Do proton pump inhibitors increase mortality? A systematic review and in-depth analysis of the evidence.

Proton pump inhibitors (PPIs) were primarily approved for short-term use (2 to 8 weeks). However, PPI use continues to expand. Widely believed to be safe, we reviewed emerging evidence on increased mortality with PPI long-term use. Our 2016 systematic PPI drug class review found that mortality was not reported as an outcome in randomized controlled trials (RCTs) that directly compared different PPIs. We sought more recent and comprehensive data on PPI harm outcomes from research syntheses as a follow-on. A search was conducted from January 2014 to January 2020. We searched MEDLINE, EMBASE, and Cochrane Central for evidence from systematic reviews (SRs) and primary studies reporting all-cause mortality in adults treated with a PPI for any indication (duration >12 weeks) compared to patients without PPI treatment (no use, placebo, or H2RA use). Two independent investigators assessed study eligibility, synthesized evidence, and assessed the quality of the included studies. Data on all-cause mortality were sought, analyzed, critically examined, and interpreted herein. From 1304 articles, one SR was identified that reported on all-cause mortality. The SRs pooled three observational studies with data to 1 year: odds ratio, 95% confidence interval (CI) 1.53-1.84. A RCT, the COMPASS (Cardiovascular Outcomes for People Using Anticoagulant Strategies) RCT with data to 3 years: hazard ratio (HR) 1.03, 95% CI 0.92-1.15. The US Veterans Affairs cohort study using a large national dataset with data to 10 years found a HR of 1.17, 95% CI (1.10-1.24) and (NNH) of 22. The most common causes of death were from cardiovascular and chronic kidney diseases, with an excess death of 15 and 4 per 1000 patients, respectively, over the 10-year period. Harms arising from real-world medication use are best evaluated using a pharmacovigilance "convergence of proof" approach using data from a variety of sources and various study designs. Given that most PPI indications for use recommended a treatment duration of less than 12 weeks, it seems clear that PPIs were significantly overused in older patients. The median exposure time to PPI ranged from 1 to 4.6 years. Signals of serious harms including increased mortality with long-term PPI use are reported in observational studies. The COMPASS trial findings are not inconsistent with contemporaneous findings from observational studies. The COMPASS RCT was unlikely to detect an increase in mortality given the trial was not powered to detect this outcome. The potential increase in mortality in older patients associated with prolonged PPI exposure needs to be conveyed to health professionals. Clinicians and patients may be able to reverse the relentless expansion of long-term PPI exposure by reviewing indications and considering potential harms as well as benefits.

Overuse and Limited Benefit of Chemotherapy for Stage II Colon Cancer in Young Patients.

BACKGROUND: Few studies have confirmed a benefit for adjuvant chemotherapy (aCTX) in stage II colon cancer. We used the National Cancer Database to explore the use and efficacy of aCTX in patients with both normal-risk (NR) and high-risk (HR) young stage II colon cancer. PATIENTS AND METHODS: We identified patients with stage II colon cancer who underwent colectomy between 2010 and 2015. HR patients included at least: lymphovascular or perineural invasion, < 12 lymph nodes, poor/un-differentiation, T4, or positive margins. Rates of aCTX by age and risk were calculated, and adjusted factors associated with aCTX were identified. Overall survival was estimated using the Kaplan-Meier method and Cox multivariable analyses for patients < 50 years. RESULTS: Among the 81,066 stage II patients who underwent colectomy, 6093 (7.5%) were < 50 years old. Of these, 2669 patients were HR. Thirty percent of NR and almost 60% of HR patients < 50 years received aCTX, compared with 8% and 23% of patients > 50 years (P < .001). In NR patients < 50 years, 35.3% with microsatellite-stable tumors and 18% with microsatellite unstable tumors received aCTX (P < .001), whereas 63.6% and 43.2%, respectively, of HR patients did (P < .001). The most significant multivariable predictors of aCTX were risk status and age. On univariate analysis, there was no survival benefit associated with aCTX in patients < 50 years. Multivariate analysis failed to demonstrate a survival benefit for aCTX for either group (HR, 0.97; P = .84; NR, 0.1.03; P = .90). CONCLUSION: Young patients with HR and NR colon cancer received aCXT more frequently than older patients with no demonstrable survival benefit. This bears further evaluation to avoid the real risks of over-treatment in this increasing population.

Increasing rates of quetiapine overdose, misuse, and mortality in Victoria, Australia.

