Cannabis for chronic pain: cardiovascular safety in a nationwide Danish study.

BACKGROUND AND AIMS: A rising number of countries allow physicians to treat chronic pain with medical cannabis. However, recreational cannabis use has been linked with cardiovascular side effects, necessitating investigations concerning the safety of prescribed medical cannabis. METHODS: Using nationwide Danish registers, patients with chronic pain initiating first-time treatment with medical cannabis during 2018-21 were identified and matched 1:5 to corresponding control patients on age, sex, chronic pain diagnosis, and concomitant use of other pain medication. The absolute risks of first-time arrhythmia (atrial fibrillation/flutter, conduction disorders, paroxysmal tachycardias, and ventricular arrhythmias) and acute coronary syndrome were reported comparing medical cannabis use with no use. RESULTS: Among 1.88 million patients with chronic pain (46% musculoskeletal, 11% cancer, 13% neurological, and 30% unspecified pain), 5391 patients claimed a prescription of medical cannabis [63.2% women, median age: 59 (inter-quartile range 48-70) years] and were compared with 26 941 control patients of equal sex- and age composition. Arrhythmia was observed in 42 and 107 individuals, respectively, within 180 days. Medical cannabis use was associated with an elevated risk of new-onset arrhythmia {180-day absolute risk: 0.8% [95% confidence interval (CI) 0.6%-1.1%]} compared with no use [180-day absolute risk: 0.4% (95% CI 0.3%-0.5%)]: a risk ratio of 2.07 (95% CI 1.34-2.80) and a 1-year risk ratio of 1.36 (95% CI 1.00-1.73). No significant association was found for acute coronary syndrome [180-day risk ratio: 1.20 (95% CI 0.35-2.04)]. CONCLUSIONS: In patients with chronic pain, the use of prescribed medical cannabis was associated with an elevated risk of new-onset arrhythmia compared with no use-most pronounced in the 180 days following the initiation of treatment.

Changing co-morbidity and increasing deprivation among people living with HIV: UK population-based cross-sectional study.

BACKGROUND: The great success of HIV treatments means that, increasingly, people living with HIV (PLHIV) are growing old enough to develop age-associated comorbid conditions. We investigated the evolution of comorbid conditions and demographics among PLHIV in England. METHODS: In a cross-sectional study linking Clinical Practice Research Datalink (CPRD) primary care, hospitalization, death registry and Index of Multiple Deprivation data, we measured the prevalence of 304 individual health conditions, categorized into 47 condition groups (36 non-communicable, 11 communicable). Using logistic regression, we calculated odds ratios (ORs) for the likelihood of each condition and condition group in 2015 versus 2008, adjusting for age, sex and deprivation. RESULTS: In 2015, there were 964 CPRD-registered PLHIV compared with 1987 in 2008; 62% were male and 38% female in both cohorts. The 2015 cohort was older, with 51.1% aged 45-64 years and 7.2% aged 65-84 years compared with 31.8% and 3.2%, respectively, in 2008. Deprivation was higher in 2015, at 23.9% (quintile 4) and 28.7% (quintile 5) compared with 5.8% and 6.6%, respectively, in 2008. Of 36 non-communicable condition groups, 14 (39%) occurred in ≥ 10% of PLHIV in 2015, of which seven were more likely in 2015 than in 2008: renal-chronic-kidney-disease [odds ratio (OR) = 1.96 (95% CI: 1.33-2.90); endocrine-obesity [OR = 1.76 (1.12-2.77)]; rheumatology [OR = 1.64 (1.30-2.07)]; dermatology [OR = 1.55(1.29-1.85)]; genito-urinary-gynaecological [OR = 1.44(1.18-1.76)]; eyes-ears/nose/throat [OR = 1.31(1.08-1.59)]; and gastro-intestinal conditions [OR = 1.28 (1.04-1.58)]. Two condition groups, respiratory-chronic-obstructive-pulmonary-disease [OR = 0.36 (0.19-0.69)] and endocrine-diabetes [OR = 0.49 (0.34-0.70)], were less likely in 2015. Ten out of 11 communicable infectious condition groups were less likely in 2015. CONCLUSIONS: Although infections in PLHIV have fallen, chronic non-communicable comorbidity is increasingly prevalent. Alongside the marked increases in deprivation and ageing, this study suggests that socio-economic measures in addition to healthcare provision are needed to achieve holistic health for PLHIV.

