Patients with peripheral arterial disease (PAD) undergoing percutaneous coronary intervention (PCI) are at high risk for adverse cardiovascular events. Trends over time in outcomes with advances in PCI and medical therapy are unknown. We evaluated 866 patients with PAD in the National Heart, Lung, and Blood Institute (NHLBI) Dynamic Registry undergoing PCI according to treatment eras: the early bare metal stent (BMS) era (wave 1, 1997 to 1998, n = 180), the BMS era (waves 2 and 3, 1999 and 2001 to 2002, n = 339), and the drug-eluting stent (DES) era (waves 4 and 5, 2004 and 2006, n = 347). We compared in-hospital and 1-year outcomes by recruitment era. In-hospital coronary artery bypass graft surgery rates were significantly lower in the later eras (3.9%, 0.9%, and 0.6% for the early BMS, BMS, and DES eras, respectively, p for trend = 0.005), and an increasing percentage of patients were discharged on aspirin, β blockers, statins, and thienopyridines (p for trend <0.001 for all comparisons). Cumulative 1-year event rates in patients with PAD in the early BMS era, BMS era, and DES era for death were 13.7%, 10.5%, and 9.8% (p for trend = 0.21), those for myocardial infarction (MI) were 9.8%, 8.8%, and 10.0% (p for trend = 0.95), and those for repeat revascularization were 26.8%, 21.0%, and 17.2% (p for trend = 0.008). The 1-year adjusted hazard ratios of adverse events in patients with PAD using the early BMS era as the reference were 0.84 for death in the BMS era (95% confidence interval [CI] 0.46 to 1.55, p = 0.58) and 1.35 in the DES era (95% CI 0.71 to 2.56, p = 0.36), 0.89 for MI in the BMS era (95% CI 0.48 to 1.66, p = 0.72) and 1.02 in the DES era (95% CI 0.55 to 1.87, p = 0.95), and 0.63 for repeat revascularization in the BMS era (95% CI 0.41 to 0.97, p = 0.04) and 0.46 in the DES era (95% CI 0.29 to 0.73, p = 0.001). In conclusion, despite significant improvements in medical therapy and a decrease in repeat revascularization over time, patients with PAD who undergo PCI have a persistent high rate of death and MI.
In unselected patients undergoing percutaneous coronary intervention (PCI), the adverse outcomes of death and myocardial infarction (MI) have improved over time. However, trends over time in outcomes specifically of patients with peripheral arterial disease (PAD), given advances in PCI including the use of drug-eluting stents (DESs) and more aggressive medical therapy, are not known. Thus, using the National Heart, Lung, and Blood Institute (NHLBI) Dynamic Registry, we compared in-hospital and 1-year outcomes of patients with PAD undergoing PCI across 3 different treatment eras: the early bare metal stent (BMS) era, the BMS era, and the DES era.
Methods
The specific methods and characteristics of the NHLBI Dynamic Registry have been reported previously. In brief, data were collected on approximately 2,000 consecutive patients undergoing PCI during 5 recruitment “waves” across 27 clinical centers (wave 1, July 1997 to February 1998; wave 2, February to June 1999; wave 3, October 2001 to March 2002; wave 4, February to May 2004; wave 5, February to August 2006). Only patients with PAD were evaluated and were grouped in 3 distinct treatment eras: the early BMS era (wave 1), the BMS era (waves 2 and 3), and the DES era (waves 4 and 5). Patients were contacted by telephone interview at 1 year by trained nurse co-ordinators to assess vital status, symptoms, coronary events, or cardiac-related hospitalizations. Informed consent was obtained from all patients and the study protocol was approved by institutional review boards at the respective clinical sites and at the University of Pittsburgh data co-ordinating center.
