New In Coagulation: July 2022

by Donna Castellone, MS, MT (ASCP) SH • July 15, 2022



The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.

Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Appropriate Use of Dose-Adjusted and Low-Intensity DOACs Defined, Urged

Dose adjustment is then the dose is reduced such as in the case of concomitant drugs that may increase the plasma DOAC. While a lower intensity of anticoagulation is used for protection and at the same time lowering the risk of bleeding versus using full intensity DOACs.

A review of RCT’s in which dose adjusted or low intensity DOACs were tested and reviewed the labeled indications from regulatory authorities. These results were compared to data from registries to determine if they aligned with the RCT findings. There were 35 RCT that used dose adjusted DOACs including dabigatran, apixaban, rivaroxaban and edoxaban. There were 29 related to stroke prevention in AF. Efficacy and safety results for dose adjusted DOACs in large RCT of AF were similar to throm found for full dose DOACs.

Low intensity DOACS are used in extended treatment of VTE, primary prevention in orthopedic surgeries, high-risk cancer patients or in post discharge high risk medical patients. These were used in 37 RCTs.

Minor variations were noted between regulatory authorities in different regions regarding criteria for dose adjustment of DOACS and were occasionally used for different clinical scenarios from those studies in RCT. Dose adjustment is mostly relevant for AF and should be done based on approved criteria. It should not be used primary or secondary VTE. Gaps in knowledge are seen in dose reduction in patients with advanced renal dysfunction, or in regards to the optimal dose for treatment in patients of Asian descent as well as those considered too frail to safely tolerate full intensity anticoagulation.

The guidelines are used for DOACs in AF however the role of reduced dose in the treatment of VTE should be made clearer.

 

Decision-Support Tool Tied to Increased Outpatient Management of PE

A study conducted at 21 Eds participated in an original decision support intervention trial four years earlier in which 10 were intervention sites and 11 were controls. A decision support champion promotion resulted in significantly higher outpatient management at intervention sites compared with controls. A peer champion-led decision support intervention to increase outpatient management of pulmonary embolism (PE) was sustainable four years after implementation.

The main outcome was frequency of outpatient PE management using this tool. It was defined as discharge home directly from the ED, stratified by the PE severity index. The safety of outpatient care was 7 day PE related hospitalization. The study looked at 1039 patients with a median age of 65, 51% were women and 47% were rated lower risk on the PE severity index. There were 278 patients treated as outpatients with four 7 day PE related hospitalization. Patients received a follow up of less than 3 days and had access to anticoagulants with long term monitoring by a pharmacy led telephone based anticoagulation monitoring service.

Issues that were discussed were that most hospitals would have a difficult time funding, starting and facilitating this program. Also, if the clinical site has many uninsured patients they wouldn't have access to both the anticoagulation medication and close follow up.

 

Beta-Thalassemia Gene Tx Gets Ringing Endorsement From FDA Advisers

The hemoglobinopathy beta-thalassemia can be associated with life long anemia and frequent red blood cell transfusions. This results in reduced quality of life and survival. Allogeneic hematopoietic stem cell transplantation (HSCT) using human leukocyte antigen (HLA) matched donors result in the most favorable outcomes however there are few donors available.

An FDA advisory committee unanimously recommended betibeglogene autotemcel (beti-cel) for approval in patients with transfusion-dependent beta-thalassemia, a chronic inherited blood disorder. This potentially curative option should allow patients to stop transfusions with a normal or near normal hemoglobin.

Beti-cel is an LVV gene therapy that consists of a patient's own blood stem cells that have been genetically modified ex vivo with BB305 LVV. In vivo, these cells differentiate into red blood cells with sufficient functional beti-cel-derived hemoglobin A to eliminate the need for transfusions in most patients.

In the study 32/36 patients in the phase III studies achieved transfusion independence which is defined as not requiring a transfusion for 12 months while maintaining a hemoglobin of at least 9 g/dL. This was seen for all genotypes and in pediatric patients as young as 4 years old.

