Australian access to FDA-approved breakthrough therapy designation medicines: a 10-year review.

Background: Regulatory pathways adopted by the United States Food Drug and Administration (FDA) and Australian Therapeutic Goods Administration (TGA) enable expedited approval of medicines that are thought to offer significant clinical advantage over existing options for severe diseases. Objectives: To review Australian accessibility to medicines approved through the FDA breakthrough therapy designation (BTD) process including timelines and approvals by the TGA and Pharmaceutical Benefits Advisory Committee (PBAC) for listing on the Pharmaceutical Benefits Scheme (PBS). Methods: Retrospective review of published reports from the FDA, TGA, PBAC and PBS for BTDs from 1 January 2013-31 August 2023. Uniform data about BTD and milestone dates were collected. Analysis included all BTDs approved by FDA until 31-August-2022. Main outcome measures: Rates of approval by TGA and PBAC, and PBS-listing; and median (interquartile range, IQR) time from FDA submission to FDA approval, and FDA approval to TGA approval, PBAC approval and PBS listing for cancer and non-cancer medicines. Results: Of 237 BTDs across 156 medicines, 68% were approved by the TGA, and 37% were listed on the PBS. Median (IQR) time from FDA submission to FDA approval was shorter for cancer compared to non-cancer; 179 days (140-210) vs 232 days (181-245), p < 0.02. Time from FDA approval to PBS listing was similar for cancer and non-cancer; median 744 days (IQR, 549-1136) and 733 days (IQR 440-960) respectively, with improvements for cancer BTDs noted for 2018-2022 compared to 2013-2017; 566 days (IQR 319-831) vs 880 days (IQR 620-1362), p < 0.02 but not for non-cancer BTDs. Conclusion: BTD medicines are accessible in Australia approximately 2 years after FDA approval. Since 2018, time to PBS listing for cancer therapies improved, mirroring shorter FDA approval times for this category. Further understanding of clinical studies and context by therapeutic area may improve timely and safe access to life-saving medicines.

URINE TOXICOLOGY PROFILES OF EMERGENCY DEPARTMENT PATIENTS WITH UNTREATED OPIOID USE DISORDER: A MULTI-SITE VIEW.

BACKGROUND: Opioid overdose deaths in 2021 were the highest ever, driven by fentanyl and polysubstance use. OBJECTIVE: The aim of the study was to characterize drug use, assessed by urine drug screens (UDSs), in patients with untreated opioid use disorder (OUD) presenting to 28 emergency departments (EDs) nationally and by region. METHODS: We analyzed UDSs from patients enrolled in the CTN-0099 ED-INNOVATION (Emergency Department-Initiated Buprenorphine Validation) trial between July 12, 2020 and March 9, 2022. Participants were adult ED patients with OUD not engaged in addiction treatment with a UDS positive for an opioid, but negative for methadone. Sites were divided into "East" and "West" regions. RESULTS: A UDS was available for all 925 enrolled participants, 543 from East and 382 from West. Fentanyl was in 702 specimens (76%) (n = 485 [89%] East vs. n = 217 [57%] West; p < 0.01) and was the only opioid in 269 (29%). After fentanyl, the most common opioids were morphine (presumably heroin; n = 411 [44%]; n = 192 [35%] East vs. n = 219 [57%] West; p < 0.01) and buprenorphine (n = 329 [36%]; n = 186 [35%] East vs. n = 143 [37%] West; p = 0.32). The most common drugs found with opioids were stimulants (n = 545 [59%]), tetrahydrocannabinol (n = 417 [45%]), and benzodiazepines (n = 151 [16%]). Amphetamine-type stimulants were more common in West (n = 209 [55%] vs. East (n = 125 [23%]). Cocaine was more common in East (n = 223 [41%]) vs. West (n = 82 [21%]). The presence of multiple drugs was common (n = 759 [82%]). CONCLUSIONS: Most participants had UDS specimens containing multiple substances; a high proportion had fentanyl, stimulants, and buprenorphine. Regional differences were noted. Given the increased risk of death with fentanyl and polysubstance use, ED providers should be providing risk reduction counseling, treatment, and referral.

