
==== Front
Pharmacol Res Perspect
Pharmacol Res Perspect
10.1002/(ISSN)2052-1707
PRP2
Pharmacology Research & Perspectives
2052-1707
John Wiley and Sons Inc. Hoboken

10.1002/prp2.1235
PRP21235
PRP2-2024-03-0100.R1
Original Article
Original Article
Risks of oral anticoagulants: Analysis of adverse drug reactions reported to the Portuguese National Pharmacovigilance System
Martins et al.
Martins Ana Sofia https://orcid.org/0009-0004-5597-2269
1
Monteiro Cristina https://orcid.org/0000-0002-5225-6222
2 3 csjmonteiro79@gmail.com

Duarte Ana Paula https://orcid.org/0000-0003-3333-5977
2 3
1 Health Sciences Faculty University of Beira Interior Covilhã Portugal
2 UFBI‐ Pharmacovigilance Unit of Beira Interior University of Beira Interior Covilhã Portugal
3 CISCS‐UBI‐ Health Sciences Research Centre University of Beira Interior Covilhã Portugal
* CorrespondenceCristina Monteiro, UFBI‐Pharmacovigilance Unit of Beira Interior, University of Beira Interior, Covilhã, Portugal; CISCS‐UBI‐Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
Email: csjmonteiro79@gmail.com

18 9 2024
10 2024
12 5 10.1002/prp2.v12.5 e123528 5 2024
18 3 2024
22 6 2024
© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

Abstract

Cardiovascular diseases are the leading cause of death globally, making the use of oral anticoagulants for prevention increasingly important. Historically, warfarin has played a significant role in this context. In recent years, introduction of new oral anticoagulants, such as rivaroxaban, apixaban, dabigatran, and edoxaban, has been seen. This study evaluates the risk associated with the use of oral anticoagulants by analyzing spontaneous adverse drug reactions reported to the Portuguese Pharmacovigilance System from 2012 to 2021. The study includes 951 adverse drug reactions reports, with the majority (n = 770; 80.97%) classified as serious. Of the 770 serious adverse drug reactions reports, the most commonly reported seriousness criterion was “Clinically Important” (n = 350; 45.45%). In terms of demographics, there was a higher reporting rate among the elderly population, with a greater prevalence of females. The System Organ Class group with the highest number of adverse drug reactions was “Gastrointestinal disorders,” with the most commonly reported Preferred Term being “Gastrointestinal hemorrhage,” and dabigatran was the most frequently reported drug. In summary, oral anticoagulants have adverse drug reactions that require continuous monitoring. Accurate identification and monitorization of adverse drug reactions is an important starting point to improve drug safety in population.

Risks of oral anticoagulants: analysis of adverse drug reactions reported to the portuguese national pharmacovigilance system.

adverse drug reactions
direct oral anticoagulant
pharmacovigilance
risks
vitamin K antagonist
INFARMED—National Authority of Medicines and Health Products, I.P.Pharmacovigilance Unit of Beira InteriorFCT 10.13039/501100009091 Fundo Europeu deDesenvolvimento RegionalPORTUGAL 2020Programa Operacional do Centro (CENTRO 2020) 10.13039/501100014717 UIDB/00709/2020 UIDP/00709/2020 source-schema-version-number2.0
cover-dateOctober 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:18.09.2024
Martins AS , Monteiro C , Duarte AP . Risks of oral anticoagulants: Analysis of adverse drug reactions reported to the Portuguese National Pharmacovigilance System. Pharmacol Res Perspect. 2024;12 :e1235. doi:10.1002/prp2.1235
==== Body
pmcAbbreviations

ADRs Serious adverse drug reactions

AF Atrial fibrillation

DOACs Direct Oral Anticoagulants

HLGT High Level Group Term

HLT High Level Term

ICH International Conference on Harmonization

INR International Normalized Ratio

LLT Lowest Level Term

MedDRA Medical Dictionary for Regulatory Activities

N.I. Not Identified

P‐gp P‐glycoprotein

PPS Portuguese Pharmacovigilance System

PT Preferred Term

SmPC Summary of Product Characteristics

SOC System Organ Class

WHO‐UMC World Health Organization—Uppsala Monitoring Centre

1 INTRODUCTION

Cardiovascular diseases are a leading cause of global death, with 17.9 million expected in 2019, accounting for 32% of all fatalities. Among these fatalities, 85% were attributed to heart attacks and strokes, emphasizing the critical need for understanding vascular event mechanisms for acute care and prevention strategies. Ischemic strokes, 15%–30%, are often linked to cardiac embolism. 1

