Patients with hemophilia or LQTS: strong improvement needed for both accurate registration of contraindications and in patient understanding of the risks of over-the-counter drugs

doi:10.21203/rs.3.rs-4619068/v1

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Patients with hemophilia or LQTS: strong improvement needed for both accurate registration of contraindications and in patient understanding of the risks of over-the-counter drugs

https://doi.org/10.21203/rs.3.rs-4619068/v1

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Purpose Certain medications are contraindicated in patients with hemophilia or Long QT Syndrome (LQTS). Accurate registration of contraindications in electronic health record (EHR) systems is essential to minimize the risks when prescribing medication by healthcare professionals. Also, the use of certain over-the-counter (OTC) medications is contraindicated in these patients. Hence, patients must be cognizant of the potential risks associated when using these medications. We aimed to quantify the accurate registration of hemophilia and LQTS within primary and secondary care and to assess the degree to which patients take into account their medical condition when visiting healthcare professionals and using over-the-counter medication.

Methods Patients with hemophilia or LQTS being under treatment in Isala Hospital were included. Community pharmacists and General Practitioners (GPs) were surveyed regarding the accurate documentation of these conditions. An analysis was conducted on the prescribed medications for these patients over the past year, to determine if any were contraindicated. Additionally, patients were surveyed to assess their awareness of the medication safety risks of their medical condition.

Results Of the included 32 patients with hemophilia and 21 patients with LQTS the contraindications were accurately registered by pharmacists, GPs and hospital in 86.4, 70.8 and 0% (hemophilia), and 80.0, 82.4 and 28.6% (LQTS), respectively. The majority of patients reported their disease when visiting healthcare professionals. However, of the patients with hemophilia and LQTS 20% and 40%, respectively, were unaware of the potential risks associated with OTC medication.

Conclusion This study indicates that strong improvement can be achieved in accurate registration of the contraindications LQTS and hemophilia in both primary and secondary care. Enhanced registration will improve medication safety in patients when prescribed by healthcare professionals. Additionally, there is a need for increased patient education concerning medication usage, as they tend to underestimate the risks associated with (OTC) medications.

Contraindication

LQTS

Hemophilia

Medication surveillance

Primary care

Prescribing

In patients diagnosed with hemophilia or Long QT Syndrome (LQTS), the use of certain medications is absolutely contraindicated due to potentially severe complications [1], [2]. Patients with LQTS experience an abnormal heart rhythm due to a genetic mutation which may result in delayed repolarization and subsequent prolonged QT interval, potentially leading to arrhythmias. The estimated prevalence of LQTS worldwide is 1 in 2,000 individuals. Patients with LQTS face an increased risk of life-threatening Torsade de Pointes when prescribed QT-prolonging medications [1].

Hemophilia Type A and B are hereditary coagulation disorders resulting from a deficiency of clotting proteins factor 8 (Type A) or 9 (Type B). The severity of hemophilia is indicated by the percentage of clotting factors [3], [4]. This condition occurs in approximately one out of 12,000 individuals worldwide [5]. For those with the coagulation disorder hemophilia, there is an increased risk of severe bleeding with exposure to anticoagulant medications [6].

Given the significant risks associated with medication use in patients with these conditions, it is important for healthcare professionals that these conditions are accurately registered in electronic healthcare records (EHRs) to generate safety alerts when prescribing contraindicated medication. This safety system does not function when the medical condition is only recorded as plain text in the patient’s record, introducing a potential vulnerability to medication errors.

The National Classification of Contraindications/Precautions List (NCI) specifies the contraindications (CIs) upon which healthcare providers in the Netherlands conduct medication surveillance. These CIs are coded to enable automated medication surveillance. The NCI list includes several CIs, including Long QT Syndrome. Hemophilia, however, lacks its specific code and should therefore be registered under the code for coagulation disorders [7]. These pertinent patient-specific structured information can be digitally shared through a nationwide exchange network known as LSP (Landelijk SchakelPunt) in the Netherlands. The majority of community and outpatient pharmacies, GP practices, and hospitals are linked to this network.

To our knowledge, no studies have been performed on the completeness of the registration of CIs in patients with hemophilia and LQTS in different health records. A recent study, conducted by Lau et. al, found large differences in the registration of the contraindication bariatric surgery, ranging from 24 to 69% in the EHRs of the hospital, general practitioners and pharmacists [8]. Furthermore, a study on the safety of prescribed medication in patients with Brugada Syndrome suggests the need for optimization in the registration of CIs, revealing that half of the patients were prescribed potentially contraindicated medication[9].

