Methods
Study Population
Patients with severe AS, defined as an aortic valve area <1 cm, being in sinus rhythm and without symptoms at rest, who had been referred for aortic valve replacement were recruited at the Department of Cardiology, Rigshospitalet, Denmark, between November 2005 and December 2009. Patients were grouped as symptomatic or asymptomatic. Symptomatic individuals were those with angina pectoris, dizziness, syncope at exertion, or those who were classified as New York Heart Association (NYHA) functional classes II to IV by a study-independent cardiologist. We excluded patients with mitral regurgitation; those unable to perform exercise testing; and those with resting a systolic blood pressure (BP) <100 mm Hg, known renal artery stenosis or creatinine >200 μmol/L, or who had received treatment with ACE-Is or angiotensin receptor blockers during the previous month. We recorded the complete medical history, including the presence of diabetes, hypertension, and chronic obstructive pulmonary disease. A coronary angiogram was performed as part of the planned diagnostic workup of the patients, and the extent of coronary artery disease was recorded. Patients were consecutively screened, by which process we identified 166 eligible individuals, of whom 44 agreed to participate in this extensive protocol (Figure 1). The invasive nature of the study was the main reason for patient refusal. The study is registered at www.clinicaltrials.gov, with the ClinicalTrials.gov Identifier: NCT00252317.
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Figure 1.
Consort diagram.
End Points
The prespecified primary end point was the acute hemodynamic effects of ACE-I treatment, including systolic and diastolic parameters, at rest and during exercise, measured invasively by a Swann-Ganz catheter (cardiac output [CO], stroke volume [SV], and pulmonary capillary wedge pressure [PCWP]) and noninvasively by echocardiography (LV ejection fraction, LV end systolic volume [LVESV], and E/e'). The primary safety end point was symptomatic hypotension, including syncope or a systolic BP <90 mm Hg or a drop in systolic BP of >40 mm Hg during treatment. Secondary outcomes were changes in systemic BP, systemic arterial compliance (SAC), valvuloarterial impedance (ZVA), N-terminal pro-brain natriuretic peptide (NT-proBNP), and exercise capacity. All noninvasive parameters were measured again at follow-up, when reports of adverse events were also recorded.
Study Design
The study was performed as a randomized, placebo-controlled, double-blinded trial. Patients were randomized in a 1:1 fashion in blocks of 12 to receive either an ACE-I or a placebo (Figure 1). Randomization was performed by the Copenhagen County Hospital Pharmacy, and the trial was fully monitored according to the rules for good clinical practice operating in the Good Clinical Practise unit in Copenhagen. Patients performed a symptom-limited exercise test at baseline and on day 3. Cardiac output, systemic vascular resistance (SVR), and PCWP were measured with a Swan-Ganz catheter, and LVESV was measured by echocardiography. All measurements were taken at rest and at peak exercise. Patients were followed up until 1 to 3 days before their planned valve replacement or for a maximum of 8 weeks, whereupon exercise echocardiography was repeated. All testing was monitored in a setting of an intensive cardiac care unit. Safety recordings of symptoms of hypotension and changes in symptomatic status and in creatinine levels were performed after 2 weeks of treatment and at the end of the study period. Drug administration started immediately after the baseline measurements on day 1 to determine tolerance to ACE-I treatment using a captopril test (6.25 mg)/placebo. If the patients were free of symptomatic hypotension and systolic BP remained >90 mm Hg (maximum drop in systolic BP of 40 mm Hg) after 1.5 hours of treatment, they were randomly assigned to daily increasing doses of trandolapril or a matching placebo. The trandolapril dose escalated from 0.5 to 1 mg on day 2 and 2 mg on day 3. All investigations were performed 7 hours after administering the study drugs. At discharge on day 3, patients were given the maximum tolerated dose of the study drug for the remainder of the study period.
Echocardiography
The echocardiographic protocol for this study has previously been reported. Briefly, the patients had an echocardiographic evaluation at rest and during exercise. Images were stored digitally for off-line analysis using the GE EchoPac analysis software, version 6.12 (Horten, Norway). The severity of AS was quantified by estimating the effective valve area using the continuity equation. The LV ejection fraction was calculated from Simpson's method of disks. Left ventricular end systolic volume was measured in the apical 4-chamber view at rest and during exercise. To ensure that imaging during exercise took no more than 1 minute to perform, measurements in the 2-chamber view were omitted. At least 3 cardiac cycles were measured, and the average was calculated for all echocardiographic variables. Concomitant heart valve disease such as mitral or tricuspid valve disease was evaluated as defined by the guidelines of the American College of Cardiology/American Heart Association.
Invasive Hemodynamic Measurements
Pulmonary capillary wedge pressure, SV, SVR, and CO were measured at rest and at peak exercise in the semisupine position using a 7.5F triple-lumen Swan-Ganz thermistor and balloon-tipped catheter (Edwards Lifesciences, Irvine, CA), introduced via the internal jugular vein.
Systemic Arterial Compliance and ZVA
Systemic arterial compliance was measured with the use of an arm-cuff sphygmomanometer. Simultaneously, SV was measured invasively with a Swan-Ganz catheter, and the SV index for body surface area/pulse pressure was calculated. Valvuloarterial impedance was measured as the global load on LV, taking both valvular and arterial factors into account. Valvuloarterial impedance was calculated as (systolic arterial pressure + mean gradient)/SV index.
Exercise Testing
Immediately following the echocardiogram and the invasive measurements, all patients performed a multistage symptom-limited semisupine cycle exercise test using an Angio V2 ergometer (Lode BV, Netherlands) and 25 W workload increments every other minute until exhaustion. Exercise capacity was defined as the duration of the exercise test. Brachial BP was measured with a cuff using a regularly calibrated aneroid sphygmomanometer while the patient was in a semisupine position. Blood pressure was measured at baseline and every other minute until the maximum workload was reached. A 12-lead electrocardiogram was continuously monitored. The test was interrupted if the subjects experienced severe symptoms of angina, significant ventricular arrhythmia, dizziness, or a drop in BP, according to European guidelines.
Blood Samples
A blood sample was taken at baseline and at the end of follow-up for the analysis of plasma NT-proBNP. The samples were centrifuged for 10 minutes at 3,000 rpm, and serum was stored at −80°C until analysis. All samples were analyzed at the end of the study period.
The authors are solely responsible for the design and conduct of this study, all study analyses, and drafting and editing of the manuscript.