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21st December 2022
Data presented at the 64th American Society of Haematology (ASH) conference in New Orleans, showed that elranatamab is efficacious and has a manageable safety profile in patients with relapsed or refractory multiple myeloma (RRMM).
Multiple myeloma (MM) is a clonal plasma cell proliferative disorder characterised by the abnormal increase of monoclonal immunoglobulins and which if left unchecked, can ultimately lead to specific end-organ damage. It is an uncommon cancer, with the global, age-standardised rate incidence estimated to be 1·78 per 100 000 people but with a mortality rate of 1·14 (95% UI 1·07-1·21) per 100 000 people in 2020. Most patients present with symptoms related to organ involvement, including hypercalcaemia, renal insufficiency, anaemia, and bone lesions (known as calcium, renal failure, anaemia, and bone lesions [CRAB] symptoms). In contrast, a minority of patients are asymptomatic but are identified through abnormal blood and/or urine tests.
At the ASH conference, data were presented for elranatamab, which is a bispecific antibody that targets expression of B-cell maturation antigen (BCMA) and CD3 on T-cells, activates and redirects the T-cell mediated immune response against MM. The findings come from the MagnetisMM-1 trial designed to assess the safety and tolerability at increasing dose levels of elranatamab in patients with relapse/ refractory multiple myeloma in order to determine the maximum tolerated dose and select the recommended Phase 2 dose. Within the trial, elranatamab was administered subcutaneously at doses from 80 to 1000µg/kg either weekly or every 2 weeks.
Elranatamab clinical response
A total of 55 patients with a median age of 64 years and of whom, 27% were Black/African American or Asian, received elranatamab at a dose ≥215μg/kg. The median number of prior regimens was 5 (range 2-14) with 91% being triple-class refractory, 69% of whom had prior stem cell transplantation, 29% had a high cytogenetic risk and 24% received prior BCMA-targeted therapy.
After a median follow-up of 12.0 months and including only those with an International Myeloma Working Group (IMWC) confirmed responses, the objective response rate (ORR) was 64% (95% CI 50 – 75%) and with 56% of participants achieving very good partial response (VGPR) or better and 38% achieving complete response (CR) or better.
Among 35 responders, the probability of being event-free at 12 months was 59% (95% CI 39-74%) and the Kaplan-Meier estimate for the median duration of response was 17.1 months (95% CI 10.6 – not estimable). Elranatamab induced durable clinical and molecular responses and 100% (12/12) of evaluable patients with confirmed CR or better achieved minimal residual disease (MRD) negativity at a sensitivity of 1×10-5 including 2 participants with MRD negativity and ongoing stringent complete response beyond 2 years.
The most common treatment-emergent adverse effects included the cytokine release syndrome in 67% of participants but this was limited to grade 1 (33%) or grade 2 (33%) severity with no grade 3 or higher responses.
The authors concluded that elranatamab induced durable clinical and molecular responses for patients with relapsed or refractory MM, with an ORR of 64% and more than half of these patients (38%) achieving CR or better, and 100% of evaluable patients able to achieve MRD negativity. They added that these results support further development of elranatamab for patients with MM.
Citation
Raje N et al. Elranatamab, a BCMA Targeted T-Cell Engaging Bispecific Antibody, Induces Durable Clinical and Molecular Responses for Patients with Relapsed or Refractory Multiple Myeloma. Abstract No 158, ASH 2022
Moderna, in conjunction with Merck, has found that the investigational, personalised cancer vaccine, mRNA-4157/V940, combined with pembrolizumab, was more effective than pembrolizumab alone at reducing the risk of death or recurrence in patients with stage III/IV melanoma following complete resection.
Melanoma of the skin is the 17th most common cancer worldwide with 324,635 new cases and 57,043 deaths in 2020. Although patients diagnosed at Stage 1 have an excellent prognosis, this drops significantly as the disease spreads. For example, regional melanoma (stage 3) has a 63.6% 5-year survival and this drops to 22.5% for those with stage 4 (metastatic) disease.