BACKGROUND: Quetiapine is misused due to its anxiolytic and hedonic effects and has been associated with deliberate self-harm. This study analyzed quetiapine-related calls to the Victorian Poisons Information Centre (VPIC), coronial data from Victorian Institute of Forensic Medicine (VIFM) and prescribed data from the Pharmaceutical Benefits Scheme (PBS) to determine current trends in overdose, misuse and mortality. METHODS: This was a retrospective review of multiple databases. Calls to VPIC and coronial data from the VIFM were reviewed from 2006 to 2016. PBS prescription data from 2000 to 2015 was obtained from the Australian Statistics on Medicines website. RESULTS: VPIC data indicated a 6-fold increase in the number of quetiapine-related calls over the 11-year period of which most were overdose-related (77%). Overdose and misuse calls increased by 6-fold and 6.6-fold, respectively. Coronial data also indicated a rise in quetiapine-related harm; a 7.4-fold increase in quetiapine-related deaths was recorded for the same period. Similarly, Australian PBS data showed that quetiapine prescriptions increased 285-fold since 2000. There was a significant positive correlation between the increase in prescribing and overdose (r = 0.75, p < 0.001), and prescribing and mortality (r = 0.82, p < 0.01). CONCLUSIONS: This study revealed an increasing trend of misuse, non-fatal and fatal overdoses in Victoria over the last decade. The increasing rates of prescriptions in Australia and thus increased quetiapine availability are likely to have contributed to increased poisoning and mortality. Further research is warranted to explore the reasons behind increased prescribing, including off-label use.

Prescription drug abuse - A timely update.

BACKGROUND: Prescription drug abuse is a rising problem in Australia and pharmaceutical drugs have been the most frequent contributors to overdose deaths in Victoria in recent years. OBJECTIVE: The objectives of this article are to examine the main prescription drugs contributing to overdose deaths and to consider how doctors may help in reducing this problem. DISCUSSION: Data from the Coroners Court of Victoria list the main drugs that contributed to drug-related deaths in 2009-15. Analysis of the data reveals that pharmaceutical drugs contributed to 80% of overdose deaths; benzodiazepines and opioids were the main drug groups involved. Strategies for reducing and managing prescription drug abuse in primary care settings are outlined in this article, including references to published evidence-based clinical guidelines from The Royal Australian College of General Practitioners (RACGP). The safety profile of buprenorphine/ naloxone over methadone is noted and raised as a consideration for clinicians when assessing a patient for opioid replacement therapy.

Patient Characteristics and Outcomes in Unintentional, Non-fatal Prescription Opioid Overdoses: A Systematic Review.

BACKGROUND: Opioid overdose continues to be a significant and growing cause of preventable mortality and morbidity. Studies suggest that unintentional, non-fatal overdose from prescription opioid analgesics constitutes a large portion of total overdose events. The societal burden associated with these events is a frequently overlooked public health concern. OBJECTIVES: To evaluate unintentional, non-fatal prescription opioid overdoses, including the identification of risk factors, societal burden, and knowledge gaps where further study is warranted. STUDY DESIGN: Systematic review of the literature for unintentional, non-fatal opioid overdose. METHODS: Preferred reporting items for systematic reviews and meta-analyses guidelines were used in constructing this systematic review. To determine the scope of the existing literature, a systematic search was conducted using the MEDLINE, CINAHL, PsycINFO, and Web of Science databases. RESULTS: This systematic review analyzes 24 articles (21 retrospective descriptive analyses, 2 prospective analyses, one phase III trial, and one meta-analysis). Articles were reviewed by authors and relevant data examined. Results show that opioid overdose morbidity is significantly more prevalent than mortality and sequelae of non-fatal events should be studied in more detail. LIMITATIONS: The limitations of this systematic review include the range of study populations and opioids discussed and the broad and variable definitions of "opioid overdose" in the literature. CONCLUSIONS: Opioid overdose morbidity and mortality is seen across the entire spectrum of inpatient and outpatient use with significant numbers of adverse events occurring in population segments not identified by high risk indicators. Increased physician awareness and a multi-modal approach could help mitigate the overdose epidemic while maintaining effective pain control for patients. KEY WORDS: Prescription, opioid, accidental drug overdose, unintentional overdose, drug poisoning, fentanyl, oxycodone, hydrocodone, methadone, oxymorphone, hydromorphone.

Predictors of hospital mortality and serious complications in patients admitted with excessive warfarin anticoagulation.

