have also been associated with an increased mortality risk and other complications in patients with and without heart failure. However, in many studies, NT-proBNP has been assessed at a single time-point and in the current work, researchers looked at changes in the biomarker over time and whether this might be prognostic for the development of heart failure among those who were initially free of the disease.
The team used data from the Atherosclerosis in the Communities (ARIC) study and included participants who had measurements of the biomarker at year 2 and 6 (i.e., 4 years apart) but had not been diagnosed with heart failure. The primary exposure variable was the change in NT-proBNP between visits 2 and 4, categorised as either <125 pg/mL or ≥125 pg/mL and the primary outcome measures were set as incident heart failure (HF) hospitalisation and all-cause mortality.
NT-proBNP and risk of heart failure
Data were available for 9,776 individuals (mean age = 57.1 years, 56.5% female) and who were included in the analysis.
Individuals with NT-proBNP levels of 125 pg/mL or higher at both visits had a significantly higher risk of incident HF compared to those with levels below this threshold (adjusted Hazard Ratio, aHR = 2.40, 95% CI 2.00 – 2.88). Similarly, there was an elevated risk of mortality (aHR = 1.68, 95% CI 1.47 – 1.91). Interestingly, those with NT-proBNP levels of 125 pg/mL or higher at visit 2 but which was lower at visit 4, still had a higher risk of HF although the result was not significant (HR = 1.01, 95% 0.71 – 1.43) when compared to those who levels were below the threshold at both visits. There was also a significant increase in HF and mortality risk based on the percent change in the biomarker per 1 standard deviation increase. There were also significant associations with cardiovascular risk factors such as systolic blood pressure, body mass index, triglyceride and low-density lipoprotein cholesterol and the change in NT-proBNP.
The authors concluded that the changes in NT-proBNP over time, reflected a dynamic change in the risk of HF events and death among those without prevalent clinical HF. They added that serial measurements of NT-proBNP could be use to improve risk stratification of patients pre-heart failure.
Citation
Jia X et al. Association of Long-term Change in N-Terminal Pro-B-Type Natriuretic Peptide With Incident Heart Failure and Death. JAMA Cardiol 2023
28th February 2023
Researchers from Washington university in the US, performed a systematic review and meta-analysis finding that the protection afforded by a prior COVID-19 infection was high against re-infection from most pre-omicron variants and remained high against severe disease for all variants and was comparable to the protection from a two-dose vaccination with mRNA vaccines.
To date, several studies have suggested that a previous infection with COVID-19 offers some degree of protection against re-infection. However, studies have included different time periods as well as COVID-19 variants yet there are no analyses that have provided an overview of how the level of protection against re-infection varies over time and in relation to the different variants.
In the current analysis, the US researchers extracted data from studies through to September 2022 that examined the reduction in risk of developing COVID-19 in those with a prior COVID-19 infection compared to those without a previous infection. The data were then analysed to show the effectiveness of a prior infection against several outcomes including the risk of re-infection, symptomatic disease and severe disease based on the variant and time since infection.
Prior COVID-19 infection and re-infection outcomes
A total of 65 studies were included in the analysis from 19 different countries.
The pooled protection against re-infection varied depending on the variant ranging from 82% against delta to 90% against alpha. In contrast, the pooled protection against re-infection with omicron BA.1 was 45.3%. The protection against symptomatic disease was broadly similar, e.g. 85% for delta and 87.2% against alpha and only 44% against omicron BA.1.
The protection against severe infection (i.e., hospitalisation or death) was high for delta (97.2%), slightly lower against alpha (79.6%) but actually also high against omicron BA.1 (81.9%).
The pooled protection against ancestral, alpha and delta variants was initially high at 85.2% after 4 weeks but reduced to 78.6% at 40 weeks. In contrast, protection against re-infection from omicron BA.1 rapidly declined to 36.1% at 40 weeks.
The authors concluded that protection against re-infection was high against most variants pre omicron BA.1 adding that this level of protection was at least equivalent, if not greater than that provided by two-dose mRNA vaccines, which has also been observed in a previous study.
Citation
COVID-19 Forecasting team. Past SARS-CoV-2 infection protection against re-infection: a systematic review and meta-analysis. Lancet 2023
Lagevrio was refused a marketing authorisation by the European Medicines Agency on the 23rd February 2023, for the treatment of adults with COVID-19. However, the manufacturer, Merck Sharp & Dohme B.V., may ask the EMA to re-examine its opinion within 15 days.