Pembrolizumab (brand name Keytruda) is a human, programmed death receptor-1 (PD-1) therapy and works to enable T cells to invade melanoma anywhere in the body. The drug is already licensed as monotherapy for the treatment of adults and adolescents aged 12 years and older with advanced (unresectable or metastatic) melanoma.
The KEYNOTE-942 study is an on-going phase 2b randomised study designed to assess whether postoperative adjuvant therapy with mRNA-4157/V940 and pembrolizumab improves recurrence free survival (RFS) compared to pembrolizumab alone in participants with complete resection of cutaneous melanoma and a high risk of recurrence. mRNA-4157/V940 is designed to stimulate an immune response by generating a specific T cell action based on the unique mutational signature of a patient’s tumour.
In the trial, and following complete surgical resection, patients were randomised to receive mRNA-4157/V940 (nine total doses of mRNA-4157) and pembrolizumab 200 mg every three weeks up to 18 cycles (for approximately one year) or pembrolizumab alone. The primary endpoint of the trial was recurrence-free survival whereas secondary endpoints include distant metastasis-free survival and safety.
mRNA-4157/V940 preliminary efficacy data
The results are for 157 patients with stage III/IV melanoma. The data show adjuvant mRNA-4157/V940 and pembrolizumab reduced the risk of recurrence or death by 44% (hazard ratio, HR = 0.56, 95% CI 0.31 – 1.08, one-sided p = 0.0266) compared with pembrolizumab alone.
In terms of safety, serious treatment-related adverse events occurred in 14.4% of patients who received the combination treatment compared to 10% with pembrolizumab alone.
Stéphane Bancel, Moderna’s Chief Executive Officer, said: ‘Today’s results are highly encouraging for the field of cancer treatment. mRNA has been transformative for COVID-19, and now, for the first time ever, we have demonstrated the potential for mRNA to have an impact on outcomes in a randomised clinical trial in melanoma.’
The companies plan to discuss the results with regulatory authorities and initiate a Phase 3 study in melanoma patients in 2023.
According the findings of a systematic review and meta-analysis undertaken by Korean researchers and presented at the American Society of Haematology conference, 2022, tafasitamab showed a trend for best efficacy among failed autologous stem cell transplantation (ASCT) or ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients.
Diffuse large B cell lymphoma is the most common lymphoma, accounting for about 25% to 30% of all the non-Hodgkin lymphomas and which presents as a rapidly growing mass or enlarging lymph nodes in a nodal or extra-nodal site. Non-Hodgkin lymphomas account for about 80% of all lymphomas and while there are more than 30 subtypes, the common ones are diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Although 5-year survival rates range from 60% to 70%, up to 50% of patients become refractory to or relapse after treatment. Moreover, outcomes for refractory or relapsed patients are poor, with one study of 861 patients, 636 of whom had refractory disease, finding that the median overall survival was 6.3 months and that only 20% of patients were alive at 2 years. For patients with relapsed/refractory disease, there are several combination chemotherapy regimens available including tafasitamab-cxix, polatuzumab vedotin-piiq, bendamustine as well as CAR T cell therapies. Nevertheless, the most effective treatment remains to be determined.
In the present study, the Korean researchers performed a systematic review and meta‐analysis to identify prospective phase II or III clinical studies evaluating the efficacy of treatments for ASCT-failed or ineligible relapse/refractory DLBCL patients. They used random effects models to estimate one-year progression-free survival rate, complete remission rate, and subgroup differences. In addition, meta-regression models were performed with adjustment for relevant covariates, particularly the median number of previous lines of systemic therapy and CAR T cell therapy was used as a reference treatment in the meta-regression analysis.
Tafasitamab and one-year progression-free survival
The researchers identified 56 cohorts in 50 studies with 3,544 relapsed/refractory DLBCL patients. For the analysis, treatment regimens were divided into nine groups: CAR T cell therapy, chemotherapy, lenalidomide-based therapy, ibrutinib-based therapy, tafasitamab-based therapy, polatuzumab plus bendamustine and rituximab (pola-BR), loncastuximab, selinexor, and others.
The pooled one-year progression-free survival rate was 0.40 (95% CI 0.35 – 0.46) for CAR T cell therapy, 0.23 (95% CI 0.16 – 0.30) for chemotherapy, 0.28 (95% CI 0.19 – 0.37) for lenalidomide and 0.46 (95% CI 0.37 – 0.56) for tafasitamab.