Despite various cardiac pathologies that can lead to embolism, atrial fibrillation (AF) stands out, especially with advancing age, as the predominant arrhythmia. The prevalence of AF increases with age, and the risk of strokes, a significant complication of AF, is notably elevated—five times higher in AF patients compared with those without AF. The vulnerability of the elderly population to thromboembolic events highlights the critical importance of stroke prevention therapy. 2

Currently, oral anticoagulants are crucial for preventing cerebrovascular events, with warfarin being a prominent option. 3 , 4 However, in recent years, new oral anticoagulants such as rivaroxaban, apixaban, dabigatran, and edoxaban have emerged in the Portuguese market. 5 , 6 These new anticoagulants were designated as Direct Oral Anticoagulants (DOACs). 7 Limited real‐world usage data exist for these newer options. 8 Historically, drug risks have been acknowledged, but heightened awareness came with advancements in the pharmaceutical industry. 9 This profile begins in the pre‐clinical phase and continues into the post‐market authorization phase. 8

Oral anticoagulants are associated with serious adverse drug reactions (ADRs), particularly hemorrhage that can lead to hospitalization. 10 Because of their potential for damage in clinical settings they are classified as high alert medications by the Institute of Safe Medication Practices. With their growing use and potential safety incidents, monitoring their ADRs becomes crucial. 4 , 10 Therefore, comprehensive monitoring during the post‐marketing phase, with Pharmacovigilance playing a pivotal role, is advisable to continuously assess the safety and efficacy of these drugs. 8

This study evaluates the risk of oral anticoagulant use by analyzing adverse drug reactions reported to the Portuguese Pharmacovigilance System (PPS) from 2012 to 2021. It is observational, retrospective, and descriptive, with no age restrictions, focusing on cases involving one or more oral anticoagulants as suspected drugs. These reports are crucial for understanding drug‐related outcomes and improving drug safety efforts.

2 METHODS

Initially, 1054 ADRs reports were recorded involving one or more oral anticoagulants as suspected drugs. Post‐analysis, 79 ADRs reports were identified and removed as duplicates, with an additional 24 deemed null. This process resulted in a dataset of 951 ADRs reports available for in‐depth analysis. Notably, each report corresponds to an affected patient, potentially linked to one or more suspected drug and one or more ADRs.

The ADRs reports were characterized by source (ADRs can be reported by the marketing authorization holders, physicians, pharmacists, other healthcare professionals, consumers and non‐healthcare professionals), gender and age group of patient, oral anticoagulant, seriousness and ADRs.

Patient age was categorized into several age groups, namely teenagers aged 12 to 17 years, adults aged 18 to 64 years, and elderly aged over 65 years. In cases where age identification was not possible, it was designated as N.I. (Not Identified). Regarding patient gender, it was defined as male, female, and N.I. for cases where gender was not specified.

Considering the seriousness parameter, ADRs reports were classified into serious and non‐serious categories. Regarding serious ADRs reports, they were further grouped according to seriousness criteria. Furthermore, an analysis was performed to characterize ADRs related to the seriousness criteria of “Hospitalization” and “Death,” considering age groups and the specific oral anticoagulant associated with each report.

It is important to highlight that ADRs can also be classified as serious if they meet one of the following criteria: life risk; causing death; motivating or prolonging hospitalization; resulting in temporary or permanent disability; causing congenital anomaly or malformation; clinically significant, meaning that without healthcare professional intervention, the case may progress to one of the other criteria described. 11 , 12 , 13

To analyze and characterize the ADRs with respect to their prior knowledge, recourse was made to the Summary of Product Characteristics (SmPC) for each anticoagulant under investigation, grouping the ADRs into two categories: Described in the SmPC or not described in the SmPC.

