Management of coronary artery disease (CAD) has evolved over the past decade, but there are few prospective studies evaluating long-term outcomes in a real-world setting of evolving technical approaches and secondary prevention. The aim of this study was to determine how the mortality and morbidity of CAD has changed in patients who have undergone percutaneous coronary intervention (PCI), in the setting of co-morbidities and evolving management. The National Heart, Lung, and Blood Institute Dynamic Registry was a cohort study of patients undergoing PCI at various time points. Cohorts were enrolled in 1999 (cohort 2, n = 2,105), 2004 (cohort 4, n = 2,112), and 2006 (cohort 5, n = 2,176), and each was followed out to 5 years. Primary outcomes were death, myocardial infarction (MI), coronary artery bypass grafting, repeat PCI, and repeat revascularization. Secondary outcomes were PCI for new obstructive lesions at 5 years, 5-year rates of death and MI stratified by the severity of coronary artery and co-morbid disease. Over time, patients were more likely to have multiple co-morbidities and more severe CAD. Despite greater disease severity, there was no significant difference in death (16.5% vs 17.6%, adjusted hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.74 to 1.08), MI (11.0% vs 10.6%, adjusted HR 0.87, 95% CI 0.70 to 1.08), or repeat PCI (20.4% vs 22.2%, adjusted HR 0.98, 95% CI 0.85 to 1.17) at 5-year follow-up, but there was a significant decrease in coronary artery bypass grafting (9.1% vs 4.3%, adjusted HR 0.44, 95% CI 0.32 to 0.59). Patients with 5 co-morbidities had a 40% to 60% death rate at 5 years. There was a modestly high rate of repeat PCI for new lesions, indicating a potential failure of secondary prevention for this population in the face of increasing co-morbidity. Overall 5-year rates of death, MI, repeat PCI, and repeat PCI for new lesions did not change significantly in the context of increased co-morbidities and complex disease.
Over the past 2 decades, there has been improved care of the cardiac patients through modification of cardiac risk factors, pharmacology, application of novel interventional approaches, and education. The mortality rate of coronary artery disease (CAD) and the incidence of ST elevation myocardial infarction have decreased. However, there are data from survey-based studies indicating poor penetrance of best practice guidelines into clinical medicine. In this study, we sought to determine how long-term (5-year) mortality and morbidity from CAD in patients treated with percutaneous coronary intervention (PCI) changed over time, in the setting of evolving technology and medical management for patients. The National Heart, Lung, and Blood Institute Dynamic Registry is unique in its long-term follow-up of unselected patients who underwent PCI, thereby allowing for evaluation of the impact of secondary prevention in patients with treated obstructive CAD. In the Dynamic Registry, consecutive patients undergoing PCI were enrolled at various intervals, reflecting periods of technological advancement plus changes in interventional and pharmacologic therapies.
Methods
The Dynamic Registry was a prospective multicenter study of patients undergoing PCI from 27 academic hospitals in the United States, Canada, and the Czech Republic. In this study, we analyzed results of 3 cohorts each followed out to 5 years (cohort 2: enrolled in 1999, n = 2,105 patients; cohort 4: enrolled in 2004, n = 2,112 patients; and cohort 5: enrolled in 2006, n = 2,176 patients). Each cohort was enriched with women and minorities, with race self-reported.
Demographic, angiographic, and procedural data were collected at baseline. Vital status and cardiac-related events after discharge were collected annually through direct contact by trained study coordinators. Self-reported events were confirmed by reviewing hospital records. Patients provided written informed consent, and the institutional review board of each participating site approved the data collection. Five-year follow-up rates were 70% for cohort 2, 85% for cohort 4, and 88% for cohort 5.
For cohorts 2 and 4, the Registry collected the Coronary Artery Surgery Study (CASS) segment number for repeat PCIs for all 5 years. After the first year of follow-up in cohort 5, the Registry stopped collecting segment numbers and instead asked for the treated vessels. PCI for new lesions was strictly defined as new obstructive stenoses requiring PCI, outside of the CASS segment stented at the time of enrollment in the Dynamic Registry or outside of the originally stented coronary artery/graft. This strict definition of additional lesions requiring PCI was applied to avoid any confounding by PCI for in-stent restenosis.
Primary outcomes of the study were deaths from any cause, myocardial infarction (MI), coronary artery bypass grafting (CABG), and any nonstaged repeat PCI. Mortality data were gathered from the study coordinators at each site, who performed a search of the National Death Index for patients who could not be located. MI was defined by evidence of at least 1 of the 2 following criteria: (1) evolutionary ST-segment elevation, development of new Q waves in ≥2 contiguous leads on an electrocardiogram, and new or presumably new left bundle branch block pattern and (2) biochemical evidence of myocardial necrosis manifested as (a) creatine kinase-MB ≥3× the upper limit of normal, (b) total creatine kinase level ≥3× the upper limit of normal, or (c) troponin level above the upper limit of normal. Repeat PCI was defined as any repeat PCI in the follow-up period, for either in-stent restenosis or additional obstructive lesions. Repeat revascularization was defined as repeat PCI and/or CABG during the follow-up period.
Secondary outcomes included the number of co-morbidities, angiographic severity of CAD, and presence of new stenoses requiring PCI in segments and/or vessels not stented at the time of enrollment PCI. The number of co-morbidities was defined as one or any combination of the following: type 2 diabetes, hypertension, hypercholesterolemia, renal insufficiency (a history or the presence of renal failure diagnosed and treated with medication, low protein diet, or dialysis), or peripheral arterial disease (history of claudication, rest pain, amputation, vascular reconstruction, bypass surgery or angioplasty to the extremities, or aortic aneurysm). Severe CAD was defined as one or any combination of the following: type C lesion, calcified lesion, total occlusion, left main stenosis ≥50%, or triple-vessel disease.
Temporal trends in patient, procedural, and lesion characteristics were assessed across the cohorts using the Cochran-Armitage test for dichotomous variables and the Jonckheere-Terpsta test for continuous and nominal/ordinal variables. Clinical event rates at 5 years for death, combined death and MI, repeat PCI, CABG, and repeat revascularization with PCI or CABG were calculated by the Kaplan-Meier approach and compared using the log-rank test for trend. Patients who did not experience the outcome of interest were censored at the last known date of contact or at 5 years, if contact extended slightly beyond their anniversary date. Cox proportional hazards regression methods were used to estimate 5-year hazard ratios of clinical events in relation to study cohort, with the time to event beginning at the time of procedure. Demographic and clinical variables were initially screened for univariate association, with clinical outcomes of interest at p ≤0.20. Individual variables identified were then assessed in a forward stepwise manner using a p value criterion of ≤0.05. In instances when the variables for recruitment cohort did not “step” into a model, they were included in the model after entry of all other significant variables. The covariates are listed in Appendix . The proportionality assumption was assessed for all Cox proportional hazards models graphically