Atorvastatin, Etidronate, or Both in Patients at High Risk for Atherosclerotic Aortic Plaques

Abstract

Background-Statins are not effective in reducing atherosclerotic plaques of the abdominal aorta, and accumulating evidence suggests that bisphosphonates have the potential to induce the regression of atherosclerotic plaques of the abdominal aorta. Methods and Results-A prospective, randomized, open-label, blinded-end-point trial involving 108 participants with hypercholesterolemia was conducted. Participants received 20 mg atorvastatin daily, 400 mg etidronate daily, or both drugs daily. The primary end point was the percent change in maximal vessel wall thickness of atherosclerotic plaques in the thoracic and abdominal aortas as measured by magnetic resonance imaging after 12 months of treatment. In both the combination therapy and atorvastatin groups, maximal vessel wall thickness of the thoracic aorta was reduced by 13.8% (95% confidence interval, −16.4 to −11.3) and 12.3% (95% confidence interval, −14.9 to −9.7), respectively. These reduction rates were comparable between groups (P=0.61). Meanwhile, in the etidronate group, maximal vessel wall thickness of the thoracic aorta remained unchanged (2.2%; 95% confidence interval, −0.3 to 4.8). Conversely, maximal vessel wall thickness of the abdominal aorta was reduced more effectively in the combination therapy group (−11.4%) than in the atorvastatin group (−0.9%; P<0.001) and the etidronate group (5.5%; P=0.006). Conclusions-Atorvastatin plus etidronate combination therapy for 12 months significantly reduced both thoracic and abdominal aortic plaques, whereas atorvastatin monotherapy reduced only thoracic aortic plaques and etidronate monotherapy reduced only abdominal aortic plaques. The effectiveness of combination therapy in reducing atherosclerotic plaques in the abdominal aorta was significantly greater than for both atorvastatin and etidronate monotherapy.

Bisphosphonates and Risk of Cardiovascular Events: A Meta-Analysis

“…These results contradict the findings from previous observational studies[ 18 – 20 ] and clinical trials of surrogate endpoints (e.g. carotid intima media thickness,[ 15 , 41 ] coronary artery calcium,[ 16 ] and aortic calcification[ 17 , 42 ]) that suggest possible benefits of bisphosphonates on atherosclerotic CV events.…”

“…[ 43 – 45 ] In humans, etidronate has been studied in several trials as an inhibitor of vascular calcification. It decreased carotid intima media thickness (by 0.038 mm),[ 15 ] coronary artery calcium score (by 372 mm 3 ),[ 16 ] and aortic calcification (by 14–15%)[ 17 ] in high-risk patients over 9–12 months. Such reduction in carotid intima media thickness was comparable to or greater than the effects observed from some statins: pitavastatin decreased carotid intima media thickness by 0.024 mm/year in patients with known atherosclerosis,[ 46 ] while rosuvastatin decreased carotid intima media thickness by 0.0014 mm/year among low-risk individuals.…”

“…In several small-scale clinical trials, etidronate modestly improved surrogate endpoints of atherosclerosis, such as carotid intima media thickness,[ 15 ] coronary artery calcium,[ 16 ] and aortic calcification. [ 17 ] However, bisphosphonate trials designed to study clinical CV endpoints are currently lacking. Epidemiologic studies found a lower risk of myocardial infarction (MI) or stroke among bisphosphonate users compared with non-users.…”

Carotid magnetic resonance imaging for monitoring atherosclerotic plaque progression: a multicenter reproducibility study

“…Lastly, an integrated plaque segmentation tool automatically classified wall area into LRNC, calcification and fibrous tissue, following a previously described algorithm [22]. After finishing all cases, slice-based area measurements were exported and aggregated for volumetric measurements (morphology: lumen, wall and outer wall volumes; composition: LRNC, calcification and fibrous tissue volumes), which indicate plaque progression patterns and are frequently used in previous studies [1–10]. …”

“…The fine delineation of vessel wall morphology by magnetic resonance imaging (MR, MRI) has made cardiovascular MR increasingly popular in longitudinal studies for monitoring atherosclerosis progression [1–10]. Additionally, the combination of contrast weightings enables accurate segmentation of plaques into areas of lipid-rich necrotic core (LRNC), calcification and fibrous tissue [11–13].…”