CLINICAL RESEARCH: VASCULAR DISEASE
Cardioprotective Medication Is Associated With Improved Survival in Patients With Peripheral Arterial Disease
Harm H.H. Feringa, MD*,
Virginie H. van Waning, MD*,
Jeroen J. Bax, MD, PhD ,
Abdou Elhendy, MD, PhD||,
Eric Boersma, PhD ,
Olaf Schouten, MD ,
Wael Galal, MD*,
Radosav V. Vidakovic, MD||,
Marco J. Tangelder, MD, PhD and
Don Poldermans, MD, PhD*,*
* Department of Anesthesiology, Erasmus Medical Center, Rotterdam, the Netherlands
Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands
Department of Vascular Surgery, Erasmus Medical Center, Rotterdam, the Netherlands
Department of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands
|| Internal Medicine, Section of Cardiology, University of Nebraska, Omaha, Nebraska
Manuscript received July 11, 2005;
revised manuscript received September 16, 2005,
accepted September 19, 2005.
* Reprint requests and correspondence: Prof. Don Poldermans, Erasmus Medical Center, University of Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands (Email: d.poldermans{at}erasmusmc.nl).
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Abstract
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OBJECTIVES: We sought to investigate the effect of cardiac medication on long-term mortality in patients with peripheral arterial disease (PAD).
BACKGROUND: Peripheral arterial disease is associated with increased cardiovascular morbidity and mortality. Treatment guidelines recommend aggressive management of risk factors and lifestyle modifications. However, the potential benefit of cardiac medication in patients with PAD remains ill defined.
METHODS: In this prospective observational cohort study, 2,420 consecutive patients (age, 64 ± 11 years, 72% men) with PAD (ankle-brachial index  0.90) were screened for clinical risk factors and cardiac medication. Follow-up end point was death from any cause. Propensity scores for statins, beta-blockers, aspirin, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, diuretics, nitrates, coumarins, and digoxin were calculated. Cox regression models were used to analyze the relation between cardiac medication and long-term mortality.
RESULTS: Medical history included diabetes mellitus in 436 patients (18%), hypercholesterolemia in 581 (24%), smoking in 837 (35%), hypertension in 1,162 (48%), coronary artery disease in 1,065 (44%), and a history of heart failure in 214 (9%). Mean ankle-brachial index was 0.58 (±0.18). During a median follow-up of eight years, 1,067 patients (44%) died. After adjustment for risk factors and propensity scores, statins (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.36 to 0.58), beta-blockers (HR 0.68, 95% CI 0.58 to 0.80), aspirins (HR 0.72, 95% CI 0.61 to 0.84), and ACE inhibitors (HR 0.80, 95% CI 0.69 to 0.94) were significantly associated with a reduced risk of long-term mortality.
CONCLUSIONS: On the basis of this observational longitudinal study, statins, beta-blockers, aspirins, and ACE inhibitors are associated with a reduction in long-term mortality in patients with PAD.
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Abbreviations and Acronyms
| | ABI = ankle-brachial index | | ACE = angiotensin-converting enzyme | | CI = confidence interval | | HR = hazard ratio | | PAD = peripheral arterial disease |
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Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis and carries a poor prognosis as a result of the frequent association with cerebral, renal, and coronary artery disease (1–4). Although patients with PAD may present with symptoms ranging from pain on exertion that is relieved by rest (intermittent claudication) to pain at rest, ulceration, or gangrene (critical limb ischemia), most patients with PAD are asymptomatic (1). The prevalence of PAD ranges from 4% in patients aged 40 years and older to more than 20% in patients aged 70 years and older (5–10).
Peripheral arterial disease remains an underdiagnosed disease in the primary care, and patients with PAD are not treated as aggressively as are patients with other manifestations of atherosclerotic disease (7,11). The treatment of PAD focuses on walking exercise, aggressive management of risk factors, lifestyle modifications, and antiplatelet therapy (12,13). Cardiovascular events are a major cause of morbidity and mortality in patients with PAD. However, the potential benefit of cardiac medication therapy remains ill defined. Beta-adrenergic receptor blockers were considered relatively contraindicated in PAD; however, several studies have revealed that beta-blockers do not adversely affect walking capacity, symptoms of intermittent claudication, and peripheral skin microcirculation (14–16).
