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Expert Opinion on Drug Safety Apr 2024To investigate the risk of hemorrhage associated with Immune Checkpoint Inhibitors (ICIs) and characterize its clinical features.
OBJECTIVES
To investigate the risk of hemorrhage associated with Immune Checkpoint Inhibitors (ICIs) and characterize its clinical features.
METHODS
We systematically reviewed randomized clinical trials (RCTs) of hemorrhage related to ICIs and calculated odds ratios (ORs) with 95% confidence intervals (CIs). Pharmacovigilance studies were conducted by collecting ICIs-related hemorrhage cases from the FAERS database and assessing disproportionalities by reporting odds ratios (RORs) and information components (ICs).
RESULTS
A total of 79 RCTs involving 45,100 patients were finally included in the systematic review, with four published RCTs ( = 1965) and 75 unpublished RCTs ( = 43135). The primary analysis showed no significant difference in ICIs compared to the control group (OR 1.18 [95% CI 1.00-1.38], = 0.05). In subgroup analyses, anti-PD-L1 combined with anti-CTLA-4 increased the risk of hemorrhage (OR 1.95, = 0.03), and anti-CTLA-4 increased the risk of hemorrhage in the gastrointestinal system (OR 2.23, = 0.04). 3555 cases of hemorrhage from the FAERS database were included in the disproportionate analysis, and the result suggested that ICIs increased the risk of hemorrhage (IC = 0.23).
CONCLUSION
Our study suggests that ICIs increase the risk of hemorrhage, and in particular, anti-CTLA-4 significantly increases the risk of hemorrhage in the gastrointestinal system.
Topics: Humans; CTLA-4 Antigen; Databases, Factual; Hemorrhage; Immune Checkpoint Inhibitors; Pharmacovigilance; Randomized Controlled Trials as Topic
PubMed: 38556702
DOI: 10.1080/14740338.2024.2327504 -
Vaccine Apr 2024The cross-protection of pneumococcal conjugate vaccines (PCV) against serotype 6C is not clearly documented, although 6C represents a substantial burden of pneumococcal...
BACKGROUND
The cross-protection of pneumococcal conjugate vaccines (PCV) against serotype 6C is not clearly documented, although 6C represents a substantial burden of pneumococcal disease in recent years. A systematic review by the World Health Organization that covered studies through 2016 concluded that available data were insufficient to determine if either PCV10 (which contains serotype 6B but not 6A) or PCV13 (containing serotype 6A and 6B) conferred protection against 6C.
METHODS
We performed a systematic review of randomized controlled trials and observational studies published between January 2010 - August 2022 (Medline/Embase), covering the direct, indirect, and overall effect of PCV10 and PCV13 against 6C invasive pneumococcal disease (IPD), non-IPD, nasopharyngeal carriage (NPC), and antimicrobial resistance (AMR).
RESULTS
Of 2548 publications identified, 112 were included. Direct vaccine effectiveness against 6C IPD in children ranged between 70 and 85 % for ≥ 1 dose PCV13 (n = 3 studies), was 94 % in fully PCV13 vaccinated children (n = 2), and -14 % for ≥ 1 dose of PCV10 (n = 1). Compared to PCV7, PCV13 efficacy against 6C NPC in children was 66 % (n = 1). Serotype 6C IPD rates or NPC prevalence declined post-PCV13 in most studies in children (n = 5/6) and almost half of studies in adults (n = 5/11), while it increased post-PCV10 for IPD and non-IPD in all studies (n = 6/6). Changes in AMR prevalence were inconsistent.
CONCLUSIONS
In contrast to PCV10, PCV13 vaccination consistently protected against 6C IPD and NPC in children, and provided some level of indirect protection to adults, supporting that serotype 6A but not 6B provides cross-protection to 6C. Vaccine policy makers and regulators should consider the effects of serotype 6A-containing PCVs against serotype 6C disease in their decisions.
Topics: Child; Adult; Humans; Infant; Anti-Bacterial Agents; Serogroup; Drug Resistance, Bacterial; Streptococcus pneumoniae; Pneumococcal Vaccines; Pneumococcal Infections; Vaccines, Conjugate
PubMed: 38553292
DOI: 10.1016/j.vaccine.2024.03.065 -
Research in Social & Administrative... Feb 2024Adverse drug reactions (ADRs) are known to cause hospitalisation, longer hospital stays, as well as higher healthcare costs and mortality. Unrecognised ADRs are... (Review)
Review
Understanding factors influencing the implementation of medicine risk communications by healthcare professionals in clinical practice: a systematic review using the Theoretical Domains Framework.