It is also important for patients themselves to be aware of the potential risks associated with over-the-counter (OTC) medication. For example, the use of xylometazoline and proton pump inhibitors in patients with LQTS or nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with hemophilia are (relatively) contraindicated [2], [10], [11]. So far, no studies have been performed about the risks associated with OTC-medication in patients with hemophilia or LQTS.

This study aims to assess the completeness and accuracy of the registered CIs among patients in primary and secondary healthcare settings. Furthermore, it aims to examine the prevalence of prescribing contraindicated medications and assess patients' awareness regarding the risks associated with over-the-counter (OTC) medications.

Inclusion of patients

In this retrospective observational study, patients being under treatment in Isala Hospital (Zwolle, the Netherlands) with a diagnosis of hemophilia or LQTS were included.

Patients with hemophilia were identified based on declaration data for hemophilia between 2016 and 2022 in the EHRs. Patients diagnosed with LQTS were identified utilizing the validated CTcue search program, which is a clinical data aggregator specifically developed to extract structured and unstructured data from electronic health records (EHRs) within hospital databases via predefined queries [12]. The search criteria were “LQTS” and “prolonged QT syndrome”. All patients with one of the criteria in their records were identified. Patients were screened by a pharmacist. All patients with proven or probable LQTS were screened by a cardiologist specialized in cardiac rhythm disorders. Only patients with proven LQTS were included in the study.

Registration of medical conditions in primary and secondary care

After the written consent of the patients, their general practitioners and public pharmacists were inquired by phone about the registration of the medical condition. Since hemophilia is not included in the NCI it is not possible to register the condition as contraindication. Therefore we checked whether the contraindication ‘coagulation disorder’ was registered. To prevent the exchange of the registration of CIs during this study, the GPs and pharmacists were contacted consecutively. In the case of a pharmacy-owning general practitioner, the registration was considered for only the GP’s EHR.

Additionally, a manual analysis was conducted for each patient to determine whether the specific contraindication was registered in the hospital’s EHR.

Prescription of potentially contraindicated medication

The prescription of potentially contraindicated medication was investigated by reviewing all dispensed medication. The Dutch nationwide medication monitoring, established by the Health Base Foundation, lists medications contraindicated in individuals with hemophilia, categorizing them as absolute or relative CIs [13], [14]. Regarding LQTS, recommendations for medication usage were derived from the Crediblemeds® database. The recommendations were divided into absolute or relative CIs based on the risk of developing Torsades de Pointes (TdPs) [15].

Overviews of dispensed medications over the last 12 months were requested from the patient's general pharmacy or through LSP.

Patient awareness of the medical condition

To assess patient awareness about the medication safety risks of their medical condition, the following questions were asked in phone interviews:

Do you disclose your rare condition to every healthcare provider?

Are you aware of potential risks for complications when using OTC medications?

Do you check whether OTC medications can be used safely? For instance, do you consult various websites or discuss with your own pharmacist or general practitioner?

We contacted the parents of patients under the age of 16. In cases where a parent was also included in this study, only one result has been incorporated into the analysis of the patient’s awareness to avoid bias.

Data analysis

Patient characteristics were described with continuous variables presented as medians and interquartile range, and categorical variables as count and percentage.

Patient characteristics

From the Hospital EHRs, we identified 47 patients with hemophilia and 73 patients with LQTS. Patients were excluded due to incorrect inclusion, mortality, unreachability, or refusal to participate. Eventually, our analysis included 32 patients with hemophilia and 21 patients with LQTS. A flow chart of the included patients is presented in Supplementary File 1.

The patient characteristics of the study population are summarized in Table 1. Of the included patients with hemophilia or LQTS, 81.3% and 33.3% are male, respectively.

Table 1

Overview of patient characteristics. *Data obtained from patients’ hospital EHRs. LQTS = Long QT Syndrome. ICD = Implantable cardioverter defibrillator. JLN = Jervell and Lange Nielsen Syndrome.*
Characteristic		Hemophilia (n = 32)		LQTS (n = 21)
Sex	Male, n (%)	26 (81.3%)		7 (33.3%)
Median age, years (range)		59 (4–86)		42 (1–78)
Type	Severe hemophilia, n (%) Mild hemophilia, n (%) Unknown, n (%)	6 (18.8%) 20 (62.3%) 6 (18.8%)		- - -
	Hemophilia A, n (%) Hemophilia B, n (%) Unknown, n (%)	27 (84.4%) 2 (6.25%) 3 (14.3%)		- - -
	LQTS type 1, n (%) LQTS type 2, n (%) LQTS type 3, n (%) JLN, n (%) Unknown, n (%)		- - - - -	5 (23.8%) 7 (33.3%) 1 (4.8%) 2 (9.5%) 6 (28.6%)
Prescribed medication for disease, n (%)		11 (34.4%)		8 (38.1%)
ICD, n (%)		-		3 (14.3%)