In this report, we sought to determine the effect of chronic treatment with cardiac medication, including statins, beta-blockers, aspirins, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, diuretics, nitrates, coumarins, and digoxin on long-term mortality among patients with PAD. In this observational cohort study, we used propensity analysis to adjust for selection bias in the comparison of treatments.
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Methods
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Assessment of baseline characteristics.
The Erasmus Medical Center serves a population of approximately 3 million people and acts as a tertiary referral center for approximately 30 affiliated hospitals. Patients with suspected or known PAD who were referred to the Erasmus Medical Center, Rotterdam, the Netherlands, between January 1983 and January 2005, for the diagnosis and management of PAD were evaluated. The ankle-brachial index (ABI) at rest was measured in each patient and patients with PAD (ABI 0.90) were included in the study.
On the basis of hospital records and personal interviews at the time of the visit, a medical history was recorded. Information on the presence of previous myocardial infarction, angina pectoris, previous coronary artery revascularization, congestive heart failure, previous stroke or transient ischemic attack, diabetes mellitus, hypertension, current smoking, hypercholesterolemia, and renal dysfunction were obtained. Diabetes mellitus was recorded if patients presented with a fasting glucose level of  7.0 mmol/l, or in those who required treatment. Hypertension was recorded if patients presented with a blood pressure 140/90 mm Hg or if patients were medically treated for hypertension. Hypercholesterolemia was recorded when patients presented with the diagnosis, made by the referring physician, or if patients were taking lipid-lowering agents. Renal dysfunction was recorded if patients presented with a serum creatinine level 2.0 mg/dl (177 µmol/l) or in those who required dialysis. A baseline 12-lead electrocardiography was obtained and was considered abnormal in the presence of one or more of the following: Q waves, ST-segment depression or elevation, left ventricular hypertrophy, right or left bundle branch block, and atrial fibrillation.
Use of medication.
All prescription and over-the-counter medications were noted at the time of the visit and were classified as follows: statins, beta-blockers, aspirins, ACE inhibitors, calcium channel blockers (dihydropyridines or non-dihydropyridines), diuretics, nitrates, coumarins, and digoxin. To ascertain the long-term use of cardiovascular medication, medication had to be documented at least at two months after the visit.
Follow-up.
Patients were followed during a median time of 8 years (interquartile range, 4 to 11 years) for the occurrence of all-cause death. End point was mortality. Information about the patient’s vital status was obtained by approaching the Office of Civil Registry. For patients who died at our hospital during follow-up, hospital records and autopsy results were retrieved and reviewed. For patients who died outside our hospital, general practitioners were approached to ascertain the cause of death.
Statistical analysis.
Continuous data with a normal distribution were expressed as mean and compared using the Student t test. Categorical data are presented as percent frequencies, and differences between proportions were compared using the chi-square test with Yates’ correction. The Kaplan-Meier method with log-rank test was used to compare survival curves in two or more groups. We applied univariate and multivariate Cox proportional hazards regression analyses to study the relation between cardiac medication therapy and long-term survival. Cardiac medication use was not randomly assigned in these patients, and the impact of selection bias may profoundly distort the results of our study.
