Author + information
- Received June 21, 2010
- Revision received October 26, 2010
- Accepted October 28, 2010
- Published online March 8, 2011.
- Ayman A. Hussein, MD⁎,
- Kiyoko Uno, MD⁎,
- Kathy Wolski, MPH⁎,
- Samir Kapadia, MD⁎,
- Paul Schoenhagen, MD⁎,
- E. Murat Tuzcu, MD⁎,
- Steven E. Nissen, MD⁎ and
- Stephen J. Nicholls, MBBS, PhD⁎,†,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Stephen J. Nicholls, Department of Cardiovascular Medicine, Cleveland Clinic, Mail Code JJ-65, 9500 Euclid Avenue, Cleveland, Ohio 44195
Objectives The purpose of this analysis was to characterize the progression of coronary atherosclerosis in patients with concomitant peripheral arterial disease (PAD).
Background Peripheral arterial disease is associated with adverse cardiovascular outcomes. The impact of concomitant PAD on coronary atherosclerosis progression in patients with coronary artery disease has not been well established.
Methods The burden and progression of coronary atherosclerosis was investigated in 3,479 patients with coronary artery disease with (n = 216) and without (n = 3,263) concomitant PAD who participated in 7 clinical trials that employed serial intravascular ultrasound imaging.
Results Patients with PAD had a greater percent atheroma volume (40.4 ± 9.2% vs. 38.5 ± 9.1%, p = 0.002) and percentage of images containing calcium (35.1 ± 26.2% vs. 29.6 ± 24.2%, p = 0.002), in association with smaller lumen volume (275.7 ± 101.6 mm3 vs. 301.4 ± 110.3 mm3, p < 0.001) and vessel wall volume (467.7 ± 166.8 mm3 vs. 492.9 ± 169.8 mm3, p = 0.01). On serial evaluation, patients with PAD demonstrated greater progression of percent atheroma volume (+0.58 ± 0.38 vs. +0.23 ± 0.3%, p = 0.009) and total atheroma volume (−0.17 ± 2.69 mm3 vs. −2.05 ± 2.15 mm3, p = 0.03) and experienced more cardiovascular events (26.3% vs. 19.8%, p = 0.03). In patients with PAD and without PAD, respectively, achieving levels of low-density lipoprotein cholesterol <70 mg/dl was associated with less progression of percent atheroma volume (+0.16 ± 0.27% vs. +0.76 ± 0.20%, p = 0.04; and +0.05 ± 0.14% vs. +0.29 ± 0.13%, p < 0.001) and total atheroma volume (−3.0 ± 1.9 mm3 vs. +1.0 ± 1.4 mm3, p = 0.04; and −3.3 ± 1.1 mm3 vs. −1.6 ± 1.0 mm3, p < 0.001).
Conclusions Patients with concomitant PAD harbor more extensive and calcified coronary atherosclerosis, constrictive arterial remodeling, and greater disease progression. These changes are likely to contribute to adverse cardiovascular outcomes. The benefit for all patients achieving low levels of low-density lipoprotein cholesterol supports the need for intensive lipid lowering in patients with PAD.
The adverse cardiovascular outcomes observed among patients with peripheral arterial disease (PAD) (1–3) highlight the need for intensive risk factor modification (4). However, only one-quarter of PAD patients receive guideline-recommended therapies (5). Most of these clinical events are attributed to the coronary vasculature (1–3), regardless of whether a diagnosis of coronary artery disease (CAD) is already established (6). While the underlying mechanisms remain incompletely understood, it is unknown whether coronary disease progression is different in the setting of concomitant PAD.
Intravascular ultrasound (IVUS) has been increasingly employed in clinical trials and has enabled investigation of the clinical factors associated with disease progression. Accordingly, the objective of the current analysis was to assess the impact of an established clinical diagnosis of PAD on the burden and progression of coronary atherosclerosis.
This analysis included 3,479 CAD patients who underwent serial IVUS examinations in 7 clinical trials (7–13). PAD was determined on the basis of 1) symptoms of intermittent claudication with a documented low ankle-brachial index (<0.9); 2) obstructive disease on femoral angiography; or 3) a history of arterial revascularization within the lower limbs. Each of the trials was approved by the institutional review board at the participating sites, and all patients provided informed written consent before enrollment.
