Adverse Drug Reactions Attributed to Fondaparinux and Unfractionated Heparin in Cardiovascular Care Unit: An Observational Prospective Pilot Study in a Tertiary Care Hospital.

INTRODUCTION: This study was carried out to collect and analyze the adverse drug reactions (ADRs) reported with use of anticoagulants, heparin and fondaparinux. These drugs are vital in the treatment of unstable coronary artery diseases and emergencies.
MATERIALS AND METHODS: A cross-sectional study with active reporting of ADRs from cardiology and medicine department was conducted. The type of reaction was assessed by Rawlins and Thomson criteria, causality by Naranjo probability scale, severity by modified Hartwig criteria, and preventability by Schumock and Thornton criteria. RESULT: Of the 67 patients observed, 16 showed ADRs. Fifteen reactions were attributable to unfractionated heparin and one to fondaparinux following assessment by the Naranjo causality scale. Severity of the ADRs assessed by modified Hartwig criteria showed that although 12 of 16 (75%) were mild, 4 (25%) were moderate in severity. Modified Schumock and Thornton criteria showed that 9 of 16 (56.25%) reactions could not have been prevented whereas 5 (31.25%) were probably preventable and 2 (12.5%) were definitely preventable.
CONCLUSION: Incidence of ADRs with fondaparinux was lower than with heparin, hence emphasizing its better safety profile. The study also highlights the need for nurses and other caretakers in the coronary care unit to enquire for and report ADRs, particularly with high-potency medicines that are associated with an equally high potential to induce ADRs.

INTRODUCTION

With great advancements in the field of drug therapy, society has had to also bear adverse drug reactions (ADRs), at times of gargantuan proportions. ADR is defined as “any noxious change which is suspected to be due to a drug, occurs at doses normally used in a person, requires treatment or decrease in doses or indicates caution in the future use of the same drug.”[1]

Pharmacovigilance is the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems.[12] The World Health Organization (WHO) established its program for international drug monitoring following the thalidomide disaster in 1961, for promoting pharmacovigilance at a global and national level.[3]

The Pharmacovigilance Program of India (PvPI) is responsible for safeguarding the lives of 1.27 billion Indians. National Co-ordination Programme of PvPI monitors ADRs in Indian population and helps the regulatory authority Central Drugs Standard Control Organization (CDSCO) to take decisions on safe use of medicines.

Acute coronary syndromes (ACSs) and related emergencies are the leading cause of morbidity and mortality in India and place a large financial burden on the health-care system. It is essential to monitor the adverse reactions caused by the drugs used in their treatment. A study conducted by Mohebbi et al.[4] showed that 42 of a total of 189 (22.2%) ADRs reported in an 8-month study analyzing ADRs induced by cardiovascular drugs in coronary care unit (CCU) were serious.

ACS is the unifying term representing a common end result of acute myocardial ischemia seen in unstable angina, non-ST elevated myocardial infarction (NSTEMI), or ST-elevated myocardial infarction. Venous thromboembolism (VTE), a common consequence of ACS, is a very frequent form of vascular disease and impacts a great number of patients worldwide. Acute deep vein thrombosis (DVT) and acute pulmonary embolism (APE) are subsets of VTE and are traditionally treated with anticoagulation.

Fondaparinux and unfractionated heparin are parenterally administered anticoagulants, which are used not only to reduce risk of ischemic events but also to improve long-term mortality and morbidity associated with conditions such as ACS, DVT, or APE. Fondaparinux sodium is a newer synthetic pentasaccharide anticoagulant that specifically inhibits factor Xa, whereas unfractionated heparin inactivates thrombin and factor Xa through an antithrombin-dependent mechanism.[567]

A rare case of fondaparinux-induced major bleeding in a 58-year-old woman prescribed for NSTEMI was assessed by Sharma et al.[8] As this reaction was unpredictable as per the known mechanism of action and was not studied for a dose-dependent response, they could not clearly be labeled it as a type A or B class of ADR.

Reports like these highlight the need for clinicians to have a sound understanding of anticoagulant toxicity and predict the risk of bleeding; hence, the risk–benefit ratio can be assessed.

Studies on ADRs caused by cardiovascular drugs used in CCUs, particularly anticoagulants, have not been well documented in India. It was observed that fondaparinux and heparin are the most prescribed anticoagulants by the cardiologists. Therefore, this study was aimed to detect, document, assess, and report suspected ADRs due to these two drugs. The ultimate aim was to increase the level of awareness about them among all staff (doctors, nurses, and technicians) working in the CCU; to improve pharmacovigilance in the cardiology department; and to compare the ADR reporting surveillance when conducted actively and passively.