Adverse Events Associated With Coprescription of Phosphodiesterase Type 5 Inhibitors and Oral Organic Nitrates in Male Patients With Ischemic Heart Disease : A Case-Crossover Study.

BACKGROUND: Concomitant use of oral organic nitrates (nitrates) and phosphodiesterase type 5 (PDE5) inhibitors is contraindicated. OBJECTIVE: To measure temporal trends in the coprescription of nitrates and PDE5 inhibitors and to measure the association between cardiovascular outcomes and the coprescription of nitrates with PDE5 inhibitors. DESIGN: Case-crossover design. SETTING: Nationwide study of Danish patients from 2000 to 2018. PATIENTS: Male patients with International Classification of Diseases, 10th Revision (ICD-10) codes for ischemic heart disease (IHD), including those who had a continuing prescription for nitrates and a new, filled prescription for PDE5 inhibitors. MEASUREMENTS: Two composite outcomes were measured: 1) cardiac arrest, shock, myocardial infarction, ischemic stroke, or acute coronary arteriography and 2) syncope, angina pectoris, or drug-related adverse event. RESULTS: From 2000 to 2018, 249 541 male patients with IHD were identified. Of these, 42 073 patients had continuing prescriptions for nitrates. During this period, the prescription rate for PDE5 inhibitors in patients with IHD who were taking nitrates increased from an average of 0.9 prescriptions (95% CI, 0.5 to 1.2 prescriptions) per 100 persons per year in 2000 to 19.5 prescriptions (CI, 18.0 to 21.1 prescriptions) in 2018. No statistically significant association was found between the coprescription of nitrates with PDE5 inhibitors and the risk for either composite outcome (odds ratio [OR], 0.58 [CI, 0.28 to 1.13] for the first outcome and OR, 0.73 [CI, 0.40 to 1.32] for the second outcome). LIMITATION: An assumption was made that concurrently filled prescriptions for nitrates and PDE5 inhibitors equaled concomitant use. CONCLUSION: From 2000 to 2018, the use of PDE5 inhibitors increased 20-fold among Danish patients with IHD who were taking nitrates. A statistically significant association between concomitant use of these medications and cardiovascular adverse events could not be identified. PRIMARY FUNDING SOURCE: Ib Mogens Kristiansens Almene Fond and Helsefonden.

Systemic antibiotic sales and WHO recommendations, India.

Objective: To analyse sales of fixed-dose combination and single antibiotics in India in relation to World Health Organization (WHO) recommendations and national regulatory efforts to control antibiotic sales. Methods: We extracted data on sales volumes of systemic antibiotics in India from a market research company sales database. We compared the market share of antibiotic sales in 2020 by WHO AWaRe (Access, Watch and Reserve) category and for those under additional national regulatory controls. We also analysed sales of fixed-dose combinations that were: formally approved for marketing or had a no-objection certificate; on the national essential medicines list; and on the WHO list of not-recommended antibiotics. Findings: There were 78 single and 112 fixed-dose combination antibiotics marketed in India, accounting for 7.6 and 4.5 billion standard units of total sales, respectively. Access, Watch and Reserve antibiotics comprised 5.8, 5.6 and 0.1 billion standard units of total market sales, respectively. All additionally controlled antibiotics were Watch and Reserve antibiotics (23.6%; 2.9 billion standard units of total sales). Fixed-dose combinations on the WHO not-recommended list were marketed in 229 formulations, with 114 formulations (49.8%) having no record of formal approval or no-objection certificate. While there were no not-recommended fixed-dose combinations on the national list of essential medicines, 13 of the top-20 selling antibiotic fixed-dose combinations were WHO not-recommended. Conclusion: The sale of Watch group drugs, and antibiotics banned or not approved, needs active investigation and enforcement in India. The evidence base underpinning formal approvals and no-objection certificates for not-recommended fixed-dose combinations should be audited.

