Amendment No. 1, dated 29 November 2012, was applicable in Argentina. To comply with local requirements of the Medicine Agency of Argentina - ANMAT (Administración Nacional de Medicamentos, Alimentos y Tecnología Médica) for the implementation of the clinical trial in Argentina, a pregnancy test at the beginning of the study and at every patient visit for women with childbearing potential was added. Finally, due to dynamic recruitment in other participating countries together with regulatory timelines, there were no Argentinian centres opened for participation in this study.

Amendment No. 2, dated 29 April 2013, concerned all investigational sites in all countries. The main changes were: Following the European Medicine Agency scientific advice (issued on the 17th of January 2013):  Given the importance of clinical data on the ivabradine IR and MR formulations switch, the number of patients evaluated in the setting of 3-month switch period was increased from 60 to 120 in each treatment arm.  Patient’s background treatment (in particular beta-blockers) at the time of formulation switch was collected. In order to reach the target of 120 patients for PK assessment, the total number of patients planned to be evaluated was increased from 700 up to approximately 850. Documentation of events of special interest for ivabradine (bradycardia, ECG prolonged QT interval, eye disorders, rhythm and conduction disorders, increase in blood pressure in hypertensive patients, immune disorders) was detailed, in order to harmonise the study protocol with the latest proposed version of the EU-Risk Management Plan (RMP) of ivabradine hydrochloride (issued on the 22nd of January 2013). The amendment also included diverse adaptations to improve the study patient’s follow-up by the investigators, spelling corrections.