Propensity analyses are reliable tools to correct for selection bias and the rationale for using propensity scores has been previously described (17). Therefore, separate propensity scores were calculated and ranged from 0.04 to 0.92 for statins, 0.002 to 0.98 for beta-blockers, 0.05 to 0.92 for aspirin, 0.04 to 0.95 for ACE inhibitors, 0.08 to 0.76 for calcium channel blockers, 0.0001 to 0.87 for diuretics, 0.04 to 0.91 for nitrates, 0.35 to 0.91 for coumarins, and 0.15 to 0.77 for digoxin, which were constructed using multiple logistic regression analysis. Variables (including baseline characteristics as listed in Table 1 and medication use as listed in Table 2) that were independently associated with the decision to prescribe statins, beta-blockers, aspirin, ACE inhibitors, calcium channel blockers, diuretics, nitrates, coumarins, and digoxin (p < 0.25) were included in the multivariate propensity score. In multivariate analysis, we adjusted for baseline clinical variables, irrespective of the significance level in univariate analysis. Propensity scores were added in separate multivariate models. Hazard ratios are given with 95% confidence intervals (CIs). For all tests, a p value <0.05 (two-sided) was considered significant. All analyses were performed using SPSS-11.0 statistical software (SPSS Inc., Chicago, Illinois).
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Results
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Baseline characteristics of the 2,420 study participants are presented in Table 1. The mean age was 64 ± 11 years, and 1,748 patients (72%) were men. Severe PAD (ABI 0.70) was identified in 1,863 patients (77%). The mean ABI was 0.58 ± 18. An abnormal electrocardiogram was observed in 1,127 patients (47%). Table 2 shows cardiac medication in the study population. As demonstrated in Figure 1, the prescription of ACE inhibitors, statins, aspirin, and beta-blockers increased from 12%, 13%, 15%, and 17%, respectively, in the periods 1983 to 1989 to 30%, 32%, 27%, and 40%, respectively, in the periods 2000 to 2004 (all p < 0.001). Propensity analysis demonstrated that patients were more likely (p < 0.001) to be prescribed statins if they had hypercholesterolemia, beta-blockers if they had coronary artery disease or hypertension, aspirin if they had coronary artery disease or a history of cerebrovascular disease, and ACE inhibitors if they had a history of congestive heart failure.
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Figure 1 The prescription of statins, beta-blockers, aspirins, and angiotensin-converting enzyme (ACE) inhibitors in patients who were included in different periods of time.
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During follow-up, death occurred in 1,067 patients (44%). The unadjusted and adjusted associations between clinical variables and long-term mortality are presented in Table 3. In a multivariate model that mutually adjusted for clinical risk factors and propensity scores, statins, beta-blockers, aspirin, and ACE inhibitors were independently associated with a reduced incidence of long-term mortality (hazard ratio [HR] 0.46, 95% CI 0.36 to 0.58; HR 0.68, 95% CI 0.58 to 0.80; HR 0.72, 95% CI 0.61 to 0.84); and HR 0.80, 95% CI 0.69 to 0.94, respectively (Table 4).
Calcium channel blockers, diuretics, nitrates, coumarins, and digoxin, however, were not significantly and independently associated with long-term mortality. In patients using beta-blockers, no difference was observed between selective and non-selective beta-blockers on the long-term outcome (selective beta-blockers: HR 1.31, 95% CI 0.87 to 1.72).
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Discussion
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In this cohort study of consecutive patients referred to our center for the evaluation of PAD, we found that statins, beta-blockers, aspirins, and ACE inhibitors were significantly associated with a reduction of all-cause mortality, independent of baseline clinical variables and independent of PAD severity.
Statins.
5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor drugs (statins) have been shown to reduce cardiovascular morbidity and mortality in high-risk patients (18–22). The Medical Research Council and the British Heart Foundation (MRC/BHF) Heart Protection Study randomly allocated 20,536 patients adults with coronary disease, other occlusive arterial disease, or diabetes to receive either simvastatin or placebo and demonstrated in a subgroup analysis of 6,748 patients with PAD that statins were significantly associated with a reduction in the rate of major vascular events (22). The beneficial effect of statins may not only be the result of its lipid-lowering effect but may also be the result of the inhibition of the inflammatory processes of atherosclerosis (23). It has been shown that a reduction in the inflammatory component through the use of statins improved the clinical outcome in patients with coronary artery disease, regardless of the reduction in cholesterol levels (24,25). In patients with PAD, statin use has been demonstrated to favorably influence leg functioning, walking performance, ABI values, and symptoms of claudication (26–28). The association of statin use and superior leg functioning also was demonstrated in patients with an ABI of 0.90 to 1.49, which may reflect the favorable influence of statins on subclinical PAD (26). A recent study by Schillinger et al. (29) showed that statin therapy was associated with an improved survival of patients with severe PAD with elevated high-sensitivity C-reactive protein levels (>0.42 mg/dl). The observation that patients with low inflammatory activity had no survival benefit supports the view that statins may exert beneficial effect though anti-inflammatory properties.