Subsequently, ADRs that were not described in the SmPC but were considered serious by the regulatory authority were analyzed regarding causality attribution, based on World Health Organization—Uppsala Monitoring Centre (WHO‐UMC) categories: Definite, Probable, Possible, Improbable, Conditional/Not classified, and Not classifiable. 14

Furthermore, ADRs are coded according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology. This international medical terminology was developed in October 1994 by the International Conference on Harmonization (ICH). The aim was to harmonize international medical terminology and address the numerous problems arising from the use of various medical terminologies among different stakeholders. 15 Regarding the terms in the MedDRA terminology, they are organized into hierarchical levels: System Organ Class (SOC), High Level Group Term (HLGT), High Level Term (HLT), Preferred Term (PT), and Lowest Level Term (LLT). The SOC represents the broadest level in this terminology for data retrieval, and the LLT is the most specific level in this terminology. 15 In this context, ADRs were initially categorized based on the SOC, and ultimately, they were organized according to the PT Term.

Regarding the progression of ADRs, they were grouped into the following categories: “Cure,” “Cure with collateral damage,” “Death,” “Unknown,” “In recovery” and “Persist without Recovery”. This classification was based on the information provided by the reporter.

The data collection process used Microsoft Office Excel 365, where subsequent statistical analysis was conducted within the same tool. This was followed by the construction of pertinent tables and graphical representations based on the variables outlined in the study.

3 RESULTS

3.1 Characterization of the adverse drug reactions reports by source and reporter

The ADRs reports were made by various types of reporters, as shown in Figure 1. Marketing authorization holders accounted for approximately 675 ADRs reports (70.98%), representing the most prominent type of reporter. Following by physicians (n = 136; 14.30%) and pharmacists (n = 102; 10.73%).

FIGURE 1 Characterization of ADRs reports based on the type of reporter.

3.2 Characterization of adverse drug reactions reports by year

As previously mentioned, this study analyzed ADRs reports sent to the PPS between 2012 and 2021, where at least one oral anticoagulant was identified as a suspected drug. It was observed that the reports rate was not consistent throughout the years covered in the study. Within the years under analysis, the highest number of reports occurred in 2018, with 155 ADRs reports. Until 2016, there was a growth in the number of ADRs reports; however, in 2017, there was a decline in the reports rate. More recently, in 2020 and 2021, there was also a decrease compared with the years 2018 and 2019 (Figure 2).

FIGURE 2 Characterization of ADRs reports received per years.

3.3 Demographic characterization of the population

According to Figure 3, in cases where it was not possible to obtain information about age, 166 ADRs reports were identified. Among these, 20 ADRs reports did not include information about the patient's age or gender. In the remaining age groups, the majority of patients with reported ADRs were elderly females (349 ADRs reports), whereas elderly males accounted for 285 ADRs reports. Regarding adults, there were 64 ADRs reports for males and 59 for females. There were 3 cases in adolescents, 2 females and one male.

FIGURE 3 Characterization of ADRs reports by gender and age group.

3.4 Characterization of adverse drug reactions reports by oral anticoagulant

Through the analysis of Figure 4, it can be observed that the most frequently reported drug was dabigatran (n = 388; 40.80%), followed by rivaroxaban (n = 213; 22.40%), and warfarin (n = 163; 17.14%). The least reported oral anticoagulants were apixaban (n = 129; 13.56%) and edoxaban (n = 52; 5.47%). Regarding the most reported combination, it was apixaban plus rivaroxaban (n = 4; 0.63%), followed by the combination of rivaroxaban plus warfarin and dabigatran plus edoxaban, both with 1 ADRs report each, corresponding to 0.11%.

FIGURE 4 Characterization of ADRs reports by Oral Anticoagulant.

3.5 Characterization of ADRs reports regarding seriousness and seriousness criteria

The reports of ADRs related to anticoagulants were distributed according to seriousness. According to Figure 5, most reports were considered serious (n = 770; 80.97%), with the remaining 181 ADRs reports considered non‐serious, accounting for 19.03%.

FIGURE 5 Characterization of ADRs reports by Seriousness.

Regarding the seriousness criteria for each serious ADRs report, the criterion “Clinically Important” (n = 350; 45.45%) was the most frequently reported, followed by the criterion “Hospitalization” (n = 245; 31.82%),the criteria “Death” (n = 82; 10.65%), “Life‐Risk” (n = 81; 10.52%), “Disability” (n = 10; 1.30%), and finally, “Congenital Anomaly” (n = 2; 0.26%) (Figure 6).