Prescribing direct-acting oral anticoagulants - Mind the evidence gap.

Direct-acting oral anticoagulants (DOACs) are licensed for the prevention of thromboembolism in non-valvular atrial fibrillation, amongst other indications. Prescribers use information derived from the summary of product characteristics which is based on the key trials supporting the DOAC's market authorisation. However, prescribers may not be aware of the limitations within these trials regarding underrepresentation of patient populations commonly encountered in clinical practice and how this may adversely impact them. This review highlights the gaps in the licensing evidence using four clinical vignettes that explore prescribing challenges in older adults, female patients, patients with obesity and patients from non-Europid ethnic backgrounds.

Effect of long-term beta-blocker treatment following myocardial infarction among stable, optimally treated patients without heart failure in the reperfusion era: a Danish, nationwide cohort study.

AIMS: We aimed to investigate the long-term cardio-protective effect associated with beta-blocker (BB) treatment in stable, optimally treated myocardial infarction (MI) patients without heart failure (HF). METHODS AND RESULTS: Using nationwide registries, we included patients with first-time MI undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) during admission and treated with both acetyl-salicylic acid and statins post-discharge between 2003 and 2018. Patients with prior history of MI, prior BB use, or any alternative indication or contraindication for BB treatment were excluded. Follow-up began 3 months following discharge in patients alive, free of cardiovascular (CV) events or procedures. Primary outcomes were CV death, recurrent MI, and a composite outcome of CV events. We used adjusted logistic regression and reported standardized absolute risks and differences (ARD) 3 years after MI. Overall, 30 177 stable, optimally treated MI patients were included (58% acute PCI, 26% sub-acute PCI, 16% CAG without intervention). At baseline, 82% of patients were on BB treatment (median age 61 years, 75% male) and 18% were not (median age 62 years, 68% male). BB treatment was associated with a similar risk of CV death, recurrent MI, and the composite outcome of CV events compared with no BB treatment [ARD (95% confidence intervals)] correspondingly; 0.1% (-0.3% to 0.5%), 0.2% (-0.7% to 1.2%), and 1.2% (-0.2% to 2.7%). CONCLUSIONS: In this nationwide cohort study of stable, optimally treated MI patients without HF, we found no long-term effect of BB treatment on CV prognosis following the patients from 3 months to 3 years after MI admission.

The use of validated and nonvalidated surrogate endpoints in two European Medicines Agency expedited approval pathways: A cross-sectional study of products authorised 2011-2018.

BACKGROUND: In situations of unmet medical need or in the interests of public health, expedited approval pathways, including conditional marketing authorisation (CMA) and accelerated assessment (AA), speed up European Medicines Agency (EMA) marketing authorisation recommendations for medicinal products. CMAs are based on incomplete benefit-risk assessment data and authorisation remains conditional until regulator-imposed confirmatory postmarketing measures are fulfilled. For products undergoing AA, complete safety and efficacy data should be available, and postauthorisation measures may include only standard requirements of risk management and pharmacovigilance plans. In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints reduce drug development time compared with waiting for the intended clinical outcomes. Whether surrogate endpoints supporting products authorised through CMA and AA pathways reliably predict clinical benefits of therapy has not been studied systematically. Our objectives were to determine the extent to which surrogate endpoints are used and to assess whether their validity had been confirmed according to published hierarchies. METHODS AND FINDINGS: We used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorised through CMA or AA pathways during January 1, 2011 to December 31, 2018. We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame. Where pivotal trials reported surrogate endpoints, we conducted PubMed searches for evidence of validity for predicting clinical outcomes. We used 2 published hierarchies to assess validity level. Surrogates with randomised controlled trials supporting the surrogate-clinical outcome relationship were rated as 'validated'. Fifty-one products met the inclusion criteria; 26 underwent CMAs, and 25 underwent AAs. Overall, 26 products were for oncology indications, 10 for infections, 8 for genetic disorders, and 7 for other systems disorders. Five products (10%), all AAs, were authorised based on pivotal trials reporting clinical outcomes, and 46 (90%) were authorised based on surrogate endpoints. No studies were identified that validated the surrogate endpoints. Among a total of 49 products with surrogate endpoints reported, most were rated according to the published hierarchies as being 'reasonably likely' (n = 30; 61%) or of having 'biological plausibility' (n = 46; 94%) to predict clinical outcomes. EPARs did not consistently explain the nature of the pivotal trial endpoints supporting authorisations, whether surrogate endpoints were validated or not, or describe the endpoints to be reported in the confirmatory postmarketing studies. Our study has limitations: we may have overlooked relevant validation studies; the findings apply to 2 expedited pathways and may not be generalisable to products authorised through the standard assessment pathway. CONCLUSIONS: The pivotal trial evidence supporting marketing authorisations for products granted CMA or AA was based dominantly on nonvalidated surrogate endpoints. EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorisations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by nonvalidated surrogate endpoints, postauthorisation measures to confirm clinical benefit need to be imposed by the regulator on the marketing authorisation holders.