Data on lagevrio had initially revealed how treatment with the drug treatment led to a reduction in the risk of hospitalisation or death among unvaccinated individuals with at least one risk factor for more severe disease. However, with the introduction of widespread COVID-19 vaccination, the question of whether the drug would still offer benefit to at-risk and vaccinated patients, remained unanswered. Nevertheless, while there was some preliminary data which suggested that the drug retained anti-viral activity against several COVID-19 variants, even among those who had been vaccinated, more definitive data were required.
The PANORAMIC trial was designed to examine if the addition of lagevrio to usual care could reduce hospital admission and COVID-10-related mortality among patients who had been vaccinated against the virus. PANORAMIC was a huge, randomised trial, recruiting over 26,000 patients and assigning nearly 13,000 to lagevrio. The results clearly showed that lagevrio failed to reduce the frequency of COVID associated hospitalisations or deaths in high-risk, vaccinated individuals. In fact, the authors of the PANORAMIC trial went as far as to say that the observed avoidance of both hospitalisation and mortality due to COVID-19 were largely as a result of extensive vaccination.
In a letter explaining the decision, the EMA noted that after an evaluation of the data provided by the manufacturer, it was concluded that clinical benefits of the drug among patients who are not receiving supplemental oxygen but still at risk of developing severe COVID-19, could not be demonstrated. In fact, the EMA stated that ‘based on the totality of the data, it was not possible to conclude that Lagevrio can reduce the risk. of hospitalisation or death or shorten the duration of illness or time to recovery in adults at risk of severe disease.’ Adding that ‘it was not possible to identify a specific group of patients in whom a clinically relevant benefit of Lagevrio could be demonstrated.’
27th February 2023
The Medicines and Healthcare Products Regulatory Agency said it had initiated a review after regulators in France alerted the European Medicines Agency (EMA) about a small number of cases.
EMA officials first announced they were looking into the issue on 10 February 2023 following concerns about posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) related to use of the decongestant medicines.
Both conditions can lead to reduced blood supply to the brain and may cause major and life-threatening complications, including seizures, the EMA said.
There had been a small number of reported cases of PRES and RCVS associated with pseudoephedrine-containing medicines and a committee would look at the evidence to decide whether the marketing authorisation in the EU should be maintained, varied, suspended or withdrawn.
The MHRA stressed that the side effects that had been reported with use of the medicines were extremely rare.
The products, which include Sudafed, Actifed and Neurofen Cold and Flu, already include warnings about the rare side effects as well as more common ones such as headache and dizziness.
Officials said they had received two Yellow Card reports on this issue including one case of PRES where the person recovered and one for RCVS where the outcome was reported as unknown.
A spokesman said: ‘We keep the safety of all medicines under close review to ensure that the benefits outweigh any risks – the safety of the public is our top priority.
‘We are reviewing the available evidence regarding the use of medicines containing pseudoephedrine and the risk of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS), which have been very rarely reported with these medicines. We will provide any further advice as appropriate.
‘We would also like to remind patients and parents/carers to report any suspected side effects to our Yellow Card scheme.
‘If you have any concerns about your medicine, please seek advice from a healthcare professional.’
This article first appeared in our sister publication Pulse
In an appraisal consultation document from NICE, rimegepant is not being recommended within its marketing authorisation, for the acute treatment of migraine with or without aura in adults, or for the prevention of episodic migraine in adults, who experience at least 4 attacks per month.
Rimegepant belongs to a class of drugs referred to as ‘gepants’ which are calcitonin gene-related peptide receptor antagonists. Calcitonin gene-related peptide has been associated with sensitisation and pain generation but also plays a role in vasodilatation. In a recent phase 2/3 trial, oral rimegepant, when taken every other day, was found to be effective as a preventive treatment of migraine, with its tolerability similar to placebo.
It is proposed by the manufacturer that rimegepant is used for acute migraine treatment in patients who have failed to respond to two or more triptans. However, in its consultation document, while accepting that the drug is likely to reduce pain at 2 hours post-dose more than placebo, NICE added that the evidence submitted by the manufacturer, for patients who have not responded to two triptans, is uncertain and hence requires more evidence.
Moreover, while it also reduces monthly migraine days, NICE argued that there is an absence of comparative long-term evidence to support this view. As a result, the organisation believes that this clinical uncertainty affects the certainty of the cost-effectiveness estimate and which is likely to be above what NICE considers to be an acceptable use of NHS resources.
In response to the consultation, the Migraine trust has expressed concern, stating that ‘a significant proportion of those seeking help from The Migraine Trust have an inadequate response, or contraindication to the best current acute treatment triptans, or have medication overuse headache as a result of inadequate care and treatment of their migraine.’