FIGURE 6 Characterization of ADRs reports by Seriousness Criteria.

Regarding ADRs reports where the seriousness criterion was death the most frequently reported anticoagulant was dabigatran (n = 50; 60.98%), followed by rivaroxaban (n = 10; 12.20%) and warfarin (n = 10; 12.20%) (Figure 7).

FIGURE 7 Oral Anticoagulants associated with reports where the Seriousness Criterion was “Death”.

The majority of patients with the outcome “Death” were elderly. Among them, 34 were male, and 30 were female. There are 3 ADRs reports related to adult males (n = 2) and females (n = 1). It is important to note that in one report, it was not possible to identify the age and gender of the patient, and in 14 ADRs reports, the age of the patients was not identified (Figure 8).

FIGURE 8 Characterization of ADRs reports by gender and age group where the Seriousness Criterion was “Death”.

In the case of ADRs reports where the seriousness Criterion was “Hospitalization” (Figure 9), the most frequently reported anticoagulant was dabigatran (n = 132; 53.88%), followed by warfarin (n = 61; 24.90%). Regarding rivaroxaban, it had 31 ADRs reports, accounting for a percentage of 12.65%. Next is apixaban (n = 13; 5.31%), edoxaban (n = 7; 2.86%), and finally, the combination of warfarin plus rivaroxaban (n = 1; 0.41%).

FIGURE 9 Oral Anticoagulants associated with ADRs reports where the Seriousness Criterion was “Hospitalization”.

Regarding the characterization of these patients, the majority of hospitalized patients were elderly. Among them, 94 were male, and 69 were female. Then, the most reported group was adults with 22 ADRs reports for females and 15 for males. There was 1 ADRs report related to the hospitalization of an adolescent. In 7 ADRs reports, it was not possible to identify the age and gender of the patient (Figure 10).

FIGURE 10 Characterization of ADRs reports by gender and age group where the Seriousness Criterion was “Hospitalization”.

3.6 Characterization of adverse drug reactions

In the 951 reports considered in the study, a total of 2726 ADRs were recorded. This number corresponds to an average of 2.87 ADRs per reported case. There were 11 ADRs reports classified as “not applicable,” described as “drug ineffective.” As shown in Figure 11, of the remaining 2715 ADRs, 2453 were described (90.35%), and 262 were not described (9.65%).

FIGURE 11 Characterization of ADRs according to its description in the SmPC.

Following that, as shown in Figure 12, the ADRs that were not reported in the SmPC and were classified as serious were assessed, by the regulatory authority, for causality attribution. Of the 262 undescribed ADRs, 153 ADRs (equivalent to 58.40%) had causality attributed.

FIGURE 12 Analysis of causality studied in ADRs not described.

The causality relationship was “Improbable” in 7 ADRs, “Possible” in 58 ADRs, “Probable” in 69 ADRs, and “Definite” in 17 ADRs. There were no ADRs classified as “Not Classifiable” (Figure 13).

FIGURE 13 Characterization of undescribed ADRs according to the degree of causality.

As shown in Table 1, the 951 ADR were grouped into SOC for each reported anticoagulant. According to Table 1, the SOC group with the most reports is “Gastrointestinal disorders” accounting for 441 SOC reactions. This is followed by the “Nervous system disorders” group and “General disorders and administration site conditions” group. The SOC groups with fewer reports were “Pregnancy, puerperium, and perinatal conditions” and “Social circumstances.”

TABLE 1 Characterization of ADRs by affected systems and organs according to the SOC Groups.