Threats to global antimicrobial resistance control: Centrally approved and unapproved antibiotic formulations sold in India.

AIMS: Rising antimicrobial resistance (AMR) is a global health crisis. India has among the highest resistance rates and antibiotic consumption internationally. Extensive use of fixed-dose combination (FDC) antibiotics and of unapproved formulations are claimed contributory factors but there has been no systematic examination of formulations or volumes sold. The aim of the present study was to investigate the regulatory approval status and sales volumes of systemic antibiotics marketed in India. METHODS: This was an ecological study using regulatory records in India, the UK and the US to determine the approval status in each country of systemic antibiotic FDCs and single-drug formulations (SDFs) sold in India. Pharmatrac® sales data were used to determine the formulations and volumes sold (2007-2012), branded-product numbers and manufacturers. RESULTS: Of 118 systemic antibiotic FDC formulations sold in India, 43 (36%) were approved but 75 (64%) had no record of regulatory approval; four (3%) formulations were approved in the UK and/or US. Almost half of formulations (58/118; 49%) comprised dual antimicrobials, most unapproved in India (43/58; 74%), and many were pharmacologically problematic. In contrast, 80/86 (93%) SDFs were approved in India and over two-thirds in the UK and/or US. Total antibiotic sales increased by 26%, from 2056 million units (2007-08) to 2583 million units (2011-12). FDC sales rose by 38% vs. 20% for SDFs. By 2011-12, FDCs comprised one-third of sales (872 million units). Over one-third of FDCs sold (300.26 million units; 34.5%) were of unapproved formulations. Multinational companies manufactured unapproved formulations and accounted for 19% of all FDC and SDF sales annually. CONCLUSIONS: Sales in India of antibiotic FDCs, including unapproved formulations, are rising. In the context of increasing AMR rates nationally and globally, unapproved antibiotic FDCs undermine India's national AMR strategy and should be banned from sale.

Use of Fixed Dose Combination (FDC) Drugs in India: Central Regulatory Approval and Sales of FDCs Containing Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Metformin, or Psychotropic Drugs.