Beta-blockers.
Although beta-blockers were considered relatively contraindicated in patients with PAD, several studies showed that beta-blockers do not adversely affect walking capacity, symptoms of intermittent claudication, and peripheral skin microcirculation (14–16). Beta-blockers are effective antihypertensive agents and improve the prognosis of patients with ischemic heart disease and congestive heart failure and are thus indicated in a majority of patients with PAD. However, it seems that beta-blockers have been underused by vascular surgeons and primary care providers, perhaps because of concerns that beta-blockers will aggravate symptoms of intermittent claudication (30,31). Patients with PAD are at increased risk for cardiovascular morbidity and mortality, and recent studies have demonstrated the beneficial effect of beta-blockers in these patients. In a study cohort of 575 patients with symptomatic PAD and with a previous myocardial infarction, Aronow and Ahn (32) demonstrated that beta-blocker therapy was associated with a 53% significant reduction in new coronary events, independent of other confounding variables (32). This was confirmed in a more recently published study demonstrating a three-fold reduction in cumulative cardiac mortality in 78 patients after infarction with intermittent claudication who were treated with beta-blocker therapy compared with patients not treated with beta-blocker therapy (33). It has been shown that hemodynamic forces (blood pressure and heart rate) are associated with the development of disruption of the vulnerable plaque, which consists of an atheromatous plaque core covered by a thin fibrous cap with ongoing inflammation (34). Beta-blockers may prevent plaque disruption by reducing heart rate and blood pressure. In addition, it can be hypothesized that anti-inflammatory properties of beta-blockers may limit the phased progression of cardiovascular disease (35).
Aspirin.
Antiplatelet drugs are now established agents for preventing cardiovascular and cerebrovascular ischemic events. The meta-analysis of the Antithrombotic Trialists’ Collaboration showed a proportional reduction of 23% in serious vascular events among 9,214 patients with PAD using antiplatelet therapy (primarily aspirin), compared with those using no antiplatelet therapy (5.8% vs. 7.1%, p < 0.004) (36). Limited information is available regarding the optimal antiplatelet treatment choice in patients with PAD. Potential adverse effects, including diarrhea, neutropenia, and thrombotic thrombocytopenic purpura, may limit the use of ticlopidine. On the basis of current evidence, aspirin or clopidogrel seem to be the first-line oral antiplatelet drugs of choice.
Use of ACE inhibitors.
The use of ACE inhibitors have been shown to inhibit the atherosclerotic process and to improve peripheral blood pressure and blood flow in patients with PAD (37). The Heart Outcomes Prevention Evaluation (HOPE) study investigators showed that the use of ramipril significantly reduced the rate of mortality, myocardial infarction, and stroke in 9,297 high-risk patients without a low ejection fraction or heart failure (38). A recent randomized placebo-controlled study demonstrated the beneficial effect of ramipril in patients with clinical or subclinical PAD for preventing major cardiovascular events (39). Activation of the renin-angiotensin system seems to be associated with an increased risk of cardiovascular events. Growing evidence suggest that ACE inhibitors directly inhibit the atherosclerotic process and improve vascular endothelial function (40,41). In addition, the benefit of ACE inhibitors may be independent of the antihypertensive properties of these agents (42).
Study limitations.
