Causality assessment of adverse drug reaction: A narrative review to find the most exhaustive and easy-to-use tool in post-authorization settings.

BACKGROUND: The core motive of pharmacovigilance is the detection and prevention of adverse drug reactions (ADRs), to improve the risk-benefit balance of the drug. However, the causality assessment of ADRs remains a major challenge among clinicians, and none of the available tools of causality assessment used for assessing ADRs have been universally accepted. OBJECTIVE: To provide an up-to-date overview of the different causality assessment tools. METHODS: We conducted electronic searches in MEDLINE, EMBASE, and the Cochrane database. The eligibility of each tool was screened by three reviewers. Each eligible tool was then scrutinized for its domains (the reported specific set of questions/areas used for calculating the likelihood of cause-and-effect relation of an ADR) to discover the most comprehensive tool. Finally, we subjectively assessed the tool's ease-of-use in a Canadian, Indian, Hungarian, and Brazilian clinical context. RESULTS: Twenty-one eligible causality assessment tools were retrieved. Naranjo's tool and De Boer's tool appeared the most comprehensive among all the tools, covering 10 domains each. Regarding "ease-of-use" in a clinical setting, we judged that many tools were hard to implement in a clinical context because of their complexity and/or lengthiness. Naranjo's tool, Jones's tool, Danan and Benichou's tool, and Hsu and Stoll's tool appeared to be the easiest to implement into various clinical contexts. CONCLUSION: Among the many tools identified, 1981 Naranjo's scale remains the most comprehensive and easy to use for performing causality assessment of ADRs. Upcoming analysis should compare the performance of each ADR tool in clinical settings.

Impact of COVID-19 on the Prescribing Pattern of Oral Anticoagulants for Atrial Fibrillation After Cardiac Surgery.

BACKGROUND: Because of logistic challenges associated with the COVID-19 pandemic, direct oral anticoagulants (DOAC) were favored over warfarin in patients presenting postoperative atrial fibrillation (AF) after cardiac surgery in our institution. Considering the limited evidence supporting the use of DOAC in this context, we sought to evaluate the safety and efficacy of this practice change. METHODS: A retrospective study was performed with patients from the Quebec City metropolitan area who were hospitalized at the Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval following cardiac surgery and who required oral anticoagulant (OAC) for postoperative AF. The primary objective was to compare the pre- and peri-COVID-19 period for OAC prescribing patterns and the incidence of thrombotic and bleeding events at 3 months post-surgery. The secondary objective was to compare DOAC to warfarin in terms of thrombotic events and bleeding events. RESULTS: A total of 233 patients were included, 142 from the pre-COVID-19 and 91 from the peri-COVID-19 period, respectively. Both groups had equivalent proportions of preoperative AF (48%) and new-onset postoperative AF (52%). The proportion of patients treated with a DOAC increased from 13% pre-COVID-19 to 82% peri-COVID-19. This change in practice was not associated with a significant difference in the incidence of thrombotic or bleeding events 3 months postoperatively. However, compared to DOAC, warfarin was associated with a higher incidence of major bleeding. Only 1 thrombotic event was reported with warfarin, and none were reported with DOAC. CONCLUSION: This study suggests that DOAC are an effective and safe alternative to warfarin to treat postoperative AF after cardiac surgery and that this practice can be safely maintained.

Reporting Rates of Opioid-Related Adverse Events Since 1965 in Canada: A Descriptive Retrospective Study.

