ACE Inhibitors After Heart Transplantation
What is the safety and efficacy of the angiotensin-converting enzyme inhibitor (ACEI) ramipril on the development of cardiac allograft vasculopathy early after heart transplantation (HT)?
A total of 96 HT recipients, including seven pediatric patients (12-19 years old), were randomized to ramipril or placebo in this prospective, multicenter, randomized, double-blind, placebo-controlled trial. Within 8 weeks of HT, the study cohort underwent coronary angiography, endothelial function testing, measurement of fractional flow reserve (FFR), coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR), and intravascular ultrasound (IVUS) of the left anterior descending coronary artery. At 1 year, the invasive assessment was repeated. Circulating endothelial progenitor cells (EPCs) were quantified at baseline and 1 year. The primary endpoint of the study was the difference in plaque volume, as assessed by IVUS examination of the LAD at 1 year between those in the ramipril and placebo groups. The investigators assumed that with a plaque volume at 1 year of 170 mm3 in the control arm and a plaque volume of 133 mm3 in the ramipril-treated patients with a standard deviation of 60 mm3, a sample size of 43 was required in each arm to have 80% power to detect a significant difference. Key secondary endpoints included the safety and efficacy of ramipril administration early after HT, the effect of ramipril on coronary endothelial function, coronary physiology, and circulating endothelial progenitor cell number.
The study investigators found that plaque volume at 1 year was similar between the ramipril and placebo groups (162.1 ± 70.5 vs. 177.3 ± 94.3 mm3, p = 0.73). HT patients receiving ramipril had improvement in microvascular function, as evidenced by a significant decrease in IMR (21.4 ± 14.7 to 14.4 ± 6.3, p = 0.001) and increase in CFR (3.8 ± 1.7 to 4.8 ± 1.5, p = 0.017) from baseline to 1 year. This did not occur with IMR (17.4 ± 8.4 to 21.5 ± 20.0, p = 0.72) or CFR (4.1 ± 1.8 to 4.1 ± 2.2, p = 0.60) in the placebo-treated patients. EPCs decreased significantly at 1 year in the placebo group, but not in the ramipril group. The blood urea nitrogen, creatinine, and potassium levels were all significantly higher in the ramipril group, but no patient had to stop ramipril because of renal dysfunction or hyperkalemia. There was no significant difference between the ramipril and placebo groups with regard to the change in creatinine (0.14 ± 0.31 vs. 0.10 ± 0.29, respectively; p = 0.56) or potassium (0.0 ± 0.6 vs. -0.2 ± 0.5, respectively; p = 0.12).
The investigators found that ramipril does not slow development of epicardial plaque volume, but does stabilize EPC levels and improve microvascular function, which have been associated with improved long-term survival after HT.
This is an important study because it suggests ACE inhibition is safe in HT patients. However, given its propensity to cause azotemia, practitioners may be hesitant to initiate such therapy until there are data demonstrating prognostic benefit in HT patients.
Clinical Topics: Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Cardiac Surgery and Heart Failure, Acute Heart Failure, Heart Transplant, Interventions and Imaging, Angiography, Echocardiography/Ultrasound, Nuclear Imaging
Keywords: Allografts, Angiotensin-Converting Enzyme Inhibitors, Azotemia, Blood Urea Nitrogen, Coronary Angiography, Creatinine, Fractional Flow Reserve, Myocardial, Heart Failure, Heart Transplantation, Hyperkalemia, Plaque, Atherosclerotic, Ramipril, Ultrasonography
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