The results of our study are in accordance with previously published studies demonstrating the effect of statins, beta-blockers, aspirin, and ACE inhibitors for reducing complications in patients with PAD. Several limitations of our study should be addressed. The major limitation of this study is that the use of cardiac medication was not assigned randomly to patients with PAD. However, properly conducted observational studies might not produce misleading or biased results (43). Moreover, we used propensity analysis and in multivariate analysis we adjusted for known possible confounding factors. The strength of using propensity score methods lies in its ability to adjust for selection bias because subjects in an observational study have not been randomized to exposure groups. A propensity score generally is defined as the conditional probability of assignment to a particular treatment given a vector of observed covariates (44). To assess the effect of a treatment in a situation in which randomization is difficult or impossible, propensity scores are a useful method for matching members of different groups. Comparisons of different groups reveal reliable information on the impact of the treatment of interest with a small residual bias (17).
Conclusions.
On the basis of this observational longitudinal study, statins, beta-blockers, aspirin, and ACE inhibitors are associated with a reduction in long-term mortality risk in patients with PAD that is independent of clinical risk factors and adjusted for propensity scores. The use of cardiac medications as therapeutic and preventive agents in patients with PAD seems to be promising in reducing long-term mortality and could be incorporated among other management strategies, including walking exercise and risk factor modification. Future studies should be conducted to determine which patients with PAD would mostly benefit from statins, beta-blockers, aspirin, and ACE inhibitor therapy.
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Footnotes
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Supported by an unrestricted educational grant from Sanofi-Aventis/BMS.
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References
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J. P. Cooke and A. M. Wilson
Biomarkers of Peripheral Arterial Disease
J. Am. Coll. Cardiol.,
May 11, 2010;
55(19):
2017 - 2023.
[Abstract]
[Full Text]
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A. T Hirsch, L. Hartman, R. J Town, and B. A Virnig
National health care costs of peripheral arterial disease in the Medicare population
Vascular Medicine,
August 1, 2008;
13(3):
209 - 215.
[Abstract]
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G. M.J.M. Welten, O. Schouten, S. E. Hoeks, M. Chonchol, R. Vidakovic, R. T. van Domburg, J. J. Bax, M. R.H.M. van Sambeek, and D. Poldermans
Long-Term Prognosis of Patients With Peripheral Arterial Disease: A Comparison in Patients With Coronary Artery Disease
J. Am. Coll. Cardiol.,
April 22, 2008;
51(16):
1588 - 1596.
[Abstract]
[Full Text]
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V. Salomaa, R. Paakkonen, H. Hamalainen, M. Niemi, and T. Klaukka
Use of secondary preventive medications after the first attack of acute coronary syndrome
European Journal of Cardiovascular Prevention & Rehabilitation,
June 1, 2007;
14(3):
386 - 391.
[Abstract]
[Full Text]
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D. G Hackam and J. W Eikelboom
Antithrombotic treatment for peripheral arterial disease
Heart,
March 1, 2007;
93(3):
303 - 308.
[Abstract]
[Full Text]
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K. I. Paraskevas, G. Hamilton, D. P. Mikhailidis, and C. D. Liapis
Letter to the Editor
Vascular and Endovascular Surgery,
February 1, 2007;
41(1):
87 - 87.
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S. Rajagopalan, S. Dellegrottaglie, A. L. Furniss, B. W. Gillespie, S. Satayathum, N. Lameire, A. Saito, T. Akiba, M. Jadoul, N. Ginsberg, et al.
Peripheral Arterial Disease in Patients With End-Stage Renal Disease: Observations From the Dialysis Outcomes and Practice Patterns Study (DOPPS)
Circulation,
October 31, 2006;
114(18):
1914 - 1922.
[Abstract]
[Full Text]
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J. A. Beckman, M. R. Jaff, and M. A. Creager
The United States Preventive Services Task Force Recommendation Statement on Screening for Peripheral Arterial Disease: More Harm Than Benefit?
Circulation,
August 22, 2006;
114(8):
861 - 866.
[Abstract]
[Full Text]
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