BACKGROUND: Patients with chronic or acute/postoperative pain frequently use opioids. However, opioids may cause considerable adverse reactions (ARs), such as respiratory depression, which could be lethal. Unfortunately, only 5% of drug-related ARs (including those to opioids) are reported to health authorities. Therefore, little is known regarding the occurrence of opioid-related ARs at the population level. OBJECTIVE: The aim of this study was to investigate how the rates of reported opioid-related ARs have changed in Canada since 1965. METHODS: Our retrospective study examined trends of reported opioid-related ARs occurring in hospitalized and outpatients. Data on opioid-related ARs and mortality between 1965 and 2019 were obtained from the Canada Vigilance and Statistics Canada databases. Descriptive and Joinpoint regression analyses were performed. RESULTS: Oxycodone and normethadone were the most and least involved opioid agents, respectively, among the 18,407 reported ARs. The highest rate of reported opioid ARs (3.8 per 100,000 person-years) was recorded in 2012, whereas the lowest was recorded in 1965 (0.1 per 100,000 person-years). Between 1965 and 2019, annual rates climbed by 4.2% (95% confidence interval [CI] 3.1-5.2), and many fluctuations were observed: 1965-1974: +22.3% (95% CI 12.0-33.6); 1974-2000: - 4.1% (95% CI - 5.3 to - 2.9); 2000-2008: +30.3% (95% CI 22.6-38.4); 2008-2014: +4.1% (95% CI - 1.5 to 10.1); 2014-2017: -26.0% (95% CI - 44.7 to - 0.9); and, finally, 2017-2019: +35.4% (95% CI 3.8-76.7). CONCLUSION: Reported opioid-related ARs have increased since 1965, although fluctuations were observed in recent decades. The absolute number of opioid-related ARs might be seriously underestimated. Future studies should look into how to close this gap.

Long-Term Retrospective Analysis of Gene Therapy with Alipogene Tiparvovec and Its Effect on Lipoprotein Lipase Deficiency-Induced Pancreatitis.

Alipogene tiparvovec (Glybera) is a gene therapy product approved in Europe under the "exceptional circumstances" pathway as a treatment for lipoprotein lipase deficiency (LPLD), a rare genetic disease resulting in chylomicronemia and a concomitantly increased risk of acute and recurrent pancreatitis, with potentially lethal outcome. This retrospective study analyzed the frequency and severity of pancreatitis in 19 patients with LPLD up to 6 years after a single treatment with alipogene tiparvovec. An independent adjudication board of three pancreas experts, blinded to patient identification and to pre- or post-gene therapy period, performed a retrospective review of data extracted from the patients' medical records and categorized LPLD-related acute abdominal pain events requiring hospital visits and/or hospitalizations based on the adapted 2012 Atlanta diagnostic criteria for pancreatitis. Both entire disease time period data and data from an equal time period before and after gene therapy were analyzed. Events with available medical record information meeting the Atlanta diagnostic criteria were categorized as definite pancreatitis; events treated as pancreatitis but with variable levels of laboratory and imaging data were categorized as probable pancreatitis or acute abdominal pain events. A reduction of approximately 50% was observed in all three categories of the adjudicated post-gene therapy events. Notably, no severe pancreatitis and only one intensive care unit admission was observed in the post-alipogene tiparvovec period. However, important inter- and intraindividual variations in the pre- and post-gene therapy incidence of events were observed. There was no relationship between the posttreatment incidence of events and the number of LPL gene copies injected, the administration of immunosuppressive regimen or the percent triglyceride decrease achieved at 12 weeks (primary end point in the prospective clinical studies). Although a causal relationship cannot be established and despite the limited number of individuals evaluated, results from this long-term analysis suggest that alipogene tiparvovec was associated with a lower frequency and severity of pancreatitis events, and a consequent overall reduction in health care resource use up to 6 years posttreatment.

Immune responses to intramuscular administration of alipogene tiparvovec (AAV1-LPL(S447X)) in a phase II clinical trial of lipoprotein lipase deficiency gene therapy.