Although CAR T cell treatment was significantly better than many of the others, in fact, loncastuximab, pola-BR, and tafasitamab were all shown to have no significant difference in efficacy to CAR T cell therapy after adjustment for the median number of prior lines of treatment in the meta-regression analysis.
The authors concluded that tafasitamab showed a trend of best efficacy and that CAR T cell therapy was no more effective than tafasitamab, loncastuximab or pola-BR. However, because of the high level of heterogeneity, the authors called for randomised controlled trials to confirm their findings.
Citation
Kim J et al. Comparison of Several Salvage Treatments of Relapsed/Refractory Large B-Cell Lymphoma Including Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review and Meta‐Analysis. Abstract 2986 ASH conference 2022
Glucagon-like peptide-1 (GLP1) receptor agonists provide the same degree of glycaemic control as that achieved following bariatric surgery but the latter still confers the highest reductions in weight according to a systematic review and meta-analysis by researchers from Ontario, Canada.
According to the World Health Organisation, more than 1 billion people worldwide are obese and the organisation has estimated that by 2025, approximately 167 million people – adults and children – will become less healthy because they are overweight or obese. One particular disease linked to obesity is type 2 diabetes.
Moreover, lifestyle interventions such as a decreased caloric intake and increased physical activity in patients with type 2 diabetes, has been shown to result in a weight loss of 8.6%. An alternative approach to lifestyle modification, in those with type 2 diabetes is bariatric surgery, with 5-year outcome data showing that when combined with medical therapy, surgery was more effective than intensive medical therapy alone at decreasing, or in some cases resolving, hyperglycaemia. GLP1 agonists such as semaglutide have been shown to provide a sustained and clinically relevant reduction in body weight.
Nevertheless, there is a lack of evidence directly comparing GLP1 agonists with bariatric surgery in terms of weight loss and glycaemic control. Consequently, for the present study, the Canadian researchers undertook a systematic review and meta-analysis to directly compare the weight-lowering and glycaemic effect of GLP1 agonists and bariatric surgery in adults with obesity, defined as body mass index (BMI) > 25 kg/m2 in both randomised trial and observational cohort studies.
The primary outcome was the absolute change in weight from baseline to the end of the study period, whereas secondary outcomes were absolute change in body mass index and glycated haemoglobin (HbA1c) in patients with concurrent type 2 diabetes.
GLP1 agonists weight loss and glycaemic control outcomes
A total of 6 studies, both randomised trials and observational studies, with 332 participants were included in the final analysis.
The pooled treatment effect for the change in weight from baseline between bariatric surgery and GLP1 agonists was −22.68 kg (95% CI −31.41 to −13.96) in randomised trials and −25.11 kg (95% CI −40.61 to −9.60) among the observational studies and in both types of study, these results favoured bariatric surgery.
In terms of body mass index, as with overall weight, there was a higher effect from bariatric surgery compared with the GLP1 agonists across all studies. However, the change in glycaemic control (based on HbA1c) levels, based only on randomise trial evidence (due to missing data with the observational studies), was a nonsignificant difference of −1.28% (95% CI −1.94% to −0.61%).
This finding, the authors suggested, indicated that the improvement in glycaemic control achieved from GLP1 agonists may be comparable with metabolic surgery for patients with type 2 diabetes and obesity.
They concluded that among adults with obesity, bariatric surgery, while still providing the greatest level of weight loss conferred similar effects on glycaemic control to GLP1 agonists.
Citation
Sarma S et al. Weight loss between glucagon-like peptide-1 receptor agonists and bariatric surgery in adults with obesity: A systematic review and meta-analysis. Obesity (Silver Spring) 2022.
In a head-to-head trial, zanubrutinib provided superior progression-free survival compared to ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, according the the results to a study by team of international researchers.