BACKGROUND: In 2012, an Indian parliamentary committee reported that manufacturing licenses for large numbers of fixed dose combination (FDC) drugs had been issued by state authorities without prior approval of the Central Drugs Standard Control Organization (CDSCO) in violation of rules, and considered that some ambiguity until 1 May 2002 about states' powers might have contributed. To our knowledge, no systematic enquiry has been undertaken to determine if evidence existed to support these findings. We investigated CDSCO approvals for and availability of oral FDC drugs in four therapeutic areas: analgesia (non-steroidal anti-inflammatory drugs [NSAIDs]), diabetes (metformin), depression/anxiety (anti-depressants/benzodiazepines), and psychosis (anti-psychotics). METHODS AND FINDINGS: This was an ecologic study with a time-trend analysis of FDC sales volumes (2007-2012) and a cross-sectional examination of 2011-2012 data to establish the numbers of formulations on the market with and without a record of CDSCO approval ("approved" and "unapproved"), their branded products, and sales volumes. Data from the CDSCO on approved FDC formulations were compared with sales data from PharmaTrac, a database of national drug sales. We determined the proportions of FDC sales volumes (2011-2012) arising from centrally approved and unapproved formulations and from formulations including drugs banned/restricted internationally. We also determined the proportions of centrally approved and unapproved formulations marketed before and after 1 May 2002, when amendments were made to the drug rules. FDC approvals in India, the United Kingdom (UK), and United States of America (US) were compared. For NSAID FDCs, 124 formulations were marketed, of which 34 (27%) were centrally approved and 90 (73%) were unapproved; metformin: 25 formulations, 20 (80%) approved, five (20%) unapproved; anti-depressants/benzodiazepines: 16 formulations, three (19%) approved, 13 (81%) unapproved; anti-psychotics: ten formulations, three (30%) approved, seven (70%) unapproved. After 1 May 2002, the proportions of approved FDC formulations increased for NSAIDs (26%/28%) and anti-psychotics (0%/38%) and decreased for metformin (100%/75%) and anti-depressants/benzodiazepines (20%/18%), and the overall proportion approved remained similar before and after that date. FDC formulations gave rise to multiple branded products, ranging from 211 anti-psychotic FDC products from ten formulations to 2,739 NSAID FDC products from 124 formulations. The proportions of FDC sales volumes arising from unapproved formulations were as follows: anti-depressants/benzodiazepines, 69%; anti-psychotics, 43%; NSAIDs, 28%; and metformin, 0.4%. Formulations including drugs banned/restricted internationally comprised over 12% of NSAID FDC sales and 53% of anti-psychotic FDC sales. Across the four therapeutic areas, 14 FDC formulations were approved in the UK and 22 in the US. CONCLUSIONS: There was evidence supporting concerns about FDCs. Metformin excepted, substantial numbers of centrally unapproved formulations for NSAID, anti-depressant/benzodiazepine, and anti-psychotic FDCs were marketed; sales volumes were high. The legal need for central approval of new drugs before manufacture has been in place continuously since 1961, including for FDCs meeting the applicable legal test. Proportions of centrally unapproved formulations after 1 May 2002 did not decrease overall, and no ambiguity was found about states' licensing powers. Unapproved formulations should be banned immediately, prioritising those withdrawn/banned internationally and undertaking a review of benefits and risks for patients in ceasing or switching to other medicines. Drug laws need to be amended to ensure the safety and effectiveness of medicines marketed in India.

Interprofessional training for final year healthcare students: a mixed methods evaluation of the impact on ward staff and students of a two-week placement and of factors affecting sustainability.

BACKGROUND: Multiple care failings in hospitals have led to calls for increased interprofessional training in medical education to improve multi-disciplinary teamwork. Providing practical interprofessional training has many challenges and remains uncommon in medical schools in the UK. Unlike most previous research, this evaluation of an interprofessional training placement takes a multi-faceted approach focusing not only on the impact on students, but also on clinical staff delivering the training and on outcomes for patients. METHODS: We used mixed methods to examine the impact of a two-week interprofessional training placement undertaken on a medical rehabilitation ward by three cohorts of final year medical, nursing and therapy students. We determined the effects on staff, ward functioning and participating students. Impact on staff was evaluated using the Questionnaire for Psychological and Social factors at work (QPSNordic) and focus groups. Ward functioning was inferred from standard measures of care including length of stay, complaints, and adverse events. Impact on students was evaluated using the Readiness for Interprofessional Learning Survey (RIPLS) among all students plus a placement survey among medical students. RESULTS: Between 2007 and 2010, 362 medical students and 26 nursing and therapy students completed placements working alongside the ward staff to deliver patient care. Staff identified benefits including skills recognition and expertise sharing. Ward functioning was stable. Students showed significant improvements in the RIPLS measures of Teamwork, Professional Identity and Patient-Centred Care. Despite small numbers of students from other professions, medical students' rated the placement highly. Increasing student numbers and budgetary constraints led to the cessation of the placement after three years. CONCLUSIONS: Interprofessional training placements can be delivered in a clinical setting without detriment to care and with benefits for all participants. While financial support is a necessity, it appears that having students from multiple professions is not critical for a valuable training experience; staff from different professions and students from a single profession can work successfully together. Difficulty in aligning the schedules of different student professions is commonly cited as a barrier to interprofessional training. Our experience challenges this and should encourage provision of authentic interprofessional training experience.

Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction.

IMPORTANCE: Antithrombotic treatment is indicated for use in patients after myocardial infarction (MI); however, concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) could pose safety concerns. OBJECTIVE: To examine the risk of bleeding and cardiovascular events among patients with prior MI taking antithrombotic drugs and for whom NSAID therapy was then prescribed. DESIGN, SETTING, AND PARTICIPANTS: Using nationwide administrative registries in Denmark (2002-2011), we studied patients 30 years or older admitted with first-time MI and alive 30 days after discharge. Subsequent treatment with aspirin, clopidogrel, or oral anticoagulants and their combinations, as well as ongoing concomitant NSAID use, was determined. EXPOSURES: Use of NSAIDs with ongoing antithrombotic treatment after first-time MI. MAIN OUTCOMES AND MEASURES: Risk of bleeding (requiring hospitalization) or a composite cardiovascular outcome (cardiovascular death, nonfatal recurrent MI, and stroke) according to ongoing NSAID and antithrombotic therapy, calculated using adjusted time-dependent Cox regression models. RESULTS: We included 61,971 patients (mean age, 67.7 [SD, 13.6] years; 63% men); of these, 34% filled at least 1 NSAID prescription. The number of deaths during a median follow-up of 3.5 years was 18,105 (29.2%). A total of 5288 bleeding events (8.5%) and 18,568 cardiovascular events (30.0%) occurred. The crude incidence rates of bleeding (events per 100 person-years) were 4.2 (95% CI, 3.8-4.6) with concomitant NSAID treatment and 2.2 (95% CI, 2.1-2.3) without NSAID treatment, whereas the rates of cardiovascular events were 11.2 (95% CI, 10.5-11.9) and 8.3 (95% CI, 8.2-8.4). The multivariate-adjusted Cox regression analysis found increased risk of bleeding with NSAID treatment compared with no NSAID treatment (hazard ratio, 2.02 [95% CI, 1.81-2.26]), and the cardiovascular risk was also increased (hazard ratio, 1.40 [95% CI, 1.30-1.49]). An increased risk of bleeding and cardiovascular events was evident with concomitant use of NSAIDs, regardless of antithrombotic treatment, types of NSAIDs, or duration of use. CONCLUSIONS AND RELEVANCE: Among patients receiving antithrombotic therapy after MI, the use of NSAIDs was associated with increased risk of bleeding and excess thrombotic events, even after short-term treatment. More research is needed to confirm these findings; however, physicians should exercise appropriate caution when prescribing NSAIDs for patients who have recently experienced MI.

Temporal trend of first-line drug choice and treatment continuity for hypertension among citizens 75 years or over - a register-based, cohort study.