Beti-cel's saftery profile is similar to HSCT. However gene therapy is also associated with a prevalent delay in platelet engraftment and prolonged thrombocytopenia. Future concerns include the development of acute myeloid leukemia and myelodysplastic syndromes reported with LVV products for sickle cell disease.

 

A New Treatment of Choice for Basilar Thrombosis, Plus Other Recent Stroke Data

REVIEW OF A COMMENTARY on the results from the 8th European Stroke Organization Congress about the treatment of basilar thrombosis.

Previously there were two small trials in China, BEST and BASICS that were unable to show a benefit of thrombectomy over best medical care in people with occlusion of the basilar artery. Two new large randomized trials from China now show that thrombectomy is superior.

The BAOCHE trial looked at patients with a NIH stroke scale of 6 or more presenting within a time of 24 hours were included. The primary endpoint of a modified Rankin Scale of 0-3 after 90 days was achieved with thrombectomy in 51/110 patients versus 26/107 in those receiving best medical treatment. Benefits for mortality with thrombectomy were also seen (31% vs 42%). With only a small risk for ICH.

The ATTENTION trial used a shorter time interval of 12 hours and patients were randomized 2:1 to receive either endovascular treatment or best medical management and used the same endpoint as the BAOCHE trial. This was achieved in 104/220 patients with thrombectomy versus 26/114 receiving best medical management. A reduction in mortality from 36% to 55% was seen. The rate of ICH was 5% with thrombectomy versus 0%.

Treatment for thrombolysis is Tenecteplase which is given as a bolus and also alteplase which is given as a bolus and then 1 hour infusion.

The Canadian Alteplase Compared to Tenecteplase trial compared tenecteplase in a dose of 0.25 mg/kg body weight with standard dose of alteplase in 1600 patients. The primary endpoint was a modified Rankin Scale score of 0-1 at day 90, and the inclusion time was 4.5 hours. No difference was seen in the primary or secondary endpoints and outcomes. Tenecteplase is easier to use however it is not approved in many countries or reimbursed. The NOR-TEST 2 trial used a higher dose of Tenecteplase versus alteplase and had to be terminated after 216 patients because there was a significant increased risk for hemorrhage.

The ACTIMIS study looked at a new antithrombotic glenzocimab which is a monoclonal antibody against the platelet glycoprotein GPVI which inhibits thrombosis. This was investigated for safety in 106 patients and demonstrated no difference in any bleeding. A favorable outcome was seen in the risk of ICH (1% vs 8%) and mortality (8% vs 19%). A larger phase 3 trial is being conducted.

 


 

JOURNAL CLUB

 

Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke

A Post Hoc Analysis From the AUGUSTUS Trial

M. Cecilia Bahit, MD1; Amit N. Vora, MD, MPH2,3; Zhuokai Li, PhD3; et alDaniel M. Wojdyla, MS3; Laine Thomas, PhD3; Shaun G. Goodman, MD, MSc4,5; Ronald Aronson, MD6; J. Dedrick Jordan, MD, PhD7; Brad J. Kolls, MD, PhD3,7; Keith E. Dombrowski, MD8; Dragos Vinereanu, MD, PhD9; Sigrun Halvorsen, MD, PhD10; Otavio Berwanger, MD, PhD11; Stephan Windecker, MD12; Roxana Mehran, MD13,14; Christopher B. Granger, MD3; John H. Alexander, MD, MHS3; Renato D. Lopes, MD, MHS, PhD3

Author Affiliations

JAMA Cardiol. Published online May 25, 2022. doi:10.1001/jamacardio.2022.1166

Importance Data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with atrial fibrillation (AF) and recent acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI).

Objective Determine the efficacy and safety of apixaban or vitamin K antagonists (VKA) and aspirin or placebo according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE).

Design, Setting, and Participants In this prospective, multicenter, 2-by-2 factorial, randomized clinical trial, post hoc parallel analyses were performed to compare randomized treatment regimens according to presence or absence of prior stroke/TIA/TE using Cox proportional hazards models. Patients with AF, recent ACS or PCI, and planned use of P2Y12 inhibitors for 6 months or longer were included; 33 patients with missing data about prior stroke/TIA/TE were excluded.