Chronic lymphocytic leukaemia (CLL) is an adult leukaemia characterised by abnormal accumulation of immunologically incompetent lymphocytes in blood, bone marrow, lymph nodes, and spleen and accounts for 25–30% of all leukaemias in Western Countries, leading to over 100,000 incident cases with more than 40,000 global deaths reported in 2019. In contrast, small lymphocytic lymphoma (SLL) comprises approximately 7% of newly-diagnosed cases of non-Hodgkin’s lymphomas although often at the time of diagnosis, most patients present with advanced-stage disease including generalised lymphadenopathy, hepatosplenomegaly and bone marrow involvement.
Bruton’s tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signalling and which is critical for proliferation and survival of leukaemia cells in many B cell malignancies. Moreover, oral irreversible BTK inhibitors such as ibrutinib, have been shown to provide a high response rates in patients with relapsed/refractory CLL and mantle-cell lymphoma. Zanubrutinib is a highly selective Bruton tyrosine kinase inhibitor that is well tolerated and demonstrated activity in patients with relapsed/refractory mantle cell lymphoma. In a multinational, phase 3, randomised trial, the same international research group, performed a head-to-head comparison of zanubrutinib with ibrutinib as treatment for relapsed or refractory CLL or small lymphocytic lymphoma (SLL). At a pre-specified interim analysis, the results showed that zanubrutinib provided a significantly higher overall response rate, lower atrial fibrillation rate and improved progression-free survival compared to ibrutinib after 15 months. In the current study, researchers provided an update on progression-free survival after nearly 30 months. In the trial, participants with relapsed or refractory CLL or SLL and who had received at least one previous course of therapy, were randomised 1:1 receive zanubrutinib at a dose of 160 mg twice daily or ibrutinib at a dose of 420 mg daily until the occurrence of disease progression or unacceptable toxic effects.
Zanubrutinib and progression-free survival
A total of 652 patients with a median age of 67 years (68.3% male) were included and randomised to zanubrutinib (327) or ibrutinib and followed for a median of 29.6 months.
In terms of progression-free survival, zanubrutinib was superior for disease progression or death with 87 vs. 118 occurrences of disease progression or death (hazard ratio, HR = 0.65, 95% CI 0.49 – 0.86, p = 0.002). At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group.
Furthermore, the safety profile of zanubrutinib was better than ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death.
The authors concluded that among those with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib and that the drug was associated with fewer cardiac adverse events.
Citation
Brown JR et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med 2022
Cannabidiol (CBD) oil given to patients with advanced cancer receiving palliative care provided no additional benefit to that care according to the findings of a randomised trial by Australian researchers.
Although there have been several advances in medical care, a proportion of patients with advanced cancer still experience substantial symptom distress. The use of palliative care seeks to improve both symptom control and quality of life but despite this, some symptoms can be difficult to control, necessitating more effective medications. Both cannabis and cannabinoid drugs containing cannabidiol, are widely used to treat disease or alleviate symptoms. However, a 2015 meta-analysis concluded that whilst there was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity, there was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy. In a feasibility study, Australian researchers examined the use of global symptom burden measures to assess the response to medicinal cannabis with both cannabidiol and tetrahydrocannabinol. They concluded that doses of both cannabidiol and tetrahydrocannabinol were generally well tolerated and that the outcome measure of total symptom distress was promising as a measure of overall symptom benefit.
Based on the these early and promising findings, the same group undertook a randomised trial to determine whether cannabidiol oil could improve symptom distress in patients with advanced cancer receiving palliative care. They included adult participants with advanced cancer and symptom distress which was measured using the Edmonton Symptom Assessment Scale [ESAS]. Participants received titrated CBD oil 100 mg/mL, 0.5 mL once daily to 2 mL three times a day, or matched placebo for 28 days. The ESAS scale is designed to rate the intensity of nine common symptoms experienced by cancer patients, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being and shortness of breath. For the trial participants, the inclusion criterion was an ESAS score greater than or equal to 10/90. The primary outcome was set as the total ESAS symptom distress score (TSDS) at day 14, with a response defined as a decrease greater than or equal to, 6 at day 14.
Cannabidiol oil and symptom distress
A total of 58 patients receiving CBD and 63 placebo, reached the primary analysis point (i.e., day 14) and the median dose of participant-selected CBD was 400 mg per day.