BACKGROUND: Limited knowledge of antihypertensive treatment of the elderly potentially impedes effective strategies for hypertension management in this growing patient group. We aimed to investigate temporal trends for first-line drug choice for antihypertensive treatment and treatment continuity among patients ≥75 years from 2000 to 2021. METHODS: Using nationwide Danish registers, patients ≥75 years initiated for the first time on antihypertensive drugs: Angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB), beta blockers (BB), calcium channel blockers (CCB), thiazides, or combinations, were identified. Patients with other indications than hypertension were excluded. Treatment continuity was described using claimed prescriptions the first 180 days following study entry. RESULTS: From 2000 to 2021, 170,769 patients (median age 80 years [interquartile range:77-84], 60.3% female) were included. From 2000 to 2003 to 2015-2021 the proportion of first-line drug choice increased for ACEi (8.7% to 14.9%), ARB (4.1% to 23.9%), and CCB (10.7% to 27.6%), decreased for thiazides (60.6% to 15.9%) and remained stable for BB (12.9% to 14.1%) and combinations (2.9% to 3.6%). For 157,457 patients alive after 180 days, discontinuation was highest among patients initiated on thiazides (28.3%) whereas most patients continued the same single drug regimen if they started on ACEi (55.2%), ARB (65.0%), BB (57.2%) or CCB (59.3%). CONCLUSIONS: From 2000 to 2021 thiazides have been replaced by ACEi, ARB and CCB. Thiazides had the lowest treatment continuity while ARB appeared preferred slightly over ACEi. Differences in adherence in relation to first-line drug choice may warrant scrutiny regarding recommendations for the elderly.

Long-Term Cardiovascular Risk Associated With Treatment of Attention-Deficit/Hyperactivity Disorder in Adults.

BACKGROUND: Incrementing numbers of patients treated for attention-deficit/hyperactivity disorder (ADHD) call for scrutiny concerning long-term drug-safety. OBJECTIVES: This study aims to investigate associations between long-term use of ADHD treatment and cardiovascular outcomes. METHODS: Using nationwide registers, adult patients first-time initiated on ADHD treatment between 1998 and 2020 were identified. Exposure groups were prior users, <1 defined daily dose (DDD) per day, ≥1 DDD per day determined at start of follow-up, and 1 year after patients' first claimed prescription. Outcomes were acute coronary syndromes, stroke, heart failure, and a composite of the above. RESULTS: At start of follow-up, 26,357, 31,211, and 15,696 individuals were correspondingly categorized as prior users (42% female, median age: 30 years [Q1-Q3: 23-41 years]), <1 DDD per day (47% female, median age: 31 years [Q1-Q3: 24-41 years]), and ≥1 DDD per day (47% female, median age: 33 years [Q1-Q3: 25-41 years]), respectively. Comparing ≥1 DDD per day with prior users, elevated standardized 10-year absolute risk of stroke (2.1% [95% CI: 1.8%-2.4%] vs 1.7% [95% CI: 1.5%-1.9%]), heart failure (1.2% [95% CI: 0.9%-1.4%] vs 0.7% [95% CI: 0.6%-0.8%]), and the composite outcome (3.9% [95% CI: 3.4%-4.3%] vs 3.0% [95% CI: 2.8 %-3.2%]) was found-with corresponding risk ratios of 1.2 (95% CI: 1.0-1.5), 1.7 (95% CI: 1.3-2.2), and 1.3 (95% CI: 1.1-1.5). No apparent associations were found for acute coronary syndrome (1.0% [95% CI: 0.8%-1.2%] vs 0.9% [95% CI: 0.8%-1.0%]). CONCLUSIONS: Possible associations between elevated long-term cardiovascular risk and increasing dosage of ADHD treatment use in a young patient group should warrant further investigation.

Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries.

BACKGROUND: Certain non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., rofecoxib [Vioxx]) increase the risk of heart attack and stroke and should be avoided in patients at high risk of cardiovascular events. Rates of cardiovascular disease are high and rising in many low- and middle-income countries. We studied the extent to which evidence on cardiovascular risk with NSAIDs has translated into guidance and sales in 15 countries. METHODS AND FINDINGS: Data on the relative risk (RR) of cardiovascular events with individual NSAIDs were derived from meta-analyses of randomised trials and controlled observational studies. Listing of individual NSAIDs on Essential Medicines Lists (EMLs) was obtained from the World Health Organization. NSAID sales or prescription data for 15 low-, middle-, and high-income countries were obtained from Intercontinental Medical Statistics Health (IMS Health) or national prescription pricing audit (in the case of England and Canada). Three drugs (rofecoxib, diclofenac, etoricoxib) ranked consistently highest in terms of cardiovascular risk compared with nonuse. Naproxen was associated with a low risk. Diclofenac was listed on 74 national EMLs, naproxen on just 27. Rofecoxib use was not documented in any country. Diclofenac and etoricoxib accounted for one-third of total NSAID usage across the 15 countries (median 33.2%, range 14.7-58.7%). This proportion did not vary between low- and high-income countries. Diclofenac was by far the most commonly used NSAID, with a market share close to that of the next three most popular drugs combined. Naproxen had an average market share of less than 10%. CONCLUSIONS: Listing of NSAIDs on national EMLs should take account of cardiovascular risk, with preference given to low risk drugs. Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity. Diclofenac should be removed from EMLs.