Cellular immune responses to adeno-associated viral (AAV) vectors used for gene therapy have been linked to attenuated transgene expression and loss of efficacy. The impact of such cellular immune responses on the clinical efficacy of alipogene tiparvovec (Glybera; AAV1-LPL(S447X); uniQure), a gene therapy consisting of intramuscular administration of a recombinant AAV1 mediating muscle-directed expression of lipoprotein lipase (LPL), was investigated. Five subjects with LPL deficiency (LPLD) were administered intramuscularly with a dose of 1 × 10(12) gc/kg alipogene tiparvovec. All subjects were treated with immune suppression starting shortly before administration of alipogene tiparvovec and maintained until 12 weeks after administration. Systemic antibody and T cell responses against AAV1 and LPL(S447X), as well as local cellular immune responses in the injected muscle, were investigated in five LPLD subjects. Long-term transgene expression was demonstrated despite a transient systemic cellular response and a stable humoral immune response against the AAV1 capsid protein. Cellular infiltrates were found in four of the five subjects but were not associated with adverse clinical events or elevation of inflammation markers. Consistent herewith, CD8+ T cells in the infiltrates lacked cytotoxic potential. Furthermore, FoxP3+/CD4+ T cells were found in the infiltrates, suggesting that multiple mechanisms contribute to local tolerance. Systemic and local immune responses induced by intramuscular injection of alipogene tiparvovec did not appear to have an impact on safety and did not prevent LPL transgene expression. These findings support the use of alipogene tiparvovec in individuals with LPLD and indicate that muscle-directed AAV-based gene therapy remains a promising approach for the treatment of human diseases.

Gene therapy for lipoprotein lipase deficiency.

PURPOSE OF REVIEW: The present review summarizes the clinical development of adeno-associated viral vector (AAV)1-lipoprotein lipase (LPL)S447X gene therapy (alipogene tiparvovec) for lipoprotein lipase deficiency. Lipoprotein lipase deficiency is a rare inherited disease characterized by severe hypertriglyceridaemia, chylomicronaemia and risk of recurrent pancreatitis or other complications. AAV1-LPLS447X gene therapy is based on the rationale that by adding episomal copies of functional LPL genes into muscle cells lacking active LPL, metabolic function could be improved or restored. RECENT FINDINGS: AAV1-LPLS447X is a nonreplicating and nonintegrating AAV of serotype 1 designed to deliver and express the human LPL gene variant S447X. The clinical development programme for AAV1-LPLS447X consisted of two observational studies, three open-label interventional studies and one case note review analysis. Intramuscular administration of AAV1-LPLS447X was generally well tolerated and was associated with reduction in overall pancreatitis incidence and signs of clinical improvement up to 2 years after administration. Results of interventional studies suggest that markers of postprandial metabolism could be more accurate than fasting plasma triglyceride concentration to monitor the effect of AAV1-LPLS447X . SUMMARY: The overall benefit-risk ratio of AAV1-LPLS447X gene therapy appears positive to date, particularly for the patients presenting the highest risk of complications.

Salivary pH as a marker of plasma adiponectin concentrations in Women.

BACKGROUND: Plasma adiponectin is a significant correlate of the pro-inflammatory cardiometabolic risk profile associated with obesity and type 2 diabetes. Salivary pH is influenced by several cardiometabolic risk components such as inflammation, oxidation and numerous oral and systemic health modulators, including the menopausal status. This study aimed to assess the association between plasma adiponectin concentrations and salivary pH in women according to the menopausal status. METHOD: Unstimulated saliva collection was performed in 151 Caucasian women of French-Canadian origin (53 premenopausal women (PMW) and 98 menopausal women (MW)). Student's t test, ANOVA and linear regression models were used to assess the association between plasma adiponectin concentrations and salivary pH. RESULTS: Plasma adiponectin levels increased as a function of salivary pH in the whole sample and among MW (r = 0.29 and r = 0.36, p < 0.001). The proportion of the variance of plasma adiponectin levels explained by the salivary pH (R2) was 10.8% (p < 0.001). Plasma adiponectin levels progressively increased across salivary pH quartiles (p = 0.005). CONCLUSIONS: These results suggest that salivary pH is a significant correlate of plasma adiponectin levels in women. With the increasing prevalence of type 2 diabetes and obesity, new technologies should be developed to more easily monitor health status, disease onset and progression. Salivary pH, a simple, inexpensive and non-invasive measure, could be a very promising avenue.

On-site management of investigational products and drug delivery systems in conformity with Good Clinical Practices (GCPs).

