Metoprolol-Induced Syncope and Nicoumalone-Induced Bruising: A Case Report of Dose-Dependent Adverse Drug Reactions.

Rheumatic heart disease (RHD) remains a significant cause of cardiovascular morbidity in developing nations, often leading to valvular dysfunction such as mitral regurgitation and stenosis. Despite declining prevalence in high-income countries, RHD continues to affect millions globally from low- and middle-income regions, particularly young and female adults ^{[1, 2]}. Percutaneous transvenous mitral commissurotomy (PTMC) is a widely adopted minimally invasive intervention for relief of mitral stenosis, with favorable hemodynamic and survival benefits ^[3].

Patients with RHD and atrial fibrillation (AF) are frequently associated with one another. This combination, especially in the post-PTMC period, requires long-term anticoagulation and often concomitant antiplatelet therapy to prevent thromboembolic events. However, polypharmacy in such patients increases the risk of adverse drug reactions (ADRs), which may be severe or life-threatening.

Nicoumalone, being a vitamin K antagonist, potentially can reduce the synthesis of clotting factors II, VII, IX, and X, thereby increasing the risk of bleeding and bruising ^[4]. Similarly, beta-blockers like metoprolol are frequently used for rate control in AF but can cause dose-dependent hypotension and bradyarrhythmia ^[5].

Early recognition, assessment, and management of ADRs in patients with complex cardiovascular disease are integral to optimizing therapy and preventing complications in critical care settings.

CASE PRESENTATION

A 40-year-old female with a known history of rheumatic heart disease (RHD) and severe mitral regurgitation, status post percutaneous transvenous mitral commissurotomy (PTMC), was admitted to the intensive care unit (ICU) with complaints of giddiness, syncope, and pain over the lower lip, which was suspected to be trauma-induced from a syncopal episode.

On initial examination, the patient was hemodynamically stable, with a blood pressure (BP) of 110/70 mmHg and a pulse rate of 104 bpm. Capillary blood glucose was 94 mg/dL. Laboratory investigations revealed thrombocytopenia (platelet count: 84,000/µL) and a normal international normalized ratio (INR) of 1.17. ECG showed atrial fibrillation (AF) with a rapid ventricular response (RVR).

Management was initiated with subcutaneous heparin, oral Acitrom (nicoumalone) 4 mg once daily, and Tab. Metoprolol 250 mg twice daily for rate control. The patient was also started on Tab. Clopidogrel 150 mg once daily, Tab. Atorvastatin 40 mg, penicillin prophylaxis, and supportive medications.

Over the next three days, the patient remained clinically stable. However, on Day 4, she experienced another episode of syncope, with a documented drop in BP to 90/60 mmHg. In view of the temporal relationship between high-dose metoprolol administration and the onset of hypotension and syncope, a dose-related adverse drug reaction (ADR) was suspected. Tab. Metoprolol was dose-adjusted to 100 mg twice daily, after which no further syncopal episodes were reported.

Additionally, the patient began to report spontaneous bruising over the extremities. Repeat laboratory evaluation revealed a significant increase in INR to 3.3, while platelet count remained low. In light of the elevated INR, low platelets, and bruising, Nicoumalone-induced bleeding was suspected. The dose of Tab. Nicoumalone was also reduced to 2mg, and additionally, Clopidogrel was discontinued, and low-dose aspirin (75 mg) was introduced as an alternative antiplatelet agent. The patient's bruising subsequently stabilized, and no major bleeding events were observed.

The suspected ADRs were assessed using the Naranjo Adverse Drug Reaction Probability Scale:

• Syncope due to Metoprolol: Probable (score 6)
• Easy bruising due to Nicoumalone: Possible (score 3)

This case highlights the importance of individualized drug titration and close monitoring of anticoagulant and antiplatelet therapy in patients with atrial fibrillation and valvular heart disease, especially those with baseline thrombocytopenia. It also emphasizes the need for early recognition of ADRs, particularly in the critical care setting, where polypharmacy is common.

DISCUSSION

This case illustrates two probable adverse drug reactions in a patient with rheumatic heart disease (RHD), atrial fibrillation (AF), and baseline thrombocytopenia. The first event, syncope associated with high-dose metoprolol, was likely due to excessive beta-blockade leading to hypotension. In AF cases with rapid ventricular response, the primary treatment strategy is to reduce heart rate; beta blockers such as metoprolol are recommended to slow the ventricular heart rate ^[4]. Beta-blockers, particularly at higher doses, can precipitate bradycardia, hypotension, and syncope, especially in patients with structural heart disease and limited cardiac reserve ^[5]. In this case, the patient fainted on day 4, the vital examination showed a drop in the blood pressure to 90/60mmHg. Careful dose titration is essential to balance rate control with hemodynamic stability.

Though clopidogrel, acitrom, and heparin act on different pathways, their primary aim is to prevent clots. Clopidogrel inhibits platelet activation by blocking ADP receptors on platelets, preventing aggregation. Coumarin anticoagulants inhibit vitamin K epoxide reductase, reducing the synthesis of clotting factors. Heparin enhances antithrombin III activity, which inactivates thrombin and factor Xa, preventing fibrin formation ^{[6, 7, 8]}

The second event, easy bruising and elevated INR while on clopidogrel, nicoumalone, and heparin, underscores the bleeding risks of triple antithrombotic therapy, especially in thrombocytopenic patients. Polypharmacy with anticoagulants and antiplatelets markedly increases bleeding risk, a concern supported by large clinical trials and observational data ^[5]. The synergy between platelet inhibition and anticoagulation can undermine hemostasis even in the absence of trauma.

Approximately double the risk is noticed in the patients when the INR gets above 3.0. Since Nicoumalone can increase the INR, the patient must be monitored carefully to prevent bleeding risks. The risk of bleeding doubles for each one-point increase. ^[9]

The role of the Naranjo Adverse Drug Reaction Probability Scale was crucial in objectifying causality assessment, aiding clinical decision-making ^[10]. Early identification and prompt modification of therapy by reducing the metoprolol dose and modifying antithrombotic therapy led to the resolution of symptoms without further complications.

Table 1: Naranjo ADR Probability Assessment Scale