The unadjusted change in TSDS from baseline -6.2 for the placebo group and -3.0 for those receiving CBD and this difference was non-significant (p = 0.24). Equally, there was no significant difference in proportion of responders (placebo = 58.7% and CBD = 44.8% p = 0.13).
In fact, during the study, all components of the ESAS improved (that is, reduced) over time with no difference between the placebo and CBD arms. In addition, there was no detectable effect of CBD on quality of life, depression, or anxiety. Overall, most participants reported feeling better (53% CBD vs 65% placebo) or much better (70% CBD and 64% placebo) by day 14.
The authors concluded that CBD oil did not add value to the reduction in symptom distress provided by specialist palliative care alone.
Citation
Hardy J et al. Phase IIb Randomized, Placebo-Controlled, Dose-Escalating, Double-Blind Study of Cannabidiol Oil for the Relief of Symptoms in Advanced Cancer (MedCan1-CBD). J Clin Oncol 2022
20th December 2022
Use of aprocitentan in patients with treatment-resistant hypertension provides a superior reduction in systolic blood pressure compared to placebo with a sustained action four weeks after discontinuation according to the results of a randomised, double-blind trial by Australian and US researchers.
The incidence of hypertension, which is a major factor for cardiovascular disease, appears to be on the increase. In a 2021 study, the number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 million women and 317 million men in 1990 to 626 and 652 million respectively in 2019. Resistant hypertension has been defined as above-goal elevated blood pressure in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium channel blocker, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and a diuretic. In fact, the prevalence of resistant hypertension has been found present in 10.3% of the general population. One potential pharmacological target for patients with resistant hypertension is blockage of endothelin, which is a powerful vasoconstrictor peptide derived from the endothelium. Initial studies with a selective endothelin type A antagonist, darusentan, in patients with resistant hypertension, showed that the drug provided additional reduction in blood pressure in patients who had not attained their treatment goals with three or more antihypertensive drugs. Early studies with aprocitentan, which is an orally active, dual endothelin receptor antagonist, found that it was well tolerated and that there were no clinically significant findings for any safety variable. Moreover, in a dose ranging study in patients with essential hypertension, compared to lisinopril 20 mg, aprocitentan 10, 25, and 50 mg decreased sitting systolic/diastolic unattended automated office blood pressure. This led the authors to conclude that their findings support further investigation of aprocitentan at doses of 10 to 25 mg in hypertension.
In the current study, researchers undertook the PRECISION trial, that recruited patients with a sitting systolic blood pressure of 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts. The first was a 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio. In part 2, all patients received aprocitentan 25 mg and in the final part, which was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary endpoint was the change in unattended office systolic blood pressure from baseline to week 4 and the secondary endpoint, the blood pressure changes from withdrawal baseline to week 40.
Aprocitentan and treatment outcomes
A total of 730 participants with a mean age of 61.7 years (59.3% male) were included in part 1 and of whom, 577 (94%) completed part 3 of the study. At screening, between 62 and 65% of participants were receiving > 4 antihypertensive agents.
The change in systolic blood pressure at 4 weeks was -15·3 mm Hg for aprocitentan 12·5 mg, -15·2 mm Hg for aprocitentan 25 mg, and -11·5 mm Hg for placebo. In both cases, the difference compared to placebo was statistically significant (p = 0.0042 and 0.0046) for the 12.5 and 25 mg doses respectively. There was also a significant reduction in diastolic blood pressure (-3.9 mmHg and – 4.5 mmHg) for the 12.5 and 25 mg doses.
After 4 weeks of withdrawal, the office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 – 7·9, p < 0·0001).
In terms of adverse effects, the most frequent were mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12·5 mg, 25 mg, and placebo, during the initial 4-week double-blind phase, leading to treatment discontinuation in seven aprocitentan patients.
The authors concluded that for patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40.
Citation
Schlaich MP et al. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet 2022
Use of a purified eicosapentaenoic acid (EPA) formulation in patients with coronary artery disease prescribed statins, reduced the incidence of adverse cardiovascular outcomes such as myocardial infarction and stroke compared to a control group not taking the formulation, according to the findings of a study by Japanese researchers presented at the American Heart Association (AHA) conference in Chicago.
