Peripheral artery disease (PAD) is a common manifestation of atherosclerosis and a well-known independent risk factor for cardiovascular morbidity and mortality 1–4. This elevated cardiovascular risk has led to the inclusion of PAD among the list of ‘coronary risk equivalents’, and therapeutic strategies of secondary prevention, including lipid-lowering treatment, should be implemented 4. Yet, despite their high cardiovascular risk, patients with PAD receive less intensive medical treatment and less frequently achieve all secondary prevention goals compared with patients with coronary artery disease (CAD) 5–11. However, data comparing the outcomes of the two groups are limited. The population of PAD is heterogeneous, with most patients being entirely asymptomatic and only about 10% with disabling symptoms 8. Most studies included patients with the entire clinical spectrum of PAD as well as many patients with concomitant CAD. Currently, there are no sufficient data evaluating the outcome of the specific group of patients with symptomatic PAD and without a history of coronary intervention. The aim of this study was to compare mortality rates in patients following the first coronary or peripheral vascular intervention.
Patients and methods
The study population included residents of the Sharon-Shomron District who are medically insured by the Clalit Health Services, the largest health maintenance organization in Israel. The Clalit Health Services computerized database was the source of data for our study. All medical information obtained at both primary and secondary care clinics is recorded in the database and can be accessed at the level of the individual patient. It is the primary care physician’s responsibility to routinely update the computerized medical records following each patient visit or hospital admission. The database includes a list of all diagnoses, demographic data, laboratory values, medications, and medical procedures.
Our study included men and women 18 years of age or older without a history of coronary, cerebral or peripheral artery disease who underwent first coronary or lower limb peripheral vascular intervention between 1 January 2002 and 31 December 2010 and had at least one full lipid profile available at least 6 months following the intervention. Peripheral vascular interventions included lower limb surgical vascular reconstruction or percutaneous angioplasty. Coronary interventions included percutaneous coronary interventions or coronary artery bypass grafting surgery. All vascular procedures were performed in the regional hospitals and were recorded automatically in the computerized database. Age, sex, cigarette smoking status, diabetes mellitus, hypertension, lipid levels, BMI, and medical therapy were extracted from the electronic medical records.
Follow-up and study endpoints
Participants were followed from their first vascular intervention until censorship for outcomes or 31 October 2012, whichever came first. The primary endpoint of our study was all-cause mortality. Mortality data were collected from the National Social Security records. Information on the specific causes of death was not available to us.
The study was approved by the local institutional ethics committee in keeping with the principles of the Declaration of Helsinki. In accordance with Ministry of Health regulations, the institutional ethics committee did not require written informed consent as data were collected anonymously from the computerized medical files, with no active participation of patients.
The study participants were stratified into two groups. The first group included patients following first coronary intervention. The second group included patients following the first peripheral vascular intervention. The baseline clinical characteristics of the two groups as well as the study outcomes were compared using the analysis of variance test for continuous variables and the χ2-test for nonparametric variables. The Cox proportional hazard regression model analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality according to the two study groups. This analysis was adjusted for age, sex, BMI, diabetes mellitus, hypertension, statin, aspirin, Plavix, angiotensin-converting enzyme (ACE)/angiotensin receptor blocker (ARB) use, and triglycerides, high-density lipoprotein, and low-density lipoprotein cholesterol. The Kaplan–Meier survival curve was plotted for all-cause mortality, comparing the two study groups. Statistical analysis was carried out using SPSS statistical software for Windows version 21.0 (IBM Corp., Armonk, New York, USA).
A total of 9950 patients, mean age 61.2±13.1 years, were available for analysis. Of these, 8242 (82.8%) underwent first coronary revascularization and 1708 (17.2%) underwent first lower limb vascular intervention. The baseline characteristics of the study population are presented in Table 1. Compared with the CAD group, patients following the first peripheral vascular intervention were more frequently women and current smokers and had a worse lipid profile including higher total and low-density lipoprotein cholesterol and lower levels of high-density lipoprotein cholesterol. In contrast, patients with PAD had lower rates of diabetes and hypertension and a lower BMI.
Treatment with cardioprotective medications during the study period is presented in Table 2. Compared with patients with CAD, patients with PAD were significantly less frequently treated with antiplatelet drugs including aspirin (95 vs. 70.3%) and clopidogrel (72.4 vs. 24.1%, P<0.0001). Furthermore, patients with PAD were less frequently treated with either ACE inhibitors or ARBs (62.2 vs. 86.2%, P<0.0001). In terms of lipid-lowering therapy, patients with PAD were less commonly treated with any statin (69.1 vs. 95.5%, P<0.0001) as well as with either atorvastatin or rosuvastatin (20 vs. 44.2%, P<0.0001), which are currently the most potent statins available.