Cardiovascular Disease in Patients With Breast Cancer Treated in the Modern Era.

AIMS: With improving cancer survivorship, cardiovascular disease (CVD) has become a leading cause of death in breast cancer (BC) survivors. At present, there is no prospectively validated, contemporary risk assessment tool specific to this patient cohort. Accordingly, we sought to investigate long-term cardiovascular outcomes in early-stage BC patients utilising a well characterised database at a quaternary referral centre. With the assembly of this cohort, we have derived a BC cardiovascular risk index titled the 'CRIB (Cardiovascular Risk Index in Breast Cancer)' to estimate the risk of a major adverse cardiovascular event (MACE) in women undergoing treatment for BC. METHODS: A retrospective cohort study was conducted examining all female patients aged ≥18 years of age who underwent treatment for early-stage BC at a cancer centre in Melbourne, Australia, between 2009 and 2019. The primary aim of this study was to assess causes and predictors of MACE. RESULTS: A total of 1,173 women with early-stage BC were included. During a median follow-up of 4.4 (1.8-6.7) years, 80 (6.8%) women experienced a MACE. These women were more likely to be older, with a high burden of cardiovascular risk factors and were more likely to have a history of established coronary artery disease (CAD) (p≤0.001 for all). A CRIB ≥3 (2 points: renal impairment, 1 point: age ≥65 years, body mass index [BMI]>27, diabetes, hypertension, history of smoking) demonstrated moderate discrimination (c-statistic 0.75) with appropriate calibration. A CRIB ≥3, which represented 23.9% of our cohort, was associated with a high risk of MACE (odds ratio [OR] 17.85, 95% confidence interval [CI] 6.36-50.05; p<0.001). A total of 138 (11.8%) women died during the study period. Mortality was significantly higher in patients who experienced a MACE (HR 2.72, 95%CI 1.75-4.23; p<0.001). CONCLUSION: Cardiovascular risk stratification at the time of BC diagnosis using the novel CRIB may help guide surveillance and the use of cardioprotective therapies as well as identify those who require long-term cardiac follow-up.

A Driver in Health Outcomes: Developing Discrete Categories of Transportation Insecurity.

Research suggests that transportation is an important social determinant of health, because the ability to get around is consequential for accessing health care and nutritious food and for making social connections. We used an inductive mixed-methods approach and a quantitative k-means clustering approach to identify 5 categories of transportation insecurity using the validated 16-item Transportation Security Index. The resulting 5-category measure distinguished among respondents with qualitatively different experiences of transportation insecurity. Analyzing data from 2018 that were representative of the US adult population aged 25 years or older, we demonstrated a nonparametric association between transportation insecurity and 2 different health measures (self-rated health and depressive symptoms). There was a threshold relationship between self-rated health and any level of transportation insecurity. High transportation insecurity had a very strong relationship with depressive symptoms. The categorical Transportation Security Index will be useful for clinicians who wish to screen for transportation-related barriers to health care. It will also facilitate research investigating the influence of transportation insecurity on health outcomes and provide the basis for interventions designed to address health disparities.

MRI findings in atraumatic shoulder pain-patterns of disease correlated with age and gender.

BACKGROUND: The rotator cuff is a group of muscles and tendons which support the shoulder joint. Rotator cuff disease is a frequent cause of morbidity in adulthood. AIMS: The aims of his study are to determine the prevalence and patterns of rotator cuff derangement in symptomatic patients using MRI and to attempt to correlate identified patterns of disease with age and gender METHODS: Five hundred ninety-seven patients attending for MRI of the shoulder with atraumatic shoulder pain were included for study. Patients' age and gender was recorded. Record was made of the presence or absence of rotator cuff derangement and of degenerative change in the AC and glenohumeral joints. Correlation was made between age and gender. RESULTS: There were 358 males (60%) and 239 females (40%) with a mean age of 49.4 ± 17.1 years. Subacromial bursitis was identified in 517 patients. A normal supraspinatus tendon was identified in 219 patients and supraspinatus full thickness tearing was identified in 102 patients. A normal AC joint was identified in 267 patients while degenerative AC joint changes were identified in 370 patients. A significant correlation was identified between age and rotator cuff derangement (p < .001) and between age and AC joint derangement (p < .001). No significant difference was identified between gender and patterns of cuff derangement CONCLUSION: The extent of rotator cuff and AC joint derangement increases with ageing. Impingement appears to trigger a cascade of events in sequence, from isolated subacromial bursitis through to supraspinatus tendon tearing. Patterns of rotator cuff derangement are similar in men and women.