MATERIALS AND METHODS

It was an observational prospective pilot study on the ADRs associated with fondaparinux and unfractionated heparin in ACS, DVT, and APE. The study was carried out following approval from the institutional ethics committee and was conducted over a period of 3 months (February 2016 to April 2016). The study group included all patients admitted into the CCU for ACS, coronary angiogram, coronary angioplasty, percutaneous transluminal coronary angioplasty, or the cardiothoracic and vascular surgery ward for DVT/APE prophylaxis who were on either heparin or fondaparinux. The patients who fulfilled the following criteria were included in the study.

Inclusion criteria included patients with

age ≤75 years;

body weight >50kg;

either sex;

diagnosis of ACS, APE, and DVT;

prophylactic treatment for ACS, APE, and DVT.

Exclusion criteria included patients with

congenital or acquired bleeding disorders, severe thrombocytopenia, hemorrhagic stroke, uncontrolled arterial hypertension;

ulcerative gastrointestinal conditions;

proliferative diabetic retinopathy;

recent surgery on the brain, spine, or eyes;

known hypersensitivity to heparin or fondaparinux;

moderate to severe renal insufficiency.

Laboratory investigations (bleeding time, clotting time, activated partial thromboplastin time, prothrombin time, international normalized ratio) were carried out based on the cardiologist’s assessment of the patient’s condition during the treatment course.

The dose, route, and frequency decided by the consultant cardiologist were as follows:

Inj. fondaparinux 2.5mg, subcutaneously, once daily for 5–7 days

Inj. unfractionated heparin 5000 IU, intravenously, every 6th hourly for 5–7 days

The following known adverse effects for both the drugs were enquired for daily until the patient was discharged from the hospital.

Fever, nausea, vomiting, rash, headache, abdominal pain or swelling, backache, joint pain, stiffness or swelling, and edema

Bleeding from gums when brushing teeth, blood in urine, coughing up blood, heavy bleeding from cuts and wounds, vomiting of blood/coffee-colored vomit, unexplained bruising or purplish areas on the skin, unexplained nosebleeds, and unexpected or unusually heavy menstrual bleeding

Constipation and diarrhea

Urinary retention and urinary tract infection

Dizziness, confusion, and insomnia

Hypersensitivity and allergic reactions

Other reactions apart from the aforementioned were also enquired for.

Suspected drug reaction reporting forms from CDSCO were filled out for the same and submitted to the Pharmacovigilance ADR Reporting Cell in the hospital premises.

They were classified as type A (dose-dependent and predictable) or type B (idiosyncratic with no clear dose–response relationship) according to the system introduced by Rawlins and Thompson in 1977.[9]

The degree of association of an ADR with a drug was evaluated using Naranjo probability scale,[10] which involves assigning score to a set of questions. The total score for a particular ADR was calculated and the association was termed into one of these categories: definite (score >9), probable (score 5–8), possible (score 1–4), or doubtful (score 0).

Severity was categorized using modified Hartwig criteria,[11] which has seven severity levels. Levels 1 and 2 indicate mild; levels 3 and 4 indicate moderate; and level 5 and above indicate severe ADRs.[12]

Preventability of the ADRs as per modified Schumock and Thornton criteria[13] has three categories namely definitely preventable, probably preventable, and not preventable, each consisting of three questions. If the answer to any one of the questions is yes, the ADR is included under that category.[14]

RESULTS

Demographic profile

Among the 67 patients observed in this 3-month study, 14 were women and 53 were men. A total of 16 of 67 (23.88%) adverse reactions were observed. Of these 16, 2 were in female patients and 14 were in male patients. Of the study population containing 67 patients, 58 were administered with unfractionated heparin and 9 were administered with fondaparinux. The percentage incidence of ADRs with unfractionated heparin is 15 of 58 (25.86%) whereas that with fondaparinux is 1 of 9 (11.11%). Figure 1 summarizes that although patients of diverse age groups were present, the highest incidence was in the age group of 50–59 years.

Figure 1

Age distribution of patients who developed ADRs

Nature of the ADRs

The most frequent ADRs were gastrointestinal in nature, mainly constipation. The only reaction seen with fondaparinux was loose stools and excessive sweating. Table 1 lists the ADRs that were seen during the study.

Table 1

Nature and frequency of ADRs

Type of suspect ADRs

The ADRs were categorized based on the Rawlins and Thompson classification into type A (augmented) or type B (bizarre), and most of them were type A as shown in Table 2. The most common adverse effects seen were headache lasting for 2–3 days and gastrointestinal disturbances (constipation).