SOC Groups	Dabigatran	Warfarin	Rivaroxaban	Apixaban	Edoxaban	Total per SOC group	
Gastrointestinal disorders	206	69	83	68	15	441	
Nervous system disorders	208	40	92	41	7	388	
General disorders and administration site conditions	94	47	48	42	8	239	
Investigations	58	109	28	37	1	233	
Injury, poisoning and procedural complications	99	53	47	28	1	228	
Vascular disorders	93	30	42	20	3	188	
Renal and urinary disorders	84	20	38	7	5	154	
Skin and subcutaneous tissue disorders	31	22	41	34	19	147	
Respiratory, thoracic and mediastinal disorders	41	27	35	29	6	137	
Cardiac disorders	37	30	34	14	2	117	
Blood and lymphatic system disorders	47	31	23	14	2	117	
Musculoskeletal and connective tissue disorders	6	24	16	8	3	57	
Infections and infestations	25	10	10	7	1	53	
Metabolism and nutrition disorders	20	10	5	7	0	42	
Psychiatric disorders	19	3	11	8	1	42	
Eye disorders	10	8	15	8	1	42	
Hepatobiliary disorders	7	2	8	2	0	19	
Surgical and medical procedures	17	0	0	1	1	19	
Congenital, familial and genetic disorders	2	10	2	0	0	14	
Reproductive system and breast disorders	2	0	6	3	0	11	
Neoplasms benign, malignant and unspecified (including cysts and polyps)	7	0	1	1	0	9	
Immune system disorders	1	0	2	5	0	8	
Endocrine disorders	0	0	2	4	0	6	
Ear and labyrinth disorders	0	0	2	3	0	5	
Product issues	2	0	0	2	0	4	
Pregnancy, puerperium and perinatal conditions	0	1	0	0	0	1	
Social circumstances	1	1	0	1	0	3	

ADRs were also classified according to PT Term as shown in Table 2 and Table 3. In Table 2, the most frequently reported PT was “Gastrointestinal hemorrhage,” accounting for 2.0%, followed by “Haematochezia” at 1.9%, and “Anemia” at 1.7%.

TABLE 2 Characterization of ADRs according to the 15 most frequent PT Term.

PT Term	N	Percentage	
Gastrointestinal haemorrhage	54	2.0%	
Haematochezia	51	1.9%	
Anemia	46	1.7%	
Melaena	35	1.3%	
Ischaemic stroke	30	1.1%	
Haematoma	26	1.0%	
Upper gastrointestinal haemorrhage	26	1.0%	
Haemorrhage intracranial	24	0.9%	
Lower gastrointestinal haemorrhage	22	0.8%	
Oedema peripheral	21	0.8%	
Headache	20	0.7%	
Fatigue	20	0.7%	
Cerebrovascular accident	19	0.7%	
Haemorrhagic stroke	19	0.7%	
Death	19	0.7%	

TABLE 3 Characterization of ADRs according to the 15 most frequent PT Term per oral anticoagulants.

PT Term	Dabigatran	Warfarin	Rivaroxaban	Apixaban	Edoxaban	Absolute frequency	
Gastrointestinal haemorrhage	31	6	8	4	5	54	
Haematochezia	41	2	6	2	0	51	
Anemia	27	8	6	3	2	46	
Melaena	28	3	3	1	0	35	
Ischaemic stroke	17	7	2	4	0	30	
Haematoma	18	4	2	2	0	26	
Upper gastrointestinal haemorrhage	6	7	7	6	0	26	
Haemorrhage intracranial	6	1	8	7	2	24	
Lower gastrointestinal haemorrhage	10	3	6	2	1	22	
Oedema peripheral	8	4	5	3	1	21	
Headache	3	2	11	3	1	20	
Fatigue	11	2	1	4	2	20	
Cerebrovascular accident	15	2	1	1	0	19	
Haemorrhagic stroke	10	3	4	1	1	19	
Death	11	4	3	1	0	19	

In Table 3, the most frequently reported PT Term was “Gastrointestinal hemorrhage,” with dabigatran being the most reported oral anticoagulant with 31 ADRs, followed by rivaroxaban with 8 ADRs, and warfarin with 6 ADRs. Next, the most common PT was “Haematochezia,” with dabigatran being the most reported oral anticoagulant with 41 ADRs, followed by rivaroxaban with 6 ADRs, and warfarin with 2 ADRs. For the PT “Anemia,” dabigatran was the most reported oral anticoagulant with 27 ADRs, followed by warfarin with 8 ADRs, and rivaroxaban with 6 ADRs.