Interventions Apixaban (5 mg or 2.5 mg twice daily) or VKA and aspirin or placebo.

Main Outcomes and Measures Major or clinically relevant nonmajor (CRNM) bleeding.

Results Of 4581 patients included, 633 (13.8%) had prior stroke/TIA/TE. Patients with vs without prior stroke/TIA/TE were older; had higher CHA2DS2-VASC and HAS-BLED scores; and more frequently had prior bleeding, heart failure, diabetes, and prior oral anticoagulant use. Apixaban was associated with lower rates of major or CRNM bleeding and death or hospitalization than VKA in patients with (hazard ratio [HR], 0.69; 95% CI, 0.46-1.03) and without (HR, 0.68; 95% CI, 0.57-0.82) prior stroke/TIA/TE. Patients without prior stroke/TIA/TE receiving aspirin vs placebo had higher rates of bleeding; this difference appeared less substantial among patients with prior stroke/TIA/TE (P=.01 for interaction). Aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with (HR, 0.71; 95% CI, 0.42-1.20) and without (HR, 0.93; 95% CI, 0.72-1.21) prior stroke/TIA/TE (not statistically significant).

Conclusions and Relevance The safety and efficacy of apixaban compared with VKA was consistent with the AUGUSTUS findings, irrespective of prior stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. Although aspirin may have some benefit in patients with prior stroke, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status.

 

Efficacy and Safety Considerations With Dose-Reduced Direct Oral Anticoagulants

Behnood Bikdeli, MD, MS1,2,3,4; Farbod Zahedi Tajrishi, MD5; Parham Sadeghipour, MD6,7; et alAzita H. Talasaz, PharmD8,9; John Fanikos, RPH, MBA10; Giuseppe Lippi, MD11; Deborah M. Siegal, MD, MSc12; John W. Eikelboom, MBBS13; Manuel Monreal, MD, PhD14; David Jimenez, MD, PhD15; Jean M. Connors, MD16; Walter Ageno, MD, PhD17; Geoffrey D. Barnes, MD, MSc18; Gregory Piazza, MD, MS1,2; Dominick J. Angiolillo, MD, PhD19; Sahil A. Parikh, MD4,20; Ajay J. Kirtane, MD, SM4,20; Renato D. Lopes, MD, PhD21,22; Deepak L. Bhatt, MD, MPH1; Jeffrey I. Weitz, MD23,24; Roxana Mehran, MD25; Harlan M. Krumholz, MD, SM3,26,27; Samuel Z. Goldhaber, MD1,2; Gregory Y. H. Lip, MD28,29

JAMA Cardiol. Published online June 1, 2022. doi:10.1001/jamacardio.2022.1292

Importance Dose-reduced regimens of direct oral anticoagulants (DOACs) may be used for 2 main purposes: dose-adjusted treatment intended as full-intensity anticoagulation (eg, for stroke prevention in atrial fibrillation [AF] in patients requiring dose reduction) or low-intensity treatment (eg, extended-duration treatment of venous thromboembolism [VTE]). We reviewed randomized clinical trials (RCTs) to understand the scenarios in which dose-adjusted or low-intensity DOACs were tested and reviewed the labeled indications by regulatory authorities, using data from large registries to assess whether the use of dose-reduced DOACs in routine practice aligned with the findings of RCTs.

Observations Among 4191 screened publications, 35 RCTs that used dose-adjusted DOACs were identified for dabigatran, apixaban, rivaroxaban, and edoxaban. Of these 35 RCTs, 29 were related to stroke prevention in AF. Efficacy and safety results for dose-adjusted DOACs in large RCTs of AF were similar to those found for full-dose DOACs. To our knowledge, dabigatran, apixaban, and rivaroxaban have not been studied as dose-adjusted therapy for acute VTE treatment. Low-intensity DOACs were identified in 37 RCTs. Low-intensity DOACs may be used for extended-duration treatment of VTE (apixaban and rivaroxaban), primary prevention in orthopedic surgeries (dabigatran, apixaban, and rivaroxaban), primary prevention in ambulatory high-risk cancer patients (apixaban and rivaroxaban) or (postdischarge) high-risk medical patients (rivaroxaban), in stable atherosclerotic vascular disease, or after a recent revascularization for peripheral artery disease in conjunction with aspirin (rivaroxaban). Minor variations exist between regulatory authorities in different regions regarding criteria for dose adjustment of DOACs. Data from large registries indicated that dose-reduced DOACs were used occasionally with doses or for clinical scenarios different from those studied in RCTs or recommended by regulatory authorities.