The details on IVUS image acquisition and analysis have been previously reported in detail (7–13). The percent atheroma volume (PAV), total atheroma volume (TAV), and volumes occupied by lumen and external elastic membrane were calculated (14). Substantial plaque progression and regression were defined as at least a 5% relative increase or decrease in PAV, respectively.
Patients were stratified according to the presence (n = 216) or absence (n = 3263) of PAD. Results are presented as percentages for categorical variables and mean ± SD for continuous variables. When variables were not normally distributed, their results are expressed as median (interquartile range). Clinical and plaque characteristics were compared by the Student t test or analysis of variance for continuous variables as appropriate. For categorical variables, the chi-square test or Fisher's exact test was used. Changes in measures of risk factors, atheroma burden, and vascular dimensions were compared by analysis of covariance, after controlling for baseline values, and expressed as least squared mean ± SE. In a secondary analysis, which aimed to assess the potential independent association of PAD with CAD progression, a propensity analysis was performed, in which every PAD patient was matched to non-PAD patients in a 1:3 ratio on the basis of the predicted probability for PAD. The propensity matching process accounted for baseline characteristics including age, sex, race, current smoking status, body mass index, hypertension, diabetes mellitus, hyperlipidemia, heart failure, baseline risk factor control, medications use (aspirin, beta-blockers, angiotensin-converting enzyme inhibitor, statins, oral antidiabetic, study medications), history of stroke, and myocardial infarction. A 2-sided p value <0.05 was considered statistically significant. All statistical analyses were performed with SAS version 9.1 (SAS Institute, Cary, North Carolina).
Clinical characteristics of patients with PAD and without PAD are summarized in Table 1. The PAD patients were older (p < 0.001), more likely to be smokers (p < 0.001), and had more diabetes (p < 0.001), hyperlipidemia (p < 0.001) and heart failure (p < 0.001). There was no difference between the groups with regard to use of cardioprotective therapies at baseline. Fewer patients with PAD were treated with a statin (p = 0.01). Risk factor control at baseline and during the course of the studies is summarized in Table 2. PAD patients were more likely to experience a cardiovascular event (death/myocardial infarction/revascularization/stroke: 26.3% vs. 19.8%, p = 0.03).
Atherosclerosis burden and progression
Atheroma burden and vascular dimensions at baseline and their serial change are summarized in Table 3 and Figure 1. At baseline, a greater PAV (p = 0.002) and smaller lumen volume (p < 0.001) and external elastic membrane volume (p = 0.01) were observed in PAD patients. No differences in TAV were observed between the groups (p = 0.83). A greater percentage of images containing calcium was observed in PAD patients (p = 0.002). While the smaller vessel wall volumes in PAD patients suggests a greater propensity to constrictive remodeling throughout the length of the arterial segment imaged, there was no difference between the groups with regard to the remodeling index at the most diseased site (p = 0.76).
Greater progression of both PAV (+0.58 ± 0.38% vs. +0.23 ± 0.3%, p = 0.009) and TAV (−0.17 ± 2.69 mm3 vs. −2.05 ± 2.15 mm3, p = 0.03) was observed in PAD patients (Fig. 1). Patients with PAD were more likely to undergo substantial progression (35.6% vs. 27.2%, p = 0.007) and less likely to undergo regression (15.3% vs. 22.3%, p = 0.02) (Fig. 1). Propensity matching patients with PAD (n = 202) and without PAD (n = 606) demonstrated greater progression of PAV (+0.54 ± 0.38% vs. +0.23 ± 0.33%, p = 0.03), but no difference in change in TAV (−0.36 ± 2.63 mm3 vs. −1.73 ± 2.24 mm3, p = 0.20; c-statistic 0.74) (Table 4).
Intensive lipid lowering and disease progression
The impact of intensive lipid lowering on disease progression in patients with and without PAD is summarized in Figure 2. Achieving levels of low-density lipoprotein cholesterol <70 mg/dl was associated with less progression of PAV (+0.16 ± 0.27% vs. +0.76 ± 0.20%, p = 0.04; and +0.05 ± 0.14% vs. +0.29 ± 0.13%, p < 0.001) and TAV (−3.0 ± 1.9 mm3 vs. +1.0 ± 1.4 mm3, p = 0.04; and −3.3 ± 1.1 mm3 vs. −1.6 ± 1.0 mm3, p < 0.001) in patients with PAD and without PAD, respectively. Similarly, achieving low-density lipoprotein cholesterol levels <70 mg/dl was associated with a lower frequency of progressors (24.6% vs. 39.6%, p = 0.04; and 20.8% vs. 29.6%, p < 0.001) and greater frequency of regressors (26.3% vs. 11.3%, p = 0.007; and 26.0% vs. 20.9%, p = 0.002) in patients with PAD and without PAD, respectively.