Figure 14 shows the evolution of the clinical status of patients. In about 445 (46.79%) reports, it was not possible to obtain information about their clinical progression. Among the remaining reports, 285 evolved to “Cure” (29.96%), 74 were “In recovery” (7.78%). There were 64 cases of “Death” (6.73%), 61 ADR persisted as “Persist without Recovery” (6.41%), and 23 reports evolved into “Cure with collateral damage” (2.42%).

FIGURE 14 Characterization of ADRs Reports regarding Clinical Evolution.

4 DISCUSSION

ADRs varied annually, showing a non‐uniform pattern but with an overall upward trend, consistent with the “Activity Report 2021”. 16 Reports increased from 41 in 2012 to 98 in 2021, with anomalies in 2017, 2020, and 2021. In 2017, PPS restructuring led to increased reporting and training activities in subsequent years. Consequently, an increase in reports rates and pharmacovigilance training activities was expected. 17 The COVID‐19 pandemic in 2020 caused a decrease in reports, but 2021 saw a notable increase as expected. 17

Marketing authorization holders were the primary reporters of ADRs, consistent with previous research. 18 Consumers have been actively reporting ADRs since 2012, aligning with expected trends and efforts to raise awareness. 18 There have been recent initiatives to involve healthcare professionals and consumers more in reporting to safeguard public health. 9 This study highlights the increasing significance of ADR reports by healthcare professionals and consumers alike.

The study found an increased ADR reporting rate among elderly individuals, with a higher prevalence in females. This trend may be due to the heightened susceptibility of the elderly to adverse reactions during oral anticoagulant therapy. 19 Factors such as polypharmacy, comorbidities, and age‐related pharmacodynamic and pharmacokinetic changes contribute to the increased risk of ADRs in the elderly. 20 Studies suggest that females face a higher risk of ADRs compared with males, possibly due to physiological and drug usage differences. 21 An Italian study noted higher reports rates in older age groups, evenly distributed between genders, with a slightly elevated rate in females. 22 Conversely, a Norwegian study reported higher ADRs reports in males, particularly in older age groups. 19 Another Italian study associated ADRs reports more with the elderly and adults, predominantly in males. 23

ADRs were categorized by oral anticoagulant, with dabigatran being the most frequently reported, followed by rivaroxaban, warfarin, apixaban, and edoxaban. Despite rivaroxaban being the most used in Portugal, DOACs overall had higher report rates than warfarin, likely due to increased vigilance for newer drugs. 19 Notably, warfarin exhibits a decrease in ADRs reports rates compared with DOACs, likely attributed to its well‐established reputation owing to extensive usage. 24 Dabigatran's higher report rate may be because it was the first DOAC introduced in Portugal. Edoxaban had the lowest report rate, reflecting its recent market entry. 22 Other studies support the results obtained in this study, notably that dabigatran is the most frequently reported drug, followed by rivaroxaban. 22 , 25 However, in another study, rivaroxaban is mentioned as the most reported oral anticoagulant, followed by warfarin, and only then dabigatran. 19 According to the Eudragilance data, rivaroxaban is the most frequently reported medication. In this study, it ranks second, demonstrating significant relevance in both datasets. 26

In certain cases, two oral anticoagulants were linked to some ADRs. For example, the use of apixaban with rivaroxaban is contraindicated due to an increased risk of bleeding. 27 , 28 This situation may arise from patients taking a DOAC and concurrently receiving another anticoagulant or from therapeutic duplication by different prescribing physicians. Similarly, the combination of dabigatran and edoxaban is contraindicated due to an increased bleeding risk. 29 , 30 Dabigatran and edoxaban are substrates of P‐glycoprotein (P‐gp); consequently, their co‐administration is contraindicated due to the potential for interactions. 7 Concurrent use of rivaroxaban with warfarin may involve a switch from rivaroxaban to warfarin until the International Normalized Ratio (INR) is ≥2.0. 27 This case might also involve therapeutic duplication, as mentioned earlier.

The majority of ADR reports were classified as serious, supported by several studies. 19 , 23 , 25 , 31 Healthcare professionals tend to report serious ADRs due to their association with higher healthcare costs and morbidity. 32 This underscores the importance of reporting by healthcare professionals and users, highlighting the risk profile of these drugs. 31 These data further underscore the importance of reporting by healthcare professionals and users.