Conclusions and Relevance Dose adjustment and low-intensity treatment are 2 different forms of dose-reduced DOACs. Dose adjustment is mostly relevant for AF and should be done based on the approved criteria. Dose adjustment of DOACs should not be used for acute VTE treatment in most cases. In contrast, low-intensity DOACs may be used for primary or secondary VTE prevention for studied and approved indications.

Attention should be given to routine practice patterns to align the daily clinical practice with existing evidence of safety and efficacy.

 

Effect of 15-mg Edoxaban on Clinical Outcomes in 3 Age Strata in Older Patients With Atrial Fibrillation

Masaru Kuroda, MD, PhD1; Eiji Tamiya, MD, PhD2; Takahisa Nose, MD, PhD3; et alAkiyoshi Ogimoto, MD, PhD4; Junki Taura, MS5; Yuki Imamura, MS5; Masayuki Fukuzawa, MS5; Takuya Hayashi, MS6; Masaharu Akao, MD, PhD7; Takeshi Yamashita, MD, PhD8; Gregory Y. H. Lip, MD9,10; Ken Okumura, MD, PhD11

Importance Long-term use of oral anticoagulants (OACs) is necessary for stroke prevention in patients with atrial fibrillation (AF). The effectiveness and safety of OACs in extremely older patients (ie, aged 80 years or older) with AF and at high risk of bleeding needs to be elucidated.

Objective To examine the effects of very low-dose edoxaban (15 mg) vs placebo across 3 age strata (80-84 years, 85-89 years, and ≥90 years) among patients with AF who were a part of the Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE–AF) trial.

Design, Setting, and Participants This prespecified subanalysis of a phase 3, randomized, double-blind, placebo-controlled trial was conducted from August 5, 2016, to December 27, 2019. Patients with AF aged 80 years or older who were not considered candidates for standard-dose OACs were included in the study; reasons these patients could not take standard-dose OACs included low creatinine clearance (<30 mL per minute), low body weight (≤45 kg), history of bleeding from critical organs, continuous use of nonsteroidal anti-inflammatory drugs, or concomitant use of antiplatelet drugs. Eligible patients were recruited randomly from 164 hospitals in Japan and were randomly assigned 1:1 to edoxaban or placebo.

Interventions Edoxaban (15 mg once daily) or placebo.

Main Outcomes and Measures The primary efficacy end point was the composite of stroke or systemic embolism. The primary safety end point was International Society on Thrombosis and Hemostasis–defined major bleeding.

Results A total of 984 patients (mean [SD] age: age group 80-84 years, 82.2 [1.4] years; age group 85-89 years, 86.8 [1.4] years; age group ≥90 years, 92.3 [2.1] years; 565 women [57.4%]) were included in this study. In the placebo group, estimated (SE) event rates for stroke or systemic embolism increased with age and were 3.9% (1.2%) per patient-year in the group aged 80 to 84 years (n=181), 7.3% (1.7%) per patient-year in the group aged 85 to 89 years (n=184), and 10.1% (2.5%) per patient-year in the group aged 90 years or older (n=127). A 15-mg dose of edoxaban consistently decreased the event rates for stroke or systemic embolism with no interaction with age (80-84 years, hazard ratio [HR], 0.41; 95% CI, 0.13-1.31; P=.13; 85-89 years, HR, 0.42; 95% CI, 0.17-0.99; P = .05; ≥90 years, HR, 0.23; 95% CI, 0.08-0.68; P = .008; interaction P = .65). Major bleeding and major or clinically relevant nonmajor bleeding events were numerically higher with edoxaban, but the differences did not reach statistical significance, and there was no interaction with age. There was no difference in the event rate for all-cause death between the edoxaban and placebo groups in all age strata.