Does MRI Knee in Those over 50 Years with Knee Pain in Osteoarthritis Alter Management? A Retrospective Review.

Knee osteoarthritis (OA) is a significant cause of pain and disability worldwide. Imaging provides diagnosis, prognostication, and follow-up. Radiographs are first line, useful, and inexpensive. Magnetic resonance imaging (MRI) can detect additional features not seen on radiograph, but it is of questionable usefulness in the management of knee OA. Our aim was to investigate the usefulness of MRI in the workup of knee OA and whether MRI alters management in knee OA. A retrospective review was performed of consecutive MRI knees performed for knee pain in those over 50 years. Clinical information and documentation of management plan pre- and post-MRI were collected. Assessment was made whether the MRI results influenced the final management plan. Of the 222 MRI knees included for study, the majority (62.2%) had not had a recent radiograph. OA was reported in 86.9% of radiographs and 89.6% of MRI. On MRI, the most prevalent finding was tearing/abnormality of the medial meniscus, seen in 47% of MRIs overall, increasing to all in severe OA. MRI assisted with management in 9.5% of all (21/222) patients, and changed management plans in 23% of those that had documented management plans prior to the MRI (6/26 patients). MRIs can guide tailored management in knee OA and are useful for surgical planning; however, they should only be ordered in certain cases, and a radiograph should always be performed first. MRI should be considered if symptoms are not explained by OA alone or the appropriate treatment option requires MRI.

Long-term mortality in asymptomatic patients with stable ischemic heart disease undergoing percutaneous coronary intervention.

OBJECTIVES: Patients with stable ischemic heart disease (SIHD) may present with a variety of symptoms including typical angina, angina equivalents such as dyspnea or no symptoms. We sought to determine whether symptom status affects periprocedural safety and long-term mortality in patients undergoing PCI. METHODS: Prospectively enrolled consecutive patients undergoing PCI for SIHD at six hospitals in Australia between 2005 to 2018 as part of the Melbourne Interventional Group registry. Symptom status was recorded at the time of PCI and patients undergoing staged PCI were excluded. RESULTS: Overall, 11,730 patients with SIHD were followed up for a median period of 5 years (maximum 14.0 years, interquartile range 2.2-9.0 years) with 1,317 (11.2%) being asymptomatic. Asymptomatic patients were older, and more likely to be male, have triple-vessel disease, with multiple comorbidities including renal failure, diabetes and heart failure (all P < .01). These patients had significantly higher rates of periprocedural complications and major adverse cardiovascular events at 30-days. Long-term mortality was significantly higher in asymptomatic patients (27.2% vs 18.0%, P < .001). On cox regression for long-term mortality, after adjustment for more important clinical variables, asymptomatic status was an independent predictor (Hazard ratio (HR) 1.39 95% CI 1.16-1.66, P < .001). CONCLUSIONS: In a real-world cohort of patients undergoing revascularization for SIHD, absence of symptoms was associated with higher rates of periprocedural complications and, after adjustment for more important clinical variables, was an independent predictor of long-term mortality. As the primary goal of revascularization in SIHD remains angina relief, the appropriateness of PCI in the absence of symptoms warrants justification.

Sex disparity in secondary prevention pharmacotherapy and clinical outcomes following acute coronary syndrome.