Registration of medical conditions in primary and secondary care

Among the included patients with hemophilia, the medical condition was registered as a contraindication by 86.4% of community pharmacists and 70.8% of GPs (see Table 2). None of the patients’ hospital EHRs had hemophilia registered as a contraindication. However, this information was recorded in a warning box, unable to trigger automatic medication surveillance, in 65.6% of the cases. Concerning LQTS, the contraindication was registered in 28.6% of the patients’ hospital EHR. In primary care, this was registered by 80.0% of community pharmacists and 82.4% of GPs.

Table 2 Overview of correctly registered contraindications in primary and secondary care. A different number of patients was included for each type of EHR, due to the lack and inaccessibility of their own pharmacy and general practitioner (Additional files 1A and 1B. CI = Contraindication. EHR = Electronic Health Record.

	EHR	Registered as CI, n (%)	Registered in the warning section as plain text, n (%)	Not registered as CI, n (%)
Hemophilia (n = 32)	Pharmacy (n = 22)	19 (86.4)	0 (0.0)	3 (13.6)
	General practice (n = 24)	17 (70.8)	5 (29.4)	2 (8.3)
	Hospital (n = 32)	0 (0.0)	21 (65.6)	11 (34.3)
LQTS (n = 21)	Pharmacy (n = 15)	12 (80.0)	1 (6.7)	2 (13.3)
	General practice (n = 17)	14 (82.4)	1 (5.8)	2 (11.7)
	Hospital (n = 21)	6 (28.6)	0 (0.0)	15 (71.4)

Medication that is (relatively) contraindicated was prescribed in 16.0 and 15.8% of patients with hemophilia or LQTS, respectively. In two patients with hemophilia who were prescribed apixaban and carbasalate calcium, the medical condition was not recorded by both the GP and the community pharmacist (see Table 3).

Table 3 Overview of contraindicated medication prescribed to patients with hemophilia or LQTS. EHR = Electronic Health Record. CI = Contraindication. TdP = Torsade de Pointes. GP = General Practitioner. P-GP = Pharmacy owning General Practitioner.

	Number of patients, % (n)	Medication (n)	Associated risk	Registered in the EHR
				Pharmacist	GP
Hemophilia (n = 25)	16.0 (4)	Acetylsalicylic acid (2)	Increased risk of bleeding	CI	Captured in the warning section of the EHR as plain text
				CI	CI
		Apixaban (1)	Increased risk of bleeding	No registration	No registration
		Carbasalate calcium (1)	Increased risk of bleeding	Captured in the warning section of the EHR as plain text (P-GP)
LQTS (n = 19)	15.8 (3)	Tramadol (1)	QT interval prolongation, potential risk of TdP	CI	CI
		Pantoprazole (2)	Under certain conditions, increased risk of TdP	CI	Unknown
				No registration	CI

Awareness of medical conditions among patients

Patients with hemophilia (93.3%) and LQTS (65%), routinely disclose their medical condition during visits to healthcare providers (see Fig. 1). However, 20% of patients with hemophilia are unaware of the potential risks associated with over-the-counter (OTC) medication. This same lack of awareness was observed in 40% of patients with LQTS. In 10.0% of patients with hemophilia, OTC medication is not checked for potential risks at the time of purchase, compared with 45% in patients with LQTS.

A significant percentage of patients in the first line, have their respective medical conditions registered as CIs by community pharmacists and GPs. However, in secondary care, these medical conditions are frequently either unregistered or as plain text entered in the warning box of EHRs, posing a potential medication safety risk. While there is room for improvement in the registration of CIs in primary care, a more substantial enhancement is required in secondary care.

In our hospital, the correct registration of medical conditions shows a lower percentage compared to the 69% of the contraindication bariatric surgery at the Albert Schweitzer Hospital, the Netherlands [8]. Nevertheless, the registration of the contraindication bariatric surgery in public pharmacies and GPs is lower compared to our study. We speculate that the observed variations between the regions in the Netherlands may be attributed to potential discrepancies in the education of prescribers in primary and secondary care regarding the registration of CIs. Additionally, differences in the implementation of medication reconciliation at both admission and discharge, incorporating information about CIs, could also be contributory. However, as noted by Laura et. al, the registration in the hospital appears not to significantly impact the completeness of the registration in primary care, which is also shown in our study [8]. This underscores the need for substantial improvement in the exchange of information between primary and secondary care.