Conclusions and Relevance Results of this subanalysis of the ELDERCARE–AF randomized clinical trial revealed that among Japanese patients aged 80 years or older with AF who were not considered candidates for standard OACs, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism consistently across all 3 age strata, including those aged 90 years or older, albeit with a higher but nonstatistically significant incidence of bleeding.

 

Rivaroxaban Monotherapy vs Combination Therapy With Antiplatelets on Total Thrombotic and Bleeding Events in Atrial Fibrillation With Stable Coronary Artery Disease

A Post Hoc Secondary Analysis of the AFIRE Trial

Ryo Naito, MD, MSc, PhD1; Katsumi Miyauchi, MD, PhD2; Satoshi Yasuda, MD, PhD3,4; et alKoichi Kaikita, MD, PhD5; Masaharu Akao, MD, PhD6; Junya Ako, MD, PhD7; Tetsuya Matoba, MD, PhD8; Masato Nakamura, MD, PhD9; Nobuhisa Hagiwara, MD, PhD10; Kazuo Kimura, MD, PhD11; Atsushi Hirayama, MD, PhD12; Kunihiko Matsui, MD, MPH13; Hisao Ogawa, MD, PhD14; for the AFIRE Investigators

Importance Appropriate regimens of antithrombotic therapy for patients with atrial fibrillation (AF) and coronary artery disease (CAD) have not yet been established.

Objective To compare the total number of thrombotic and/or bleeding events between rivaroxaban monotherapy and combined rivaroxaban and antiplatelet therapy in such patients.

Design, Setting, and Participants This was a post hoc secondary analysis of the Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease (AFIRE) open-label, randomized clinical trial. This multicenter analysis was conducted from February 23, 2015, to July 31, 2018. Patients with AF and stable CAD who had undergone percutaneous coronary intervention or coronary artery bypass grafting 1 or more years earlier or who had angiographically confirmed CAD not requiring revascularization were enrolled. Data were analyzed from September 1, 2020, to March 26, 2021.

Interventions Rivaroxaban monotherapy or combined rivaroxaban and antiplatelet therapy.

Main Outcomes and Measures The total incidence of thrombotic, bleeding, and fatal events was compared between the groups. Cox regression analyses were used to estimate the risk of subsequent events in the 2 groups, with the status of thrombotic or bleeding events that had occurred by the time of death used as a time-dependent variable.

Results A total of 2215 patients (mean [SD] age, 74 [8.2] years; 1751 men [79.1%]) were included in the modified intention-to-treat analysis. The total event rates for the rivaroxaban monotherapy group (1107 [50.0%]) and the combination-therapy group (1108 [50.0%]) were 12.2% (135 of 1107) and 19.2% (213 of 1108), respectively, during a median follow-up of 24.1 (IQR, 17.3-31.5) months. The mortality rate was 3.7% (41 of 1107) in the monotherapy group and 6.6% (73 of 1108) in the combination-therapy group. Rivaroxaban monotherapy was associated with a lower risk of total events compared with combination therapy (hazard ratio, 0.62; 95% CI, 0.48-0.80; P<.001). Monotherapy was an independent factor associated with a lower risk of subsequent events compared with combination therapy. The mortality risk after a bleeding event (monotherapy, 75% [6 of 8]; combination therapy, 62.1% [18 of 29]) was higher than that after a thrombotic event (monotherapy, 25% [2 of 8]; combination therapy, 37.9% [11 of 29]).

Conclusions and Relevance Rivaroxaban monotherapy was associated with lower risks of total thrombotic and/or bleeding events than combination therapy in patients with AF and stable CAD. Tapered antithrombotic therapy with a sole anticoagulant should be considered in these patients.

 

Association of Metformin Use With Risk of Venous Thromboembolism in Adults With Type 2 Diabetes

Tingting Sha; Yuqing Zhang; Changjun Li; Guanghua Lei; Jing Wu; Xiaoxiao Li; Zidan Yang; Chao Zeng; Jie Wei

Am J Epidemiol. 2022;191(5):856-866.