BACKGROUND: Investigators and research teams participating in clinical trials have to deal with complex investigational products, study designs, and research environments. The emergence of new drug delivery systems and investigational products combining more than one drug and the development of biodrugs such as monoclonal antibodies, peptides, siRNA, and gene therapy to treat orphan or common diseases constitute a new challenge for investigators and clinical sites. PURPOSE: We describe the requirements and challenges of drug management in conformity with Good Clinical Practices (GCPs) for investigators and sites participating in clinical trials. Review At all sites participating in clinical trials, standard operating procedures (SOPs) covering the critical path of drug and drug delivery systems management are required. All steps should be auditable, including reception, validation, storage, access, preparation, distribution, techniques of administration, use, return, and destruction of research products. Biodrugs require traceability and specific SOPs on the management of potential immune reactions. Investigational products must be stored under standard auditable conditions. The traceability of storage conditions (including temperature) requires these conditions to be monitored on a continuous basis. A dedicated space with restricted access limited to authorized qualified personnel facilitates the monitoring. CONCLUSIONS: The development of standardized, auditable settings and the application of dedicated, site-specific SOPs for the management of investigational products and drug delivery systems contribute to guarantee the compliance to GCP requirements.

Etiology and risk of lactescent plasma and severe hypertriglyceridemia.

BACKGROUND: Plasma lactescence is a clinical sign of severe hypertriglyceridemia (hyperTG; TG >10 mmol/L), which is likely to be observed more frequently in the next decades because of the growing prevalence of obesity and diabetes worldwide. OBJECTIVE: The objective of this study was to describe the clinical expression of plasma lactescence. METHODS: A total of 354 subjects with lactescent plasma hyperTG (mean TG ± SD: 17.1 ± 1.8 mmol/L) were classified according to blood appearance, etiology, and biochemical characteristics. The resulting phenotypes were compared with those of 364 normolipidemic controls (TG ≤2 mmol/L) and 487 clear plasma hyperTG subjects (5 < TG ≤9 mmol/L). The association of lactescent plasma with clinical covariates (obesity, coronary artery disease, peripheral artery disease, hypertension, diabetes, glucose intolerance, pancreatitis, and response to TG-lowering drugs) was performed by the use of multiple regression models. RESULTS: The risk of pancreatitis increased as a function of the plasma creamy white collar and was the greatest among nonobese individuals with early-onset lactescence not responding to current TG-lowering drugs (familial hyperchylomicronemia). Patients with lactescent plasma and yellowish palmar xanthomas (dysbetalipoproteinemia) responded significantly better to fibrates than the other severe hyperTG phenotypes but were at greater risk of peripheral atherosclerosis. Overweight and obese patients with a creamy supernatant and a cloudy, cream of tomato, infranatant caused by hyper apolipoprotein B showed the most deleterious cardiometabolic risk profile, followed by the severe hyperTG-normal apolipoprotein B phenotype, the most frequent cause of lactescent plasma. CONCLUSION: Lactescent plasma hyperTG represents a clinically heterogeneous group of high-risk patients.

Contribution of adiponectin to the cardiometabolic risk of postmenopausal women with loss-of-function lipoprotein lipase gene mutations.

OBJECTIVE: Cardiovascular risk significantly increases after menopause. Lipoprotein lipase (LPL) is a key enzyme in the metabolism of triglyceride (TG)-rich lipoproteins, which contributes to cardiometabolic homeostasis. Adiponectin is an adipocytokine, which also influences the cardiometabolic status. The objective of this study was to evaluate the contribution of plasma adiponectin to the cardiometabolic status of women with loss-of-function LPL gene variants (LPLD). METHODS: A total of 568 white women (127 women with partial LPL deficiency and 441 controls) were included. The association of plasma adiponectin with LPLD was assessed using multiple regression models. Cardiometabolic covariates included anthropometrics, lipids (TG, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B), fasting glucose, and smoking status. RESULTS: Plasma adiponectin concentration was significantly lower in women with LPLD (8.69 ± 5.13 vs 6.50 ± 4.66 µg/mL; P < 0.001). Women with LPLD also presented a significantly higher risk of coronary artery disease (P = 0.013). After menopause, adiponectin explained a significant (P < 0.01) proportion of the variance in cardiometabolic covariates in both groups. This effect was more pronounced in women with LPLD: 13% versus 8% for high-density lipoprotein cholesterol, 8% versus 4% for waist circumference, 9% versus 5% for fasting TG, and 6% versus 2% for fasting glucose. When controlling for cardiometabolic covariates, low adiponectin values independently contributed to the clinical expression of LPLD in postmenopausal women (odds ratio, 5.55; 95% CI, 0.04-0.81; P = 0.025). CONCLUSIONS: In conclusion, these results suggest that a low plasma adiponectin level significantly contributes to the cardiometabolic risk profile of postmenopausal women with LPLD, independently of anthropometrics, lipids, and other covariates.

Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency.

Alipogene tiparvovec (AAV1-LPL(S447X)) gene therapy is developed to prevent complications and decrease the clinical morbidity of lipoprotein lipase deficiency (LPLD). LPLD is an autosomal recessive disease associated with severe hypertriglyceridemia (hyperTG), severe chylomicronaemia, and low HDL. Acute pancreatitis, the most frequent serious clinical LPLD complication, is a complex and heterogeneous inflammatory condition having many causes including hyperTG and chylomicronaemia. In many patients, low fat diet and currently available lipid lowering drugs are ineffective to prevent hyperTG or pancreatitis in LPLD. The clinical development program of alipogene tiparvovec includes observational studies as well as phase I/II and II/III clinical trials. Pooled data are collected on safety and efficacy issues, including the incidence of pancreatitis.

Comparison of the efficacy of fibrates on hypertriglyceridemic phenotypes with different genetic and clinical characteristics.

UNLABELLED: Hypertriglyceridemia is a frequent and heterogeneous clinical trait, which modulates the risk of disease. Fibrates constitute an effective class of triglyceride-lowering agents. OBJECTIVE: To evaluate the effect of fibrates on fasting plasma triglycerides and other lipids levels in hypertriglyceridemia phenotypes with different genetic and clinical characteristics. METHODS: This study included 146 fasting adults: 15 with lactescent plasma and severe hypertriglyceridemia (triglyceride ≥ 10 mmol/l) and 131 with clear plasma and moderate hypertriglyceridemia (2 ≤ triglycerides <10 mmol/l). Expost comparisons of the effect of fibrates on fasting triglycerides and other lipids were made using Student's paired two-tailed t-test. RESULTS: Response to these fibrates differed significantly across the studied hypertriglyceridemia subtypes: patients with severe hypertriglyceridemia because of lipoprotein lipase deficiency and those with moderate hypertriglyceridemia because of glycerol kinase deficiency did not respond at all, whereas patients with palmar xanthomas and severe or moderate hypertriglyceridemia because of apolipoprotein (apo) E resistance (type-III dysbetalipoproteinemia, most often associated with the apo E2 allele) responded significantly better (P<0.001) than all other subtypes on several lipid fractions. CONCLUSION: These results indicate that genetic factors known to contribute to the etiology and clinical expression of hypertriglyceridemia subtypes also modulate the response to triglyceride-lowering drugs.

The ACE-DD genotype is associated with endothelial dysfunction in postmenopausal women.

OBJECTIVE: To evaluate the effects of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D), the angiotensinogen M235T and the angiotensin II type 1 receptor A1166C polymorphisms, and hormone therapy used on endothelial function in postmenopausal women without manifestation of coronary artery disease. DESIGN: Sixty-four postmenopausal women (42 hormone therapy users and 22 hormone therapy nonusers) without clinical manifestation of coronary artery disease were evaluated using external vascular ultrasonography to measure endothelium-dependent (hyperemic response, flow-mediated dilatation) and -independent (nitroglycerin) dilatation. Genotypes were determined by polymerase chain reaction amplification. RESULTS: Women with the ACE-DD genotype displayed a lower flow-mediated dilatation compared to those with the ACE-II genotype (8.4% +/- 3.9% vs 12.6% +/- 5.4%, P = 0.04). Endothelial function was not associated with the angiotensinogen M235T and anglotensin II type 1 receptor A1166C polymorphisms. ACE polymorphism seems to modulate endothelial function among postmenopausal women without hormone therapy (8.2% +/- 5.1% vs 18.4% +/- 5.9% for the DD and the II genotype, respectively, P = 0.02). However, in hormone therapy users, flow-mediated dilatation was similar according to the ACE genotypes. CONCLUSIONS: Our findings suggest that ACE-I/D polymorphism is related to endothelial dysfunction in postmenopausal women. Furthermore, a potential interaction between estrogen users and ACE polymorphism on endothelial function may be present.