AIMS: We sought to investigate if sex disparity exists for secondary prevention pharmacotherapy following acute coronary syndrome (ACS) and impact on long-term clinical outcomes. METHODS AND RESULTS: We analysed data on medical management 30-day post-percutaneous coronary intervention (PCI) for ACS in 20 976 patients within the multicentre Melbourne Interventional Group registry (2005-2017). Optimal medical therapy (OMT) was defined as five guideline-recommended medications, near-optimal medical therapy (NMT) as four medications, sub-optimal medical therapy (SMT) as ≤3 medications. Overall, 65% of patients received OMT, 27% NMT and 8% SMT. Mean age was 64 ± 12 years; 24% (4931) were female. Women were older (68 ± 12 vs. 62 ± 12 years) and had more comorbidities. Women were less likely to receive OMT (61% vs. 66%) and more likely to receive SMT (10% vs. 8%) compared to men, P < 0.001. On long-term follow-up (median 5 years, interquartile range 2-8 years), women had higher unadjusted mortality (20% vs. 13%, P < 0.001). However, after adjusting for medical therapy and baseline risk, women had lower long-term mortality [hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.79-0.98; P = 0.02]. NMT (HR 1.17, 95% CI 1.05-1.31; P = 0.004) and SMT (HR 1.79, 95% CI 1.55-2.07; P < 0.001) were found to be independent predictors of long-term mortality. CONCLUSION: Women are less likely to be prescribed optimal secondary prevention medications following PCI for ACS. Lower adjusted long-term mortality amongst women suggests that as well as baseline differences between gender, optimization of secondary prevention medical therapy amongst women can lead to improved outcomes. This highlights the need to focus on minimizing the gap in secondary prevention pharmacotherapy between sexes following ACS.

Increased incidence of acute calculous cholecystitis observed during COVID-19 social restrictions.

PURPOSE: In response to the outbreak of COVID-19 in Ireland, the government implemented a nationwide stay-at-home order, with the closure of all non-essential businesses. During this period, there was a significant increase in supermarket expenditure. It has been shown that stress, anxiety and boredom are triggers for unhealthy eating habits. Fat consumption is a risk factor for both the development of gallstones and, additionally, the development of acute calculous cholecystitis. The aim of this study was to assess the incidence of acute calculous cholecystitis during the nationwide lockdown and compare it to the same period one year prior. METHODS: A retrospective review of all emergency abdominal imaging performed during the first 5 weeks of the lockdown was completed using the hospital PACS (picture archiving and communication system). All cases of acute calculous cholecystitis were identified and compared with the same period 1 year prior. RESULTS: Eighteen cases of acute calculous cholecystitis were identified from 24 March to 27 April 2020. Eleven cases were identified during the same period in 2019. This represented an increase of 63%. Non-COVID-19-related emergency presentations decreased during this period, and imaging of emergency presentations decreased by 24%. The rate of scans positive for acute cholecystitis more than doubled (p < 0.037). CONCLUSION: A statistically significant increase in cases of acute calculous cholecystitis was observed during a nationwide lockdown during the COVID-19 pandemic. It is hypothesised that this is due to increased consumption of fatty foods during this period due to stress, anxiety and boredom.

Invasive versus conservative management in patients aged ≥85 years presenting with non-ST-elevation myocardial infarction.

BACKGROUND: Guidelines recommend early coronary angiography (CA) in patients with non-ST-elevation myocardial infarction (NSTEMI) irrespective of age. However, elderly patients are less likely to be treated according to these guidelines due to their perceived high risk and medical comorbidities. Whether an invasive strategy is associated with improved survival in patients aged ≥85 years remains uncertain due to their exclusion from randomised trials. AIMS: Patients were stratified based on whether they underwent invasive management with CA with a view to revascularisation versus conservative management. The primary outcome was long-term mortality. METHODS: Consecutive patients aged ≥85 years presenting to a tertiary centre with NSTEMI between 2008 and 2018 were included in this retrospective cohort study. RESULTS: Of 7591 patients with NSTEMI, 1052 patients aged ≥85 years were included. Ninety-nine (9.4%) patients underwent CA. Those undergoing CA were more likely to be younger, male, live independently, without mobility or cognitive issues (all P < 0.01). Overall, 495 (47%) patients died during a mean follow up of 1.3 ± 1 year. On Cox regression, after adjusting for age, pre-morbid functional status, cognition and cardiovascular risk factors, invasive management was the strongest predictor for survival (hazard ratio 0.47; 95% confidence interval 0.26-0.85; P = 0.01). Invasive management was associated with a trend to increased risk of in-hospital bleeding (6.1% vs 2.6%; P = 0.054) with no significant difference in stroke (2.0% vs 3.8%; P = 0.37). CONCLUSION: In patients aged ≥85 years who presented with NSTEMI, invasive management was associated with improved survival without significant differences in bleeding or stroke. A randomised controlled study assessing the efficacy and safety of invasive management in very elderly patients with NSTEMI is warranted.