During a mean follow-up period of 5.6±2.3 years, 1283 (12.9%) participants died. Of these, 841 (65.5%) were patients following the first coronary intervention and 442 (34.5%) following the first peripheral vascular intervention. Compared with CAD patients, patients with PAD had significantly worse long-term prognosis (Fig. 1). HRs for all-cause mortality were significantly higher in the PAD group compared with patients following the first coronary intervention (HR=2.95, 95% CI 2.6–3.3, P<0.0001) (Table 3). This association remained statistically significant following age adjustment (HR=2.72, 95% CI 2.4–3.1, P<0.0001) as well as following a multivariable analysis for age, sex, lipids, BMI, smoking status, hypertension, diabetes, and treatment with the cardioprotective medications (HR=1.86, 95% CI 1.6–2.1, P<0.0001).
This study compared the outcome of men and women with either CAD or PAD following the first vascular intervention. We have shown that even in this specific group of high-risk patients, all-cause mortality was significantly higher in PAD compared with CAD patients. These findings are very important as peripheral atherosclerosis is becoming an increasingly important health issue in the western world 12.
Welten et al. 2 were the only ones to compare the long-term outcomes of patients with symptomatic PAD and CAD following vascular interventions. This comprehensive study included 2730 patients following peripheral or aortic vascular surgery who were matched using a propensity score to the same number of CAD patients without known PAD who underwent a percutaneous coronary intervention. The PAD patients had a worse long-term prognosis compared with CAD patients, with annual all-cause mortality rates of 5.7 and 3% (P<0.001), respectively. Not surprisingly, cardiovascular complications were the main cause of long-term death. Nevertheless, among the PAD patients, about two-thirds had a history of symptomatic CAD (either previous myocardial infarction, angina pectoris, or coronary revascularization) and it can be speculated that the adverse prognosis may be attributed to a combination of both symptomatic PAD and CAD and not to the PAD itself. In our study, the PAD group did not include patients with a history of coronary intervention. The higher mortality risk of patients with PAD found in our study provides further support for the extremely high-risk nature of this condition.
The reason for worse outcome in PAD patients following the first noncoronary vascular procedure compared with patients following the first coronary intervention appears to be multifactorial and may include poor risk factor modification 9–13, underuse of cardioprotective medications 9–13, and lower patient adherence to medical therapy 11. A recent study has shown that despite improvement in the use of cardioprotective medications over time, patients with PAD alone remain less likely than those with CAD alone to use these agents 13. Indeed, in our study, PAD patients were less frequently treated with antiplatelet drugs, ACE inhibitors or ARBs, and statins. The lack of adequate secondary prevention in patients with PAD may have several possible explanations. First, evidence exists suggesting an effect of physician specialty on some of the observed differences between therapies for CAD patients and those for PAD patients 10. Although most patients with CAD are followed up by a cardiologist, PAD patients usually identify the vascular surgeon as the main physician. It has been shown previously that cardiologists were more adherent to clinical guidelines and more frequently administer aggressive lipid-lowering therapy, antiplatelets, and antihypertensive drugs when compared with vascular surgeons or primary care physicians 10. Second, we have previously shown better adherence to statins among patients with CAD 11. This may be a result of the common misconception among patients and medical staff that PAD poses lower mortality risk than CAD. Therefore, although PAD is linked strongly and independently to cardiovascular mortality and morbidity, it is less emphasized and less systematically evaluated and managed 7.
Our study has several limitations that warrant consideration. First, it included only patients who were medically followed up and had at least one full lipid profile taken during the study period. Therefore, there may have been a selection bias. Second, the PAD group included patients without a history of coronary intervention. Nevertheless, PAD patients with symptomatic CAD who were treated medically were not excluded. Third, the study did not include data on the specific indication for both the coronary and the peripheral interventions. Finally, the primary endpoint was all-cause mortality and we did not have data on specific causes of death. Nevertheless, it has been shown that cardiovascular mortality is the most common cause of death among patients with cardiovascular diseases 2.
Our study adds to the available literature by confirming that patients with symptomatic PAD are at a very high mortality risk even when compared with patients with established coronary disease. Our findings demand more effort in educating both patients and medical personnel and improved adherence to secondary prevention guidelines in all patients with cardiovascular diseases, but especially in PAD patients.
The authors thank the Data Center team of the Sharon-Shomron District for their help in data retrieval.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
coronary artery disease; mortality; peripheral artery disease