When examining the prescribed medication for the patients diagnosed with hemophilia, a relatively large percentage (16%) received medication causing an increased risk of bleeding. In only one patient no registration of the CI was present in primary care. Therefore, we presume that careful consideration has been made in the majority of patients between the risk of bleeding and the risk of clotting when prescribing medication. Additionally, Aguilar et. al conclude that there is no difference in cardiovascular risk factors between patients with and without hemophilia and treatment of cardiovascular indications is necessary under strict control [16].

For patients with LQTS who were prescribed medication carrying the potential risk of developing TdPs, alternative medication could have been prescribed without the risk of QT interval prolongation (for example oxycodone instead of tramadol and a histamine 2 receptor blocker instead of pantoprazole). It is unknown which considerations were made when prescribing the medication and whether the QT interval was monitored in these patients after initiating the therapy. Additionally, the medical condition was registered as a CI by either the GP or the pharmacist, indicating expected additional monitoring in these cases.

The prescription of contraindicated medication to patients in this study was significantly lower compared to the study involving patients with Brugada Syndrome (53%) [9]. This difference could be attributed to a longer study period (median of 5.8 years), potentially leading to a higher frequency of (contraindicated) medication prescriptions.

This research indicates that the majority of patients with hemophilia disclose their medical condition when visiting healthcare providers and are aware of the potential risks of over-the-counter (OTC) medication. However, a substantial percentage of patients seem unaware of the possible risks linked to OTC medication. This is in line with a study by Westerlund et. al. that many patients underestimate the potential risks of OTC medication [17]. Given the potential risks of using OTC medication (e.g. NSAIDs) in the context of this rare condition, these findings emphasize the urgent need to inform hemophilia patients about these risks.

A large percentage of patients with LQTS do not disclose their medical condition when visiting healthcare providers and are not aware of the potential risks associated with OTC medication compared to patients with hemophilia. A possible explanation of this difference can be that a complication such as QT prolongation is not noticed by patients with LQTS, compared to bleeding in patients with hemophilia, raising more awareness about the latter condition. In addition, other factors can contribute to this difference, such as other personal characteristics, patient educational level, and information provided by healthcare providers, but these were not investigated in our study [18]. Our findings, with high percentages of patients considering OTC medication safe, highlight the need to raise more awareness about its potential risks.

To improve better registration of CIs, pharmacy technicians will register these rare CIs in the EHRs during medication verification upon patient admission at our hospital, ensuring monitoring in secondary care for these rare conditions. Also, the prescribers have been educated on how to register CIs in the EHR of patients.

A strength of this study is the relatively large study population of studied patients, considering these rare medical conditions. Second, few studies have been performed on the awareness of patients of the medication safety risks when going to health care practitioners or buying OTC medication, providing a more comprehensive view of medication safety risks.

A limitation of the study is the low absolute number of included patients. Furthermore, only patients from one hospital were included, which may affect the generalizability of the results to patients with similar conditions in other regions or healthcare settings.

This research indicates that hemophilia and LQTS are not adequately registered by all healthcare providers. In secondary care, the registration of CIs can be greatly improved. Better medication reconciliation, including the registration of CIs, and education of prescribers on the correct method of entering CIs in the EHRs, is essential for improving medication safety. Additionally, more education is required for patients regarding their medication use, as they tend to underestimate the risks associated with (OTC) medications.

Ethical approval Ethical approval was waived for this study from the Medical ethical board Isala (METC Isala), Zwolle, the Netherlands, on April 17, 2023. This research was conducted in accordance with the Declaration of Helsinki.

Clinical trial number 20230319

Competing interests The authors declare no competing interests.

Written consent to participate Patients provided written consent for testing registration in general practitioner (GP) practices and public pharmacies.

Funding No funding.

Availability of data The datasets generated and analyzed during the current study are not publicly, but are available from the corresponding author upon request.

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No competing interests reported.

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Patients with hemophilia or LQTS: strong improvement needed for both accurate registration of contraindications and in patient understanding of the risks of over-the-counter drugs

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Version 1

Abstract

Figures

Background

Methods

Inclusion of patients

Registration of medical conditions in primary and secondary care

Prescription of potentially contraindicated medication

Patient awareness of the medical condition

Data analysis

Results

Patient characteristics

Registration of medical conditions in primary and secondary care

Awareness of medical conditions among patients

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

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