Statin therapy leads to a reduction of cardiovascular events in both primary and secondary prevention. Since no treatment is fully effective in all patients, one therapy that has attracted interest over many years has been the omega-3 polyunsaturated fatty acids (PUFAs). However, recent studies with PUFAs have been contradictory with one trial in patients with elevated triglyceride levels despite the use of statins, finding that the risk of ischaemic events, was significantly lower among those who received 2 g of icosapent ethyl twice daily (a highly purified EPA) than among those who received placebo. In contrast, a second trial, again in statin-treated patients, concluded that the addition of omega-3 to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events.
Due to these contrary findings, The Japanese team sought greater clarity of the role of PUFAs and presented data from the Randomized Trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy – statin and EPA (RESPECT-EPA) trial. Participants, all of whom had chronic coronary artery disease and were treated with statin therapy, were randomised to highly purified EPA (1800 mg/day) or control groups (i.e., no EPA therapy) and the primary endpoint was cardiovascular death, non-fatal myocardial infarction, non-fatal ischaemic stroke, unstable angina pectoris, and clinically indicated coronary revascularisation. A further inclusion criterion was a low EPA/arachidonic acid ratio (< 0.40).
Highly purified EPA and cardiovascular outcomes
A total of 2506 participants with a mean age of 68 years (17% female), of whom 45% had diabetes, were included and randomised to the highly purified EPA (icosapent ethyl 1800 mg daily, n = 1,249) or control and followed for 5 years.
The primary outcome occurred in 10.9% of the icosapent ethyl group vs. 14.9% of the control group (p = 0.055). For the secondary outcomes, sudden cardiac death, myocardial infarction, unstable angina, or coronary revascularisation, this occurred in 8.0% in the icosapent ethyl group vs. 11.3% in the control group (p = 0.031). However, there was a higher incidence of gastrointestinal disorders in the icosapent ethyl group (3.4% vs 1.2%, p < 0.001).
The authors concluded that among Japanese patients with chronic coronary artery disease and treated with statin therapy, icosapent ethyl may be associated with a reduction in adverse cardiovascular outcomes.
Citation
Bavry AA et al. Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy–Statin and Eicosapentaenoic Acid – RESPECT-EPA. Presented at the American Heart Association Scientific Sessions, Chicago, IL, November 6, 2022
PCSK9 inhibitor persistence in patients with familial hypercholesterolaemia (FH) appears to be very high over time and associated with achievement of low-density lipoprotein cholesterol (LDL-C) goals as well as an improvement in quality-of-life according to an analysis of clinical practice data by Spanish researchers.
Familial hypercholesterolaemia is associated with premature atherosclerotic cardiovascular diseases and is inherited as an autosomal dominant trait. Due to the presence of dysfunctional low-density lipoprotein (LDL) receptors because of a genetic mutation, serum LDL-C levels are considerably increased from birth. Within the general population, a recent meta-analysis of 62 studies estimated a pooled FH prevalence of 1:311. According to the 2019 ESC/EAS Guidelines for the management of dyslipidaemias, patients with FH are categorised as being at very high risk of cardiovascular disease. Consequently, the guidelines recommend a therapeutic regimen that achieves ≥50% LDL-C reduction from baseline and an LDL-C goal of <1.4 mmol/L (<55 mg/dL). In addition, studies have suggested that the use of a PCSK9 inhibitor led to a 54.9% mean reduction in LDL-C from baseline in those with severe heterozygous FH. Nevertheless, information on the persistence or adherence to treatment with PCSK9 inhibitors in patients with FH, which is required to reduce the burden of atherosclerotic disease over time, is lacking. In the current study, researchers set out to examine the persistence to treatment, efficacy and impact on quality of life of PCSK9 inhibitor use in FH patients within a real-world clinical setting.
The researchers used data from the Spanish Familial Hypercholesterolaemia cohort study (SAFEHEART), an open, prospective study in genetically defined FH patients in Spain. They included patients on stable lipid-lowering therapy and who were managed and with a PCSK9 inhibitor (PCSK9i), although the choice of which agent was decided by the treating clinician. For the study, researchers measured persistence as the % of patients staying on a PCS9Ki at the end of each year of follow-up and quality of life was assessed with the EuroQol 5D.