INTRODUCTION: Warfarin is the most commonly used oral anticoagulant and serious bleeding remains the most feared complication. Excessive warfarin anticoagulation (EWA) can be associated with adverse outcome. We aimed to identify the predictors of adverse clinical outcomes in patients admitted with EWA. METHODS AND MATERIALS: Medical records of patients admitted with EWA from March-2004 through Feb-2015 were reviewed. EWA was defined as international normalized ratio (INR)>3.5 in patients who have been receiving warfarin. Primary outcome was death within hospital and secondary outcome was major composite complications (MCC) defined as intracranial hemorrhage (ICH), a need for transfusing ≥ 4 units packed red blood cell (PRBC), a need for surgical intervention for hemostasis or death within hospital. RESULTS: 267 patients (153 females and 114 male) were enrolled. 25 patients (9.4%) died during hospitalization. ICH, upper gastrointestinal bleeding and hemoptysis were more common in patients who did not survive (P-value: <0.001, 0.033 and 0.028; respectively). There was no correlation between indication for anticoagulation and death within hospital or development of MCC. In multivariate analysis, O blood group, ICH and the number of transfused PRBC and fresh frozen plasma units were identified as independent predictors of death within hospital. Lower hemoglobin concentrations and higher pulmonary pressures on admission were independent predictors of MCC, which occurred in 47 patients (17.6%). CONCLUSION: Hospital mortality correlated with the severity of bleeding (requiring ≥ 4 units PRBC), intracranial hemorrhage and O blood group, while MCC associated with lower hemoglobin and pulmonary hypertension at the time of admission.

The Reduction in Antibiotic Use in Hospitals.

BACKGROUND: Over 350 000 patients are treated in German hospitals for sepsis or pneumonia each year. The rate of antibiotic use in hospitals is high. The growing problem of drug resistance necessitates a reconsideration of antibiotic treatment strategies. METHODS: Antibiotics were given liberally in the years 2010 and 2011 in a German 312-bed hospital. Special training, standardized algorithms to prevent unnecessary drug orders, and uniform recommendations were used in 2012 and 2013 to lessen antibiotic use. We retrospectively studied the hospital's mortality figures and microbiological findings to analyze how well these measures worked. RESULTS: Antibiotic consumption fell from 67.1 to 51.0 defined daily doses (DDD) per 100 patient days (p <0.001) from the period 2010-2011 to the period 2012-2013. The mortality of patients with a main diagnosis of sepsis fell from 1% (95/305) to 19% (63/327; p = 0.001), while that of patients with a main diagnosis of pneumonia fell from 12% (22/178) to 6% (15/235; p = 0.038). The overall mortality fell from 3.0% (623/ 20 954) to 2.5% (576/22 719; p = 0.005). In patients with nosocomial urinary tract infections with Gram-negative pathogens (not necessarily exhibiting three- or fourfold drug resistance), the rate of resistance to three or four of the antibiotics tested fell from 11% to 5%. CONCLUSION: Reducing in-hospital antibiotic use is an achievable goal and was associated in this study with lower mortality and less drug resistance. The findings of this single-center, retrospective study encourage a more limited and focused approach to the administration of antibiotics.

Prescription practices for malaria in Mozambique: poor adherence to the national protocols for malaria treatment in 22 public health facilities

Background: Current World Health Organization and national protocols recommend the 'test and treat' strategy for the management of uncomplicated malaria, to reduce over prescription of artemisinin-based combination treatment (ACT). Therefore, adherence to these protocols varies in different sub-Saharan African countries and no information is available for Mozambique. This study was conducted with the aim to evaluate the prescription practices of ACT in Mozambique. Methods: Retrospective audit of medical records corresponding to the period between July and December 2011 was conducted in 22 health units across 11 provinces in Mozambique. Two health units were selected per province according to availability of laboratory data (performing microscopy and rapid diagnostics testing-RDT or RDT only) and geographic setting (rural versus urban). At each facility, demographic data, laboratory results (blood smear or RDT), and prescription of ACT were all collected from the existing records. Results: Between July and December 2011, a total of 61,730 cases were tested for malaria, of which 42.7 % (26,369/61,730) were positive. A total of 35.361 patients were malaria negative, and ACT was prescribed to 72.0 % (25.448/35.361) of them. Prescription of ACT to malaria negative patients was higher in the central region of the country as compared to the northern and southern (81.1 % in the central region versus 72.4 and 63.7 % in the northern and southern, respectively, p = 0.000) and in urban settings (88.7 % in rural versus 58.0 % in urban settings, p = 0.000). Stock out of RDT was observed in six (27.3 %) of the health facilities. When no RDT was available, patients were empirically treated with ACT. Conclusion: Findings from this study demonstrate that health care worker's adherence to the new guidelines for malaria treatment is poor in Mozambique and prescription of ACT to malaria negative patients remains very high. Enhanced training and supervision activities, community education and external quality assurance might lead to significant improvements in the clinician's adherence to the new guideline for malaria treatment in Mozambique. Keywords: Malaria management, Over-treatment of malaria vs under-diagnosis of test-based malaria, Overtreatment of malaria