Symptomatic PAD was defined as a history or presence of claudication with rest or exertion, amputation for arterial vascular insufficiency, vascular reconstruction, bypass surgery or angioplasty to the extremities, or documented aortic aneurysm. Death was defined as all-cause mortality. In waves 1 and 2, MI was defined as evidence of ≥2 of the following: (1) typical chest pain >20 minutes in duration not relieved by nitroglycerin, (2) serial electrocardiographic recordings showing changes from baseline or serially in ST-T and/or Q waves in ≥2 contiguous leads, (3) serum enzyme increase of creatinine kinase-myocardial band >5% (total creatinine kinase >2 times normal level, lactate dehydrogenase subtype 1 higher than lactate dehydrogenase subtype 2, or troponin >0.2 μg/ml), or (4) new wall motion abnormalities. In waves 3 to 5, an MI had to satisfy ≥1 of the 2 following criteria: (1) evolutionary ST-segment elevation, development of new Q waves in ≥2 contiguous electrocardiographic leads, or new or presumably new left bundle branch pattern on electrocardiogram; (2) biochemical evidence of myocardial necrosis manifested as (a) creatinine kinase-myocardial band ≥3 times the upper limit of normal, (b) total creatinine kinase ≥3 times the upper limit of normal (if creatinine kinase-myocardial band not available), or (c) troponin level above the upper limit of normal. Elective coronary artery bypass grafting was classified as elective when surgery was deferred for >24 hours, urgent when required within 24 hours, and an emergency when required immediately. Angiographic success was classified as partial when some but not all attempted lesions were successfully treated or total when all attempted lesions were successfully treated. Procedural success was defined as partial or total angiographic success without death, Q-wave MI, or emergency coronary artery bypass grafting. A major adverse cardiac event was defined as death, MI, or repeat revascularization.
Patients were stratified by stent era and descriptive statistics were summarized as means for continuous variables and percentages for categorical variables. Temporal trends in baseline patient and lesion characteristics and outcomes at 1 year were assessed using the Cochran–Mantel–Haenszel test for dichotomous variables and the Jonckeheere–Terpstra test for continuous and nominal/ordinal variables. Cumulative event rates at 1 year were calculated by the Kaplan–Meier method and compared using log-rank statistic. Patients who did not develop the outcome of interest were censored at the last known date of contact or at 1 year if contact extended beyond 1 year.
Stepwise Cox regression was used to estimate 1-year risk ratios of clinical events in relation to stent era with the early BMS era as the reference. Covariates for multivariable models were identified from factors that differed significantly among stent eras and were associated with 1-year outcome using stepwise Cox proportional hazards regression models (p at entry = 0.30, p during stay = 0.10). The proportionality assumption was assessed for all Cox proportional hazards models graphically and statistically and assumptions were met for all models. All analyses were performed with SAS 9.2 (SAS Institute, Cary, North Carolina) and a 2-sided p value ≤0.05 was considered to indicate statistical significance.
Results
In total, 866 patients with PAD were evaluated with 180 in the early BMS era, 339 in the BMS era, and 347 in the DES era. In the more recent treatment eras, patients were less likely to have had a previous MI but were more likely to have renal disease and be diagnosed with hypertension or hyperlipidemia ( Table 1 ). Although rates of several other demographic features of high risk did not differ across the 3 waves, patients with PAD had high baseline rates of previous PCI, previous coronary artery bypass grafting, diabetes, and current tobacco use. Revascularization in patients with PAD was performed less commonly for unstable angina but more commonly for MI in later eras ( Table 2 ). Although lesion length was longer in more recent eras, there was a lower likelihood of thrombus in the treated lesion. Other characteristics of the lesion that would predict higher risk for PCI such as calcification, ulceration, or location at a bifurcation did not differ among eras. More than 40% of patients in all 3 eras had 3-vessel coronary artery disease present on coronary angiogram (early BMS era 42.8%, BMS era 45.4%, DES era 42.1%, p for trend = 0.68) and >10% of patients had involvement of the left main coronary artery (early BMS era 15.6%, BMS era 10.0%, DES era 15.0%, p for trend = 0.79).
| Variable | Early BMS Era (n = 180) | BMS Era (n = 339) | DES Era (n = 347) | p Value for Trend |
|---|---|---|---|---|
| Mean age (years) | 67.9 | 67.6 | 68.9 | 0.23 |
| Women | 42.8% | 37.8% | 34.3% | 0.06 |
| White race | 87.2% | 80.5% | 77.2% | 0.02 |
| Mean body mass index (kg/m 2 ) | 27.4 | 28.6 | 28.2 | 0.26 |
| Previous percutaneous coronary intervention | 40.0% | 40.1% | 46.5% | 0.18 |
| Previous coronary artery bypass graft | 32.2% | 33.6% | 34.5% | 0.87 |
| Previous myocardial infarction | 48.0% | 41.1% | 32.8% | <0.001 |
| Diabetes mellitus | 40.8% | 43.4% | 46.0% | 0.25 |
| Insulin treated diabetes mellitus | 17.2% | 21.2% | 17.6% | 0.85 |
| Hypertension ⁎ | 70.5% | 83.3% | 90.8% | <0.001 |
| Heart failure | 20.8% | 23.1% | 20.3% | 0.76 |
| Hypercholesterolemia † | 68.7% | 74.5% | 85.3% | <0.001 |
| Cerebrovascular disease | 18.9% | 18.3% | 21.3% | 0.41 |
| Pulmonary disease | 13.9% | 17.4% | 17.0% | 0.44 |
| Renal disease | 13.9% | 17.7% | 21.3% | 0.03 |
| Current smoker | 20.5% | 27.3% | 24.4% | 0.24 |
⁎ Blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic on 2 occasions or if the patient is currently on antihypertensive medications.