ACE-DD genotype is associated with the occurrence of acute coronary syndrome in postmenopausal women.

The insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE), the A1166C polymorphism in the angiotensin type 1 receptor (AT1R), and the M235T polymorphism of the angiotensinogen gene are associated with cardiovascular disease mostly in men. Few data are available on the effects of these genetic variations in postmenopausal women according to hormone replacement therapy (HRT) use. In this case-control study, we determine the frequency of mutant alleles in the ACE I/D, M235T and A1166C polymorphisms in postmenopausal Caucasian women with and without a diagnosis of acute coronary syndrome (ACS). Data from 198 women with ACS (63+/-10 years) and 149 controls (62+/-7 years) showed that ACE-DD genotype was more prevalent in women with ACS compared to controls (30% vs. 19%, P<0.05). There was no difference in genotype distributions for either the M235T or the A1166C polymorphisms between groups. The difference in ACE genotype distribution between ACS women and controls was driven by current HRT users with 30% of ACS and 15% of controls carrying the ACE-DD genotype (P<0.05). The oligenic combination of ACE-DD and M235T-TT genotypes was higher in ACS compared to controls. Among carriers of M235T-TT, 7% of ACS and 1% of controls also had the ACE-DD genotype, P<0.05. Thus, the ACE-DD genotype may be associated with ACS in postmenopausal women, particularly in HRT users.

Does hormonal status influence the clinical presentation of acute coronary syndromes in women?

BACKGROUND: Previous studies suggest that the clinical presentation of acute coronary syndromes (ACS) may differ between women and men. It is not known if different clinical presentations may be explained by hormonal status in women with ACS. Our objective was to compare the clinical presentation of ACS between premenopausal (PRE) women and post-menopausal women with hormone replacement therapy (HRT) and without (POST). METHODS: This was a prospective study of consecutive women admitted with a diagnosis of ACS (myocardial infarction [MI] or unstable angina). All women answered a detailed questionnaire that included a list of 27 clinical symptoms. Symptom results were adjusted for age and current coronary event diagnosis. RESULTS: Seventy-three Caucasian women were studied. No differences were found in terms of the frequency of reported typical symptoms of ACS between PRE (n = 23), HRT (n = 32), and POST (n = 18). However, PRE more often reported atypical chest symptoms than HRT and POST women (57% vs. 31% vs. 22%, PRE vs. HRT vs. POST, respectively, p = 0.05). HRT and POST women experienced substernal chest pain more frequently than PRE (44% vs. 78% vs. 83%, p = 0.03). In contrast, PRE more frequently tended to experience chest pressure (57% vs. 31% vs. 39%, p = 0.2) or chest pain in other locations (22% vs. 3% vs. 6%, p = 0.06). HRT and POST groups reported more frequent indigestion-like pain/discomfort (22% vs. 50% vs. 56%, p = 0.04) and midback pain (35% vs. 63% vs. 72%, p = 0.04) during ACS compared with PRE women. POST experienced sudden fatigue more frequently than PRE and HRT (61% vs. 53% vs. 89%, p = 0.03). CONCLUSIONS: Our results suggest that almost all women admitted with ACS experienced typical chest symptoms but frequently reported both typical and atypical symptoms. Independently of age, atypical chest symptoms occurred more frequently in premenopausal women than in postmenopausal women with or without HRT.