BACKGROUND
Adverse drug reactions (ADRs) are known to cause hospitalisation, longer hospital stays, as well as higher healthcare costs and mortality. Unrecognised ADRs are anticipated throughout the medicine lifecycle as, before the medicine reaches the market, clinical trials are conducted for a short period on a limited number of people, who might underrepresent the actual population. After the medicine reaches the market, emergent information that could affect its benefit-to-risk balance is usually shared by regulatory agencies and pharmaceutical companies through medicine risk communications. Medicines risk communications aim to prevent harm to patients by targeting their behaviour, knowledge, and attitudes, as well as those of health care professionals (HCPs). Despite their important role in translating these communications into their clinical practice, HCPs do not always adhere to the recommendations provided in risk communications. Measurement of medicine risk communications' effectiveness does not necessarily guarantee their implementation, cost-effectiveness, or transferability in real-world situations. To enhance the impact of drug regulatory interventions, implementation science has been encouraged. However, implementation science was not previously used to identify factors affecting HCPs' implementation of medicines risk communications. A recently widely used framework is the Theoretical Domain Framework (TDF). In this systematic review, the TDF was employed to categorise a range of different factors that could affect HCPs' implementation of medicine risk communications within their clinical contexts.
METHODS
The search strategy involved a set of predefined search terms and fifteen databases, such as EMBASE, PubMed, Web of Science and CINAHL PLUS. Searches were conducted from April to May 2018 and updated in June 2021 using PubMed, Scopus, and CINAHL PLUS. A second reviewer independently conducted the screening process of the initial search. The total number of records screened was 10,475. A study was included if it reported any factors influencing HCPs' uptake of medicine risk communications. Only studies with English or Arabic abstracts were included. Those studies that did not include pharmacovigilance-related medicine risk communications were excluded. Additionally, studies only assessing HCPs' practice or evaluating the effectiveness of risk minimisation measures were excluded. Likewise, studies related to occupational hazards, case reports, interventional studies, and studies not involving HCPs were excluded. In case the published information was insufficient to decide whether to include or exclude a study, the authors were contacted. Furthermore, the authors of seven eligible abstracts were contacted for full-text articles. The mixed method appraisal tool (MMAT) was used to evaluate the quality of the included studies. All included studies were assessed by one reviewer, and a total of 16 studies were assessed by two reviewers independently. Disagreements were resolved through discussion. Using thematic analysis and concept mapping, a narrative synthesis was performed, followed by a critical reflection on the synthesis process. This review presents the results of the concept mapping, which involved matching the identified factors to the TDF.
RESULTS
A total of 28 studies were included. Eleven domains influenced HCPs' implementation of medicine risk communications. A large number of studies included factors related to the "Knowledge" domain (n = 23), followed by "Beliefs about Consequences" (n = 13), "Memory, Attention and Decision Processes" (n = 12) and "Environmental Context and Resources" domains (n = 12). Seven studies reported "social influences" and six studies included factors relating to "Goals", followed by four studies involving factors related to "Social/Professional Role and Identity". Underrepresented domains included "Emotion" (n = 2), "Beliefs about Capabilities" (n = 2), "Behavioural Regulation" (n = 1), and "Reinforcement" (n = 1). On the other hand, none of the identified factors were related to the "Skills", "Optimism", or "Intentions" domains. Except for "Beliefs about Consequences", most studies contributing to the other three most commonly reported domains ("Knowledge"; "Environmental Context and Resources"; and "Memory, Attention and Decision Processes") scored low (1 or 2 out of 5) on the MMAT quality assessment. Moreover, the same number of studies (n = 5) contributing to the "Beliefs about Consequences" domain had low (1 or 2 out of 5), and intermediate (3 out of 5) scores on the MMAT.
CONCLUSION
Medicines risk communications are important tools for disseminating information that may influence the benefit-to-risk balance of medicines. Even though HCPs are required to implement the recommendations of these communications, they do not always adhere to them. Using the TDF enabled the categorization of the range of factors that affect whether or not HCPs implement the recommendations provided in a medicine risk communication. However, most of these factors relate to four domains only ("Knowledge"; "Beliefs about Consequences"; "Memory, Attention and Decision Processes"; and "Environmental Context and Resources"). Additionally, most of the studies contributing to three of these four domains were of low quality. Future research should focus on using implementation science to identify target behaviours for actionable medicine risk communications. Regulators should use such science to develop cost-effective strategies for improving the implementation of medicines risk communication by HCPs.