Serious ADR reports were characterized by criteria, with “Clinically Important” being the most reported, followed by “Hospitalization,” “Death,” “Life Risk,” “Disability,” and “Congenital Anomaly.” These results differ from some studies where “Hospitalization” was the most reported criterion. 22 , 23 , 31 The seriousness criterion “Hospitalization” also showed significant prominence in this study, whereas “Clinically Important” is often the second most reported criterion in some studies. 22 , 31 These data can be explained by the fact that high reporting here may be due to healthcare interventions preventing progression to “Hospitalization.”. The criterion “Congenital Anomaly” had relatively few reports, consistent with other studies. 23 , 31

The most reported age group for ADRs with death as the seriousness criteria was elderly males. The reasons for these findings may be attributed to males being associated with a higher proportion of serious and fatal ADRs, whereas females have a higher risk of developing ADRs. 21 , 33 , 34 Additionally, the concomitant use of drugs that can cause bleeding, such as oral anticoagulants, poses an increased risk of mortality in the elderly population. 19 Despite rivaroxaban having more reports, warfarin was linked to more serious, fatal ADRs due to its higher bleeding risk. 35 However, fatal ADR reports must be carefully analyzed, as deaths are not always drug‐related.

For ADRs with “Hospitalization” as seriousness criteria, dabigatran was most reported, followed by warfarin, rivaroxaban, apixaban, edoxaban, and warfarin plus rivaroxaban. This combination may involve switching or duplicating therapy, increasing bleeding risk and leading to hospitalization. Elderly males were the most affected age group, consistent with serious ADRs leading to death. Oral anticoagulants, widely used in the elderly and those with heart issues, often cause ADR‐related hospitalizations. In a Spanish study, more elderly males were hospitalized due to ADRs, aligning with this study's finding. 36

It is important to note that oral anticoagulant therapy is complex and carries a risk of bleeding. Therefore, its use requires appropriate management and suitable therapy selection, as many of these patients have multiple comorbidities, are on multiple drugs, and some oral anticoagulants have a high rate of drug interactions. 36

In this study, most ADRs align with those described in the SmPCs of oral anticoagulants, and the data obtained are consistent with study intituled “Spontaneous reports of adverse drug reactions related to oral anticoagulants in the Czech Republic”. 31 Underreporting may explain this, as healthcare professionals might be uncertain about the suspected drug for ADRs or assume serious ADRs are documented. Next, ADRs not described in the SmPCs were mostly classified as “Probable,” indicating an acceptable temporal relationship between drug administration and ADR occurrence. Despite few ADRs without an associated degree of causality, identifying new ADRs is crucial for updating the safety profile of oral anticoagulants.

Regarding the most described adverse reaction in the SmPCs of oral anticoagulants, it is gastrointestinal hemorrhage associated with the drug Dabigatran. This can be explained by the following mechanism: the absorption of dabigatran increases in an acidic environment, which is why it is formulated with tartaric acid. Dabigatran's absorption increases in an acidic environment due to its formulation with tartaric acid. Administered as a prodrug (dabigatran etexilate), it is converted into dabigatran by esterases. Tartaric acid's role in triggering gastrointestinal bleeding, possibly by adhering to the esophagus and damaging the mucosa, may explain why dabigatran is often associated with such bleeding. 37

The most common SOC group was “Gastrointestinal disorders,” followed by “Nervous system disorders,” consistent with other studies. 25 , 38 Post‐market studies of oral anticoagulants often report hemorrhagic events, especially in the gastrointestinal tract, which aligns with the results obtained. 31 Although these ADRs are not frequent in the SmPCs for most oral anticoagulants they are known so expectable. 27 , 28 , 29 , 30 , 39 The most frequent PT terms were “Gastrointestinal hemorrhage,” “Haematochezia,” and “Anemia,” with anemia often resulting from bleeding events. 40

As previously mentioned, the study data indicate that the most prevalent SOC group was “Gastrointestinal disorders,” followed by “Nervous system disorders,” which aligns with the Eudragilance data for most oral anticoagulants, with the exception of warfarin. 26