Table 2

Type of reaction based on Rawlins and Thompson classification

Causality assessment

The causality assessment as per Naranjo scale showed that of 16 reactions, 9 were possibly related and 7 were probably related to the anticoagulants. The single adverse reaction due to fondaparinux was assessed as possibly related.

Severity of suspect ADRs

As assessed by modified Hartwig criteria, 12 of 16 reactions (75%) were mild and 4 (25%) were moderate in severity. No severe reactions were seen. Although the adverse reactions to heparin ranged from mild to moderate, the reaction attributed to fondaparinux was mild with a score of 1, as shown in Figure 2.

Figure 2

Severity according to modified Hartwig and Siegel

Preventability of suspect ADRs

Modified Schumock and Thornton criteria showed that 9 of 16 (56.25%) reactions could not have been prevented whereas 5 (31.25%) were probably preventable and 2 (12.5%) were definitely preventable, as seen in Figure 3.

Figure 3

Preventability according to Schumock and Thornton scale

Two major serious reactions

One of the adverse drug events (ADEs) was that of a massive bleed into the patients Ryle’s tube. The 35-year-old female patient was administered streptokinase and heparin concomitantly. This led to severe bleeding and required immediate intervention. The patient was discontinued on heparin and streptokinase, and restarted on heparin only after 24 hours.

Another patient had a cutaneous allergic reaction (type A), as shown in Figure 4, at the site of administration of intravenous heparin. The patient was put on antihistaminic drugs following which the reaction regressed over 4–5 days. This was the only case that required an intervention.

Figure 4

Cutaneous allergic reaction due to intravenous administration of heparin

DISCUSSION

Anticoagulants are the most commonly prescribed drugs in CCU. Strict vigilance is required for patients especially on anticoagulants as these drugs have a narrow therapeutic range. However, very few ADRs get reported to the pharmacovigilance unit. Hence, this study was undertaken as an active surveillance so as to create an awareness among the prescribers. This would also further alert them regarding the risk factors so that preventive measures could be taken thereby reducing the morbidity.

Our study showed an incidence of 23% of ADRs. Although ADRs have been reported nonfrequently from the CCU, cardiovascular drugs and anticoagulants were the most common drug classes implicated in the studies conducted by Lisha et al.[15] and Tiaden et al.[16] In the 5-year retrospective study conducted by Piazza et al.,[17] anticoagulants again were responsible for majority of ADEs, of which 70% were preventable. As with their study and ours, the highest incidence was seen in the elderly age group with a mean of 62 and 57 years, respectively. Unfractionated heparin was responsible for 58.3% and fondaparinux for 0.7% reactions. Likewise, in this study the incidence of ADRs with unfractionated heparin is 25.86% whereas that with fondaparinux is 11.11%. As with the aforementioned studies, bleeding as a serious adverse event was associated with heparin. Fondaparinux appeared to be better tolerated as the incidence of ADRs associated with it were less compared to that of heparin. Mehta et al.[18] have shown that when compared with a heparin-based strategy, fondaparinux reduces mortality, ischemic events, and major bleeding across the full spectrum of acute coronary syndromes and is associated with a more favorable net clinical outcome in patients undergoing either an invasive or a conservative management strategy. At the same time, its cost has placed it out of reach from the needy patients especially in a large developing nation and health-care centers involved in free patient services such as ours, necessitating the use of heparin. The 2007 heparin contamination crisis resulting in several deaths in the United States and hundreds of adverse reactions worldwide revealed the vulnerability of a complex global supply chain to sophisticated adulteration as shown in study by Szajek et al.[19] This may also have favored the use of fondaparinux over heparin. In the study conducted by Palaniappan et al.,[20] active surveillance yielded 98% reports and only 2% through the spontaneous reporting system. Previously no ADRs were reported from the CCU in our tertiary care hospital. This 3-month study shows that active surveillance is much more effective as 16 (23.88%) ADRs pertaining only to anticoagulants were reported by us.

ADR monitoring and reporting activity is still in its formative years in India. It is important to define the role of drug, its risk–benefit ratio, contraindications, and precautions with its use. An important reason for inadequate reporting or documenting is the lack of awareness and interest among the health-care professionals. This study was designed not only to report ADRs, but also to increase the level of awareness in the entire team interacting with the patients in the CCU and in other wards.

CONCLUSION

The two major reactions highlight the need for nurses and other caretakers in the CCU to enquire for and report ADRs, particularly when the administrations of such high-potency medicines are associated with an equally high potential to induce ADRs. This will definitely result in better care with lesser ADRs and the complications associated with them, such as requirement of interventional medicine, prolonged hospital stay, and increased financial and mental burden on the patient, their family members, and the hospital.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.