Abstract

Metformin is hypothesized to protect against the risk of venous thromboembolism (VTE); however, there is a paucity of data supporting this hypothesis. Among individuals aged 40–90 years with a diagnosis of type 2 diabetes in the Health Improvement Network database (2000–2019), we compared the risks of incident VTE, pulmonary embolism, and deep vein thrombosis among metformin initiators with those among sulfonylurea initiators. Individuals were followed from their first prescription refill to an incident VTE, drug discontinuation, switching or augmenting, plan disenrollment, or the end of the study, whichever occurred first. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox model, adjusting for confounders using inverse probability of treatment weighting. Among 117,472 initiators of metformin and 13,835 initiators of sulfonylureas, 555 (1.3/1,000 person-years) and 75 (2.1/1,000 person-years) VTE cases occurred in each group, respectively. The multivariable-adjusted HR was 0.65 (95% CI: 0.51, 0.84). The corresponding risks for pulmonary embolism (adjusted HR = 0.71, 95% CI: 0.50, 1.01) and deep vein thrombosis (adjusted HR = 0.64, 95% CI: 0.48, 0.87) were also lower in metformin initiators than in sulfonylurea initiators. Our study provided empirical evidence to support a lower risk of VTE after initiation of metformin as compared with sulfonylureas among patients with type 2 diabetes.

 

Association of Tramadol With All-Cause Mortality, Cardiovascular Diseases, Venous Thromboembolism, and hip Fractures Among Patients With Osteoarthritis

Lingyi Li; Shelby Marozoff; Na Lu, Hui Xie; Jacek A. Kopec; Jolanda Cibere; John M. Esdaile; J. Antonio Aviña-Zubieta

Arthritis Res Ther. 2022;24(85)

Abstract

Background: The use of tramadol among osteoarthritis (OA) patients has been increasing rapidly around the world, but population-based studies on its safety profile among OA patients are scarce. We sought to determine if tramadol use in OA patients is associated with increased risks of all-cause mortality, cardiovascular diseases (CVD), venous thromboembolism (VTE), and hip fractures compared with commonly prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) or codeine.

Methods: Using administrative health datasets from British Columbia, Canada, we conducted a sequential propensity score-matched cohort study among all OA patients between 2005 and 2013. The tramadol cohort (i.e., tramadol initiation) was matched with four comparator cohorts (i.e., initiation of naproxen, diclofenac, cyclooxygenase-2 [Cox-2] inhibitors, or codeine). Outcomes are all-cause mortality, first-ever CVD, VTE, and hip fractures within the year after the treatment initiation. Patients were followed until they either experienced an event, left the province, or the 1-year follow-up period ended, whichever occurred first. Cox proportional hazard models were used to estimate hazard ratios after adjusting for competing risk of death.

Results: Overall, 100,358 OA patients were included (mean age: 68 years, 63% females). All-cause mortality was higher for tramadol compared to NSAIDs with rate differences (RDs/1000 person-years, 95% CI) ranging from 3.3 (0.0–6.7) to 8.1 (4.9–11.4) and hazard ratios (HRs, 95% CI) ranging from 1.2 (1.0–1.4) to 1.5 (1.3–1.8). For CVD, no differences were observed between tramadol and NSAIDs. Tramadol had a higher risk of VTE compared to diclofenac, with RD/1000 person-years (95% CI) of 2.2 (0.7–3.7) and HR (95% CI) of 1.7 (1.3–2.2). Tramadol also had a higher risk of hip fractures compared to diclofenac and Cox-2 inhibitors with RDs/1000 person-years (95% CI) of 1.9 (0.4–3.4) and 1.7 (0.2–3.3), respectively, and HRs (95% CI) of 1.6 (1.2–2.0) and 1.4 (1.1–1.9), respectively. No differences were observed between tramadol and NSAIDs for all events.

Conclusions: OA patients initiating tramadol have an increased risk of mortality, VTE, and hip fractures within 1 year compared with commonly prescribed NSAIDs, but not with codeine.