The findings further support the clinical importance of PAD. Patients with PAD demonstrated more extensive and calcified coronary atherosclerosis, impaired arterial remodeling, and greater disease progression. Persistence of greater disease progression after propensity matching for cardiovascular risk factors support findings from clinical cohorts (3,15) and suggest a potentially more aggressive systemic atherosclerosis in PAD patients. Despite the presence of more advanced disease, PAD patients retain the ability to derive a beneficial impact from use of intensive risk modification strategies.
The findings of smaller vessel wall volumes, despite a similar TAV, suggest a trend toward more constrictive remodeling of the coronary arteries in PAD patients. That is likely to result in more luminal narrowing and a greater need for revascularization. The impact of more calcified coronary atherosclerosis on remodeling and subsequent propensity to plaque rupture remain to be established. Nevertheless, the current findings provide further evidence to support the concept that atherosclerosis is a systemic disorder involving multiple vascular territories and that the presence of PAD is associated with a particularly aggressive form of the disease. This supports reports that accelerated disease progression of PAD is associated with more coronary events (16).
The factors underlying the relationship between accelerated atherosclerosis progression and adverse outcomes require further exploration. Reports that CAD patients with symptoms of intermittent claudication have higher circulating levels of inflammatory and prothrombotic biomarkers (17) suggest that these pathways may play a role in accelerating the disease process. The potential impact of these factors on disease burden and composition and its translation to ischemic events requires further investigation. The findings emphasize the need for greater adoption of risk-modifying strategies by patients with PAD. The need is tempered by observations that PAD is frequently underdiagnosed and undertreated (5,18).
Several caveats should be noted with regard to the current analysis. The PAD was recorded by investigators on the basis of an established clinical diagnosis, at the time of entry to the studies. As a result, it is possible that additional patients with asymptomatic PAD may have been missed. That does not diminish the importance of the current observations of more extensive disease burden and progression in patients with an established clinical diagnosis of PAD. The analysis involved a pooling of data from 7 clinical trials. However, controlling for study and use of mixed modeling in the statistical analysis and measurement of all images in a central core laboratory provide the opportunity to characterize the impact of PAD on disease progression in a large sample of subjects. The findings are derived from patients who present for a clinically indicated coronary angiogram. As a result, it is unknown whether the observations can be translated to patients with asymptomatic CAD. Although PAD patients demonstrated greater disease progression and event rates, the association between progression of coronary atherosclerosis on IVUS and clinical outcome requires ongoing elucidation.
The current findings demonstrate that patients with CAD and PAD harbor more extensive and calcified coronary atherosclerosis, constrictive vascular remodeling, and accelerated disease progression. These observations provide an important mechanistic link to the adverse cardiovascular outcomes among patients with PAD. The findings support the need for intensification of medical therapies to achieve more effective reductions in cardiovascular risk.
Dr. Nissen has received research support to perform clinical trials through the Cleveland Clinic Coordinating Center for Clinical Research from Pfizer, AstraZeneca, Novartis, Roche, Daiichi-Sankyo, Takeda, Sanofi-Aventis, Resverlogix, and Eli Lilly; and is a consultant/advisor for many pharmaceutical companies but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. Dr. Nicholls receives honoraria from AstraZeneca, Merck, and Takeda Roche; is a consultant to Pfizer, AstraZeneca, Merck, Takeda, Anthera, and NovoNordisk; and receives research support from AstraZeneca, Novartis, Resverlogix, Eli Lilly, and Anthera. All other authors have reported that they have no relationships to disclose.
- Abbreviations and Acronyms
- coronary artery disease
- intravascular ultrasound
- peripheral arterial disease
- percent atheroma volume
- total atheroma volume
- Received June 21, 2010.
- Revision received October 26, 2010.
- Accepted October 28, 2010.
- American College of Cardiology Foundation
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