Background: Patients admitted to the critical cardiac care unit (CCCU) experiencing adverse drug-drug interaction (DDI) and drug-disease interaction (DDSI) are going undetected. Detecting the clinically significant drug interactions allows the opportunity for prevention through the clinical drug decision support system (CDDSS). However, acceptance of CDDSS is poor among the physicians probably associated to alert fatigue. Objective: The general objectives of this study are to identify adverse drug events (ADE) or potential adverse drug events (PADE) (DDI and DDSI) in a CCCU in Malaysia using commercially available CDDSS and their effect on prevention of such DREStudy Design: This is a prospective observational study conducted at a critical cardiac care unit (CCCU) in a selected tertiary cardiac center in Malaysia for a duration of six months (February 2018 – July 2018). Methods: Data on PADE alerts (for interactions designated as ‘contraindicated/major’ and ‘moderate’) were acquired from CDDSS (MIMS® and MICROMEDEX®). PADE were assessed by the attending physicians for any real ADE. Physicians’ reasons for overriding the alerts and their physicians’ actions for accepting the alerts and were as clinically useful or not to the physicians in the assessment of potential patient harm at critical cardiac unit settings. Results: Evaluation of 709 patient medication profiles were conducted, resulting in 649 and 337 assessed patient profiles had one or more potential DDI and DDSI respectively with 87% of them were influenced by polypharmacy. Ninety patients (17%) were associated with one or more DDI and DDSI related ADE. Of the total 3137 potential DDI, 89.1% of the alerts were overridden. Reasons given were ‘no other suitable alternatives’ (n=840, 30.1%), ‘benefit outweighs the risk’ (n=528, 18.9%), ‘patient will be monitored for adverse effects’ (n=651, 23.3%), ‘patient has been taking the combination’ (n=658, 23.5%) and ‘clinically insignificant’ (n=352, 12.6). Conclusions: Even though, the occurrence of drug interactions is prevailing in critical cardiac patients, CDDSS differs in their ability to prevent potential ADE. Hence, issue of fatigue drug interaction alerts is still indisputable. CDDSS alone is not enough in preventing adverse drug interactions. Integrating to CPOE should be still redesigned considering the acute settings, clinical practice guidelines and patients’ previous exposure to the medications. CDDSS could be linked to the patient’s laboratory results or clinical data regarding renal or liver function, as an approach to reinforce the CDDSS quality. These systems can be useful, but their full advantages cannot be gained without collaboration between the information technology professionals and the clinicians.Imperatively, the prevalence of potential clinically relevant drug interactions can only be determined with the evidence of the adverse events.