PCSK9 inhibitors persistence and effectiveness over time
A total of 696 patients with a median age of 56.4 years (46% female) were included and followed for a median of 3.7 years with the median baseline LDL-C being 3.8 mmol/L. Background lipid lowering therapy was a statin and ezetimibe in 74.6% of cases and statin monotherapy in 17.5% of cases.
During the follow-up, persistence with PCSK9i was 96.1% for the whole period. At the last follow-up visit, the median LDL-C had reduced by 58%. In addition, at the last follow-up visit, 48% of patients had achieved the 2019 ESC/EAS LDL-C goal.
There were also improvements in quality of life after the first year and this remained stable over time.
The authors concluded that there was long-term persistence with PCSK9i in patients with FH patients within a clinical practice setting and that use of a PCSK9i vastly increased attainment of LDL-C goals.
Citation
Alonso R et al. Persistence with long-term PCSK9 inhibitors treatment and its effectiveness in Familial Hypercholesterolemia: data from the SAFEHEART study. Eur J Prev Cardiol 2022
Widespread state medical marijuana legalisation in the US is associated with a lower rate of opioid dispensing and pain-related hospital events among some adults receiving treatment for newly diagnosed cancer according to an analysis by US researchers.
Pain is an extremely common cancer symptom with a 2022 meta-analysis of 12 studies (10 with breast cancer and 2 lung cancer) patients, finding a pooled pain prevalence rate of 40%. Although paracetamol and non-steroidal anti-inflammatory drugs are universally accepted as part of the treatment of cancer pain at any stage of the WHO analgesic ladder, strong opioids are the mainstay of analgesic therapy in treating moderate to severe cancer-related pain. Nevertheless, with tightened regulations leading to a decrease in opioid prescribing across the United States, evidence points to a decline in opioid use among end-of-life care in those with cancer although there has been a rise in pain-related emergency department visits, suggesting that end of life cancer pain management may be worsening. Although medical marijuana has been studied and found to be efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids, a 2016 review suggested that while marijuana may have the potential for refractory cancer pain, much of the data are based on animal data, small trials, or are outdated.
With the potential to help patients with cancer pain, in the current study, US researchers set out to assess the associations between medical marijuana legalisation and opioid-related and pain-related outcomes for adult patients receiving cancer treatment. The team used data from national commercial claims between 2012 to 2017. The researchers assessed several measures including the proportion of patients having 1 or more days of opioids and 1 or more pain-related emergency department visits or hospital events, during the 6 months after a new cancer diagnosis.
Medical marijuana and opiate use
A total of 38,189 patients with newly diagnosed breast cancer, 12,816 with colorectal cancer (55.4% male) and 7,190 (51.1% female) with lung cancer were included in the analysis.
Medical marijuana legalisation was associated with a reduction in the rate of 1 or more opioid days from 90.1% to 84.4% (difference = 5.6, 95% CI 2.2 – 9.0, p = 0.01) among breast cancer patients. For colorectal cancer patients, there was also a reduction, this time from 89.4% to 84.4% (difference = 4.9, 95% CI 0.5 – 9.4, p = 0.03). Finally, opioid use reduced from 31.5% to 22.1% (difference = 9.4, 95% CI 0.8 – 17.9, p = 0.03) among patients with lung cancer with recent opioids.
Medical marijuana legalisation was also associated with a reduction in the rate of 1 or more pain-related hospital events from 19.3% to 13.0% (difference = 6.3, 95% CI 0.70 – 12.0, p = 0.03) among patients with lung cancer with recent opioids. However, the difference for the other two forms of cancer was not significant.
The authors concluded that medical marijuana legalisation was associated with a lower rate of opioid dispensing and pain-related hospital events among some adults receiving treatment for newly diagnosed cancer.
Citation
Bao Y et al. Medical Marijuana Legalization and Opioid- and Pain-Related Outcomes Among Patients Newly Diagnosed With Cancer Receiving Anticancer Treatment. JAMA Oncol 2022
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