Regulatory enforcement of the marketing of fixed-dose combinations in India: a case study of systemic antibiotics.

BACKGROUND: In India, states have licensed the manufacture of large numbers of fixed-dose combination (FDC) drugs without the required prior approval of the central regulator. This paper describes two major regulatory initiatives to address the problem, which began in 2007 and 2013, and examines whether they have been sufficient to remove centrally unapproved systemic antibiotic FDCs from the market. METHODS: Information was extracted from documents published by the central regulator and the ministry of health, including the National List of Essential Medicines (NLEM), and court judgments, and analysed alongside sales volume data for 2008-2020 using PharmaTrac market dataset. RESULTS: The regulatory initiatives permitted 68 formulations to be given de facto approvals ('No Objection Certificates') outside the statutory regime, banned 46 FDCs and restricted one FDC. Market data show that FDCs as a proportion of total antibiotic sales increased from 32.9 in 2008 to 37.3% in 2020. The total number of antibiotic FDC formulations on the market fell from 574 (2008) to 395 (2020). Formulations with a record of prior central approval increased from 86 (2008) to 94 (2020) and their share of the antibiotic FDC sales increased from 32.0 to 55.3%. In 2020, an additional 23 formulations had been permitted de facto approval, accounting for 10.6% of the antibiotic FDC sales. Even in 2020, most marketed formulations (70.4%, 278/395) were unapproved or banned, and comprised a 15.9% share of the antibiotic FDC sales. The share of NLEM-listed antibiotic FDC sales increased from 21.2 (2008) to 26.7% (2020). CONCLUSION: The initiatives had limited impact. Regulatory enforcement has been slow and weak, with many unapproved, and even banned, FDCs remaining on the market.

Heart Failure Following Anti-Inflammatory Medications in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Fluid retention and endothelial dysfunction have been related to use of nonsteroidal anti-inflammatory drugs (NSAIDs), and type 2 diabetes mellitus (T2DM) has been linked to both a decline in kidney function and subclinical cardiomyopathy. OBJECTIVES: The authors hypothesized that short-term use of NSAIDs could lead to subsequent development of incident heart failure (HF) in patients with T2DM. METHODS: Using nationwide Danish registers, we identified patients diagnosed with T2DM during 1998 to 2021 and included patients without previous HF, rheumatic disease, or use of NSAIDs 120 days before diagnosis. Associations between NSAIDs and first-time HF hospitalization were investigated using a case-crossover design with 28-day exposure windows, and ORs with 95% CIs were reported. RESULTS: Included were 331,189 patients with T2DM: 44.2% female, median age of 62 years (IQR: 52-71 years); 23,308 patients were hospitalized with HF during follow-up, and 16% of patients claimed at least 1 NSAID prescription within 1 year. Short-term use of NSAIDs was associated with increased risk of HF hospitalization (OR: 1.43; 95% CI: 1.27-1.63), most notably in subgroups with age ≥80 years (OR: 1.78; 95% CI: 1.39-2.28), elevated hemoglobin (Hb) A1c levels treated with 0 to 1 antidiabetic drug (OR: 1.68; 95% CI: 1.00-2.88), and without previous use of NSAIDs (OR: 2.71; 95% CI: 1.78-4.23). CONCLUSIONS: NSAIDs were widely used and were associated with an increased risk of first-time HF hospitalization in patients with T2DM. Patients with advanced age, elevated HbA1c levels, and new users of NSAID seemed more susceptible. These findings could guide physicians prescribing NSAIDs.