The statement added that ‘we believe that Rimegepant is an important opportunity to help those who have medication overuse headache and prevent others from developing it.’ These concern arose following a 2019 survey of 1,800 migraine sufferers undertaken by the trust, which found that migraine treatments caused medication overuse headache in a third of respondents.
Chief executive of the migraine trust, Rob Music said that ‘we are very disappointed by this decision and urge those affected by migraine, and particularly those without an effective treatment for migraine and who have experienced medication overuse headache, to respond to NICE’s consultation and let it know how much this new treatment option [rimegepant] is needed.’
24th February 2023
According to a press release from the manufacturer Apellis Pharmaceuticals, syfovre (pegcetacoplan), is to become the first FDA approved therapy for geographic atrophy secondary to age-related macular degeneration which is a leading cause of blindness.
Geographic atrophy (GA) represents an advanced form of age-related macular degeneration and which leads to progressive and irreversible loss of vision. Age-related macular degeneration is a common condition with one US analysis suggesting an annual incidence of 3.5 per 1,000 individuals, around 293,000 new cases per year in those 50 years of age and older.
Globally, the condition is estimated to affect some 5 million people and the median time to the development of central GA following any GA diagnosis is 2.5 years, with an average visual acuity decrease of 22 letters after 5 years.
The complement system is a component of the immune system that is central to the detection and destruction of invading pathogens and consists of three pathways. Moreover, dysregulation of this system is thought to be implicated in the development of age-related macular degeneration.
Syfovre phase 3 clinical studies
The approval of syfovre was based on the data from two trials, OAKS and DERBY, both of which were randomised, sham trials of 24 months duration and where syfovre (15 mg/0.1ml) was administered either monthly or every other month.
The results showed that in OAKS, monthly syfovre treatment reduced the rate of GA growth by 22% and by 18% when used every other month. Similarly, data from DERBY observed a 18 and 17% reduction in GA growth rate for monthly and alternate monthly injections respectively. Further details on the product can be found in the full prescribing information sheet.
According to the press release, syfovre is currently under review by the European Medicines Agency with a decision expected in early 2024.
Women who experience pregnancy hypertensive disorders such as preeclampsia have a higher risk of developing cardiovascular disorders in the future according to the findings of a Mendelian randomisation analysis by UK and Dutch researchers.
Hypertensive disorders during pregnancy affect 8% to 10% of all pregnant women and can lead to serious complications including mortality. In fact, one systematic analysis revealed how 14% of maternal deaths were due to hypertensive disorders. Moreover, observational evidence suggests that having a pregnancy-related hypertensive disorder increases the risk of cardiovascular events in later life. Nevertheless, observational data cannot be used to determine a causal relationship due to potential confounding. However, a better study design that can determine whether such a relationship is causal is the use of Mendelian randomisation (MR). This approach uses the genetic risk of disease as a proxy for the disease itself and can be used to mitigate the effect of confounding, as the MR estimate can be used to interpret the effect of the exposure, in this case pregnancy-related hypertensive diseases, on the outcome of interest (cardiovascular disease).
In the current study, researchers used estimates of genetic association obtained from genome-wide association data, to examine the association between gestational hypertension and preeclampsia and the risk of subsequently developing coronary artery disease, ischaemic stroke, heart failure and atrial fibrillation. The team also employed mediation analysis based on multivariable MR, to consider the impact of potential mediators e.g., body mass index, systolic blood pressure etc, on any identified associations.
Pregnancy hypertensive disorders and future cardiovascular risk
For any genetically predicted hypertensive disorder, there was an elevated risk of developing coronary artery disease (Odds ratio, OR = 1.24, 95% CI 1.08 – 1.43, p = 0.02). The risk was also elevated when considering gestational hypertension (OR = 1.08, p = 0.04), preeclampsia or eclampsia (OR = 1.06, p = 0.03) and ischaemic stroke (OR = 1.27, P < 0.001). However, the risks were non-significant for both gestational hypertension and preeclampsia and there were also non-significant for both heart failure and atrial fibrillation.
In the mediation analysis, there was a partial attenuation of the overall risk for CAD after adjusting for systolic blood pressure (adjusted OR = 1.10 vs 1.24) and the presence of type 2 diabetes (adjusted OR = 1.16 vs 1.24).
The authors concluded that given their findings, the presence of pregnancy-related hypertensive disorders should be considered as risk factors for cardiovascular disease.
Citation
Rayes B et al. Association of Hypertensive Disorders of Pregnancy With Future Cardiovascular Disease. JAMA Netw Open. 2023
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