Dabigatran was most associated with the PT Term “Gastrointestinal hemorrhage”, “Haematochezia” and “Anemia,” followed by rivaroxaban and warfarin. Another study indicated a higher tendency for gastrointestinal bleeding with dabigatran and rivaroxaban compared with warfarin. 23 These findings can be explained by the fact that their use in the population aged ≥75 years can lead to a decrease in elimination compared with warfarin, resulting in an increased risk of gastrointestinal bleeding. 23 Despite being associated with this increased risk of gastrointestinal bleeding, they present a favorable risk–benefit profile compared with warfarin. 41 In another study, dabigatran was also most associated with the PT Term “Haematochezia” 42 Regarding the PT “Anemia,” the second most reported anticoagulant was warfarin, followed by rivaroxaban. Dabigatran was the oral anticoagulant most associated with the PT Term “Anemia,” and this result can be explained by the high reports associated with this drug. Results associated with warfarin may be explained by the fact that it presents a higher risk of bleeding, which can affect any organ, resulting in hematoma formation and the development of anemia. 39

Considering the evolution of the clinical status of patient, “Unknown” was the most frequent result, followed by “Cure.” This result may be related to the fact that additional data are not always obtained after the initial report.

4.1 Limitations

The study noted limitations, notably high underreporting rates, which worsen ADR frequency underestimation. This impedes drug safety profile knowledge and real‐world utilization understanding. 9

Furthermore, a considerable percentage of ADRs reports submitted to the PPS were incomplete regarding patient data, hindering their analysis and subsequent characterization.

5 CONCLUSIONS

This study assessed the risks associated with oral anticoagulants by analyzing and characterizing ADRs reported to the Portuguese Pharmacovigilance System from 2012 to 2021. Despite considerable underreporting, a discernible upward trend in the report rate was observed with healthcare professionals, especially physicians and pharmacists, being the most frequent reporters. The elderly, particularly females, accounted for a higher number of ADRs, with dabigatran being the most commonly reported anticoagulant.

The study found a higher frequency of serious ADRs, with “Clinically Important” being the most reported seriousness criterion. Dabigatran was the most commonly reported medication among elderly males in ADR reports involving “Death” and “Hospitalization”. Although most reported ADRs were described in SmPC, those not mentioned were assessed for causality, with “Probable” and “Possible” being the most significant causality categories. “Gastrointestinal Disorders” and “Nervous System Disorders” were the most reported System Organ Classes, with “Gastrointestinal hemorrhage” being the top Preferred Term, often linked to dabigatran. ADR progression often resulted in “Unknown” outcomes, followed by “Cure” in most reports.

The study underscores the significant role of Pharmacovigilance in monitoring oral anticoagulants, emphasizing their association with serious ADRs requiring hospitalization or leading to death. ADRs. Healthcare professionals should remain vigilant, especially regarding the susceptibilities of the elderly population. It is also important to emphasize that the data from this study are extremely relevant; however, it was not possible to conclude whether there is a need to amend the labeling of these drugs. Further studies in this area are necessary to make such determinations and to understand the real‐world usage profile of DOACs and effectively detect and prevent ADRs.

AUTHOR CONTRIBUTIONS

After compiling the information and structuring the conclusions, A.S.M. wrote the first draft of the paper. C.M. and A.P.D. provided critical revisions for the manuscript's intellectual content and oversaw its drafting. Each author reviewed the manuscript before approving its publication, and they all made significant contributions to the effort and the final draft.

FUNDING INFORMATION

This work was supported by INFARMED—National Authority of Medicines and Health Products, I.P. through the Pharmacovigilance Unit of Beira Interior and by the CICS‐UBI CICS‐UBI, which is financed by National Funds from FCT and by Fundo Europeu deDesenvolvimento Regional (FEDER) under the scope of PORTUGAL 2020 and Programa Operacional do Centro (CENTRO 2020), with the project references UIDB/00709/2020 and UIDP/00709/2020.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflicts of interest.

ETHICS STATEMENT

This work did not require prior authorization from the Ethics Committee, since the patients’ personal information was not used.

ACKNOWLEDGMENTS

The data presented in this work belong to the Portuguese National Pharmacovigilance System. The authors would like to thank the Risk Management for Medicines Department, INFARMED. I.P. – National Authority of Medicines and Health Products, I.P., Lisbon, Portugal.

DATA AVAILABILITY STATEMENT

The raw data used in this research are available from the authors, depending on INFARMED's authorization.
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