Topics: Humans; Health Personnel; Communication; Risk Assessment; Delivery of Health Care
PubMed: 37978010
DOI: 10.1016/j.sapharm.2023.10.004 -
International Journal of Gynecological... Aug 2023To evaluate the risk of interstitial lung disease associated with poly (ADP-ribose) polymerase inhibitors (PARPi) and characterize its clinical features.
Interstitial lung disease in patients treated with poly (ADP-ribose) polymerase inhibitors (PARPi): analysis of results from clinical trials and the FDA Adverse Events Reporting System database.
OBJECTIVE
To evaluate the risk of interstitial lung disease associated with poly (ADP-ribose) polymerase inhibitors (PARPi) and characterize its clinical features.
METHODS
We systematically reviewed phase III randomized clinical trials of interstitial lung disease related to PARPi and calculated Peto odds ratios (ORs) with 95% confidence intervals (CIs). Pharmacovigilance studies were conducted by collecting cases of PARPi-related interstitial lung disease from the FDA Adverse Events Reporting System and assessing disproportionalities by reporting ORs and information components.
RESULTS
A total of five randomized clinical trials involving 2980 patients were included. Although PARPi showed a tendency to increase the risk of interstitial lung disease compared with controls, this difference was not significant (Peto OR: 4.92; 95% CI: 0.92 to 26.35). A total of 170 cases of interstitial lung disease related to PARPi were included, with a median latency of 99 days. PARPi had a significantly increased reporting of interstitial lung disease (reporting OR: 2.86; 95% CI: 2.46 to 3.33; information component (IC): 1.49; 95% CI: 1.28 to 1.74). Our sensitivity analyses showed strong robustness of the disproportionalities between PARPi as a class, olaparib, and interstitial lung disease. Some 91.9% of patients experienced discontinuation, 51.6% achieved remission, and no deaths were reported.
CONCLUSION
Our pharmacovigilance study suggested increased reporting of interstitial lung disease related to PARPi particularly olaparib.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Ribose; Ovarian Neoplasms; Randomized Controlled Trials as Topic
PubMed: 37164363
DOI: 10.1136/ijgc-2022-004042 -
Therapeutic Innovation & Regulatory... Jul 2024Linagliptin is an oral dipeptidyl peptidase DPP-4 inhibitor, which is indicated for the treatment of Type 2 diabetes mellitus (T2DM) as monotherapy or add-on to therapy... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Linagliptin is an oral dipeptidyl peptidase DPP-4 inhibitor, which is indicated for the treatment of Type 2 diabetes mellitus (T2DM) as monotherapy or add-on to therapy with other hypoglycemic drugs.
OBJECTIVES
We aimed to summarize the evidence from randomized controlled trials (RCTs) to assess the safety of linagliptin focusing on cardiovascular risks among subjects with type 2 diabetes mellitus.
METHODS
We conducted a systematic search across the following databases: Medline, Embase, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov from inception to November 2021. Randomized controlled trials (RCTs) of linagliptin compared to placebo in patients with Type 2 diabetes were included. The primary safety points were cardiovascular (CV) adverse events including non-fatal stroke, non-fatal myocardial infarction (MI), CV death, MI, stroke, and hospitalization for unstable angina. While, secondary safety points included 17 reported adverse events such as infections, hypoglycemia and abdominal pain. Three reviewers independently screened and reviewed each study to extract relevant information. Any discrepancies were resolved by consensus. We conducted a meta-analysis using the random effects model. Pooled risk ratios (RRs) of targeted adverse events with linagliptin compared to placebo were estimated using the Mantel-Haenszel test.
RESULTS
A total of 24 studies with 19,981 adult patients were included. There was no difference in the incidence of all CV adverse events or individual CV adverse events between linagliptin and the placebo arms. The pooled estimate of the risk of upper respiratory tract infection was reported in twelve trials with a 38% risk reduction among patients treated with the linagliptin group compared to the placebo group (RR = 0.62, 95% CI: 0.45-0.85, and I = 0%), while no difference was found in other infections. For gastrointestinal disorders, the risk of abdominal pain showed a 65% risk reduction among patients treated with the linagliptin group compared to the placebo group (RR = 0.35, 95% CI: 0.16-0.77, and I = 0%).
CONCLUSION
Our study showed an overall acceptable safety profile of linagliptin in patients with T2DM. Moreover, our study showed a risk reduction of upper respiratory tract infection and abdominal pain when using linagliptin compared to placebo.
Topics: Humans; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Linagliptin; Randomized Controlled Trials as Topic
PubMed: 38634983
DOI: 10.1007/s43441-024-00637-2