AtlasTrial

ATLAS TRIAL
The Assessment of Treatment with Lisinopril and Survival (ATLAS) trial, which began in October 1992 and was completed in September 1997, was designed to address whether the survival benefits demonstrated with higher doses of ACE inhibitors are also seen with the lower doses used in clinical practice. The Steering Committee was chaired by Milton Packer (USA) with Philip Poole-Wilson (UK) as Vice-chairman. Other members were Paul Armstrong (Canada), John Cleland (UK), John Horowitz (Australia), Barrie Massie (USA) and Lars Ryden (Sweden). The Data and Safety Monitoring Board was chaired by John Kjekshus (Norway) and the Mortality Endpoint Committee was composed of Kristan Thygesen (Denmark) and Barry Uretsky (USA).
Objectives
The main objective of the Assessment of Treatment with Lisinopril and Survival (ATLAS) trial was to compare the effect on mortality of a low dose of lisinopril - 2.5 or 5 mg/day - as used in clinical practice to provide the relief of symptoms of congestive heart failure, with a high dose of lisinopril - 32.5 or 35 mg/day - which better reflects the doses of ACE inhibitors used in the mortality trials.
Efficacy Assessment Endpoints
The primary aim of the ATLAS trial was to compare the effect of high and low doses of lisinopril on all-cause mortality in patients with congestive heart failure and ejection fraction less than or equal to 30%. There were also a number of secondary aims. The trial compared the effects of high and low lisinopril doses on combined all-cause mortality and all-cause hospitalisation, cardiovascular mortality, combined all-cause mortality and cardiovascular hospitalisation, combined cardiovascular mortality and cardiovascular hospitalisation and combined (fatal and non-fatal) myocardial infarctions plus hospitalisation for unstable angina.
Trial Criteria
Male or female patients 18 years or older were eligible for the trial. However, premenopausal females were only allowed if they were surgically sterile. All patients had to have congestive heart failure in NYHA Class II to IV but those in Class II had to have received emergency treatment or been hospitalised for congestive heart failure in the last six months. In addition, patients must have had evidence of an ejection fraction less than or equal to 30% as assessed by radionuclide ventriculography, echocardiography or cineangiocardiography within three months before or at entry. The patients must also have been treated with diuretics, with or without digoxin, for at least 60 days before entering the trial. Patients with unstable coronary artery disease, unstable ventricular arrhythmias, unstable congestive heart failure or those with a contraindication to the use of ACE inhibitors were excluded from the trial. In addition, if the patients had any other disorder that may have limited survival within the next 4.5 years, or had severe pulmonary disease, or alcohol or drug addiction, or a history of serious psychiatric or personality disorders, they too were excluded from the trial.
Trial Design
The ATLAS trial was a multinational, randomised, double-blind, parallel group trial which compared the effects of long-term low and high dose lisinopril on survival in patients with congestive heart failure. Provided they tolerated lisinopril, they were randomly allocated to once daily, double-blind treatment with lisinopril low dose (2.5 or 5 mg) or high dose (32.5 or 35 mg). Recruitment was completed in mid 1994 with patients entering from Europe, USA, Canada and Australia.
Trial Design 2
During the open-label tolerability period, Phase I, patients who had been previously treated with an ACE inhibitor received 12.5 or 15 mg lisinopril once daily for four weeks in place of their previous ACE inhibitor treatment. Patients not previously treated with an ACE inhibitor were given an initial dose of 2.5 mg lisinopril. Provided that this initial dose was tolerated, these patients continued on 2.5 or 5 mg once daily for two weeks, followed by an additional 10 mg dose of lisinopril once daily for a further two weeks. During Phase II, all patients were randomised to receive lisinopril or placebo, the doses of which were titrated in a double-blind fashion. Patients continued on background therapy with lisinopril 2.5 or 5 mg, but open-label treatment with lisinopril 10 mg was stopped and lisinopril 20 mg or matching placebo was added for two weeks. If this was tolerated, patients received an additional 10 mg of lisinopril (or another matching placebo tablet) for a further two weeks. At the end of this period, the patients on the high dose received 32.5 or 35 mg lisinopril once daily and those taking the low dose received 2.5 or 5 mg once daily. During Phase III, the maintenance phase, the patients were maintained on the double-blind therapy for up to 54 months from randomisation. If the patients were unable to tolerate study medication, the investigator was permitted to reduce dose or discontinue it.
Laboratory Parameters
Information recorded included documentation of the patient’s medical history, determination of the aetiology, duration, signs, symptoms and NYHA classification of congestive heart failure together with body weight measurement. Blood pressure was determined, after the patient had been seated for two minutes, using phase V for diastolic pressure. Heart rate, by radial pulse, and heart rhythm were determined. Within three months of the first visit or at the first visit the ejection fraction was determined by radionuclide ventriculography, echocardiography or angiography. To be included in the trial the ejection fraction had to be 30% or less. At the first visit a standard, supine 12 lead ECG was recorded following a 5 minute rest. Any abnormalities were documented and the ECG was repeated at any visit if deemed necessary. The chest X-ray was made erect during deep inspiration and the absence or presence of pulmonary oedema was documented.
Laboratory Parameters 2
The haematology parameters measured included haemoglobin, haematocrit, red blood cell count, white blood cell count and platelet count. The biochemistry parameters measured included potassium, sodium, urea, creatinine, total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and albumin.
Clinical Monitoring
Procedures were laid down for documenting hospitalisation for other illnesses whether cardiac or non-cardiac, and for events requiring the stopping of trial medication. Procedures were also defined for cases of worsening heart failure or renal function. For the former, sequential options included increasing the dose of diuretics, decreasing or discontinuing calcium channel blockers, adjustment of the digoxin dose, increasing the dose of other non-ACE inhibitor vasodilators and increasing the background lisinopril dose from 2.5 to 5 mg. For the latter, decreasing or discontinuing diuretics or calcium channel blockers or non-ACE inhibitor vasodilators was considered together with a decrease in background lisinopril therapy. Detailed procedures also existed for the starting and stopping of trial medication following an acute myocardial infarction. A listing of allowed and disallowed concomitant medication was provided and the procedure for recording serious adverse events was detailed.