Factor Xa Inhibition for the Treatment of Venous Thromboembolism Associated With Cancer: A Meta-Analysis of the Randomised Controlled Trials.

BACKGROUND: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients. Until recently, guidelines recommended the use of low-molecular weight heparin (LMWH) as standard of care for VTE in patients with cancer. Despite the proven efficacy of direct oral anticoagulants (DOACs) for treatment of VTE, there is equipoise supporting their use in cancer patients. METHODS: A systematic review of PubMed, Medline and EMBASE identified four randomised controlled trials (RCTs) in patients with cancer and VTE comparing a factor Xa inhibitor (FXaI) to LMWH. A meta-analysis was performed with a primary outcome of VTE recurrence and key secondary outcomes of major bleeding, clinically relevant non-major bleeding (CRNMB) and gastrointestinal (GI) bleeding. RESULTS: Four RCTs with 2,907 patients were included. 1,451 patients were randomised to FXaI and 1,456 to LMWH. VTE recurrence was lower in the FXaI group (RR 0.62, 95%CI 0.44-0.87; p=0.01; I2=24.90), with an absolute risk difference of -4% equating to a number needed to treat of 25 for prevention of recurrent VTE with FXaI. No significant difference in major bleeding was noted between groups (RR 1.33, 95%CI 0.84-2.11; p=0.23). Rates of GI bleeding (RR 1.87, 95%CI 1.06-3.29; p=0.03) and CRNMB (RR 1.57, 95%CI 1.11-2.23; p=0.01) were greater with FXaIs. CONCLUSION: In patients with cancer and VTE, the rate of VTE recurrence was significantly lower with FXaI than with LMWH without an increased risk of major bleeding. Our data supports the use of FXaIs as the standard of care for the treatment of VTE in this population.

Comparison of Long-Term Outcomes in Men versus Women Undergoing Percutaneous Coronary Intervention.

There has been a significant decrease in mortality associated with coronary artery disease (CAD) in recent decades, although at discordant rates between men and women. Using a well-established multicenter registry, we sought to examine the impact of gender on long-term mortality stratified by indication for percutaneous coronary intervention (PCI). Data from 54,440 consecutive patients (12,805, 23.5% women) undergoing PCI from the Victorian Cardiac Outcomes Registry (2013 to 2018) were analyzed. We aimed to compare gender-related differences of patients undergoing PCI for stable angina pectoris (SAP), non-ST-elevation acute coronary syndrome (NSTEACS) and ST-elevation myocardial infarction (STEMI). The primary outcome was long-term all-cause mortality. Female patients were older across all indications (SAP: 67 vs 71 years, NSTEACS: 64 vs 69 years, STEMI 61 vs 67 years; p value for all <0.001), with age-adjusted higher rates of diabetes mellitus (p value for all <0.02) and renal impairment (p value for all <0.001), and were more likely to have femoral artery access for intervention (p value for all <0.001). Unadjusted in-hospital and 30-day mortality rates were comparable between men and women across all indications. Compared to men, women had a higher rate of unadjusted long-term mortality (9.0% vs 7.37%; p <0.001). However, after adjusting for variables significant on univariate analysis, female gender was independently associated with improved long-term survival (HR 0.76, 95% CI 0.66 to 0.87; p <0.001). In conclusion, contrary to previous studies, despite being older with a differing clinical profile and interventional approach, women undergoing PCI have a long-term survival advantage.