† Repeated values for serum cholesterol >240 mg/100 ml or if a physician has medically treated the participant for high cholesterol.
| Early BMS Era | BMS Era | DES Era | p Value for Trend | |
|---|---|---|---|---|
| Patient level | ||||
| Number of patients | 180 | 339 | 347 | |
| Revascularization reason | ||||
| Stable angina pectoris | 26.1% | 18.9% | 18.4% | 0.06 |
| Unstable angina pectoris | 52.2% | 46.6% | 38.9% | 0.002 |
| Acute myocardial infarction | 11.7% | 23.0% | 22.5% | 0.01 |
| Circumstances of procedure | 0.35 | |||
| Elective | 63.3% | 51.3% | 56.8% | |
| Urgent | 26.7% | 42.8% | 33.1% | |
| Emergency | 10.0% | 5.9% | 10.1% | |
| Mean left ventricular ejection fraction | 50.6% | 48.1% | 49.5% | 0.90 |
| Mean significant lesions | 3.8 | 3.9 | 3.8 | 0.81 |
| Any total occlusion | 49.4% | 50.1% | 51.9% | 0.57 |
| Mean number of lesions attempted | 1.5 | 1.5 | 1.4 | 0.004 |
| Lesion level | ||||
| Number of patients | 275 | 503 | 475 | |
| Mean reference vessel size (mm) | 3.1 | 3.0 | 3.1 | 0.11 |
| Mean lesion length (mm) | 12.8 | 13.3 | 17.2 | <0.001 |
| Mean diameter percent stenosis | 82.6% | 81.9% | 83.0% | 0.47 |
| Evidence of thrombus | 14.6% | 8.7% | 7.7% | 0.005 |
| Calcified | 39.0% | 23.0% | 37.6% | 0.57 |
| Ulcerated | 8.8% | 9.3% | 11.4% | 0.23 |
| Bifurcation | 10.7% | 11.1% | 10.3% | 0.82 |
| Ostial lesion | 13.8% | 9.0% | 10.8% | 0.35 |
| Lesion tortuosity | 0.07 | |||
| Moderate/severe | 22.8% | 31.5% | 30.2% | |
| Lesion previously treated | 18.4% | 13.1% | 9.1% | 0.0002 |
| Stent use | 67.2% | 82.0% | 92.8% | <0.001 |
| Total angiographic success | 88.3% | 91.7% | 93.6% | 0.11 |
| Drug-eluting stent use ⁎ | — | — | 76.9% | 1 |
| Procedural success | 91.7% | 94.1% | 94.5% | 0.24 |
In-hospital complications of death (early BMS era 3.3%, BMS era 2.7%, DES era 2.0%, p for trend = 0.35) and MI (early BMS era 5.0%, BMS era 3.2%, DES era 3.2%, p for trend = 0.34) did not differ by treatment era. Although in-hospital coronary artery bypass grafting rates were less frequent in later eras (early BMS era 3.9%, BMS era 0.9%, DES era 0.6%, p for trend = 0.005), there were no differences in major entry site complications (early BMS era 6.1%, BMS era 5.0%, DES era 6.6%, p for trend = 0.68). Procedural success rates were similar among the 3 groups (early BMS era 91.7%, BMS era 94.1%, DES era 94.5%, p for trend = 0.24).
Percentage of patients discharged on medications including aspirin, β blockers, angiotensin-converting enzyme inhibitors, thienopyridines, and statins significantly increased over time across the 3 treatment waves ( Figure 1 ). In addition, mean length of stay significantly decreased over time (early BMS era 3.3 days, BMS era 2.8 days, DES era 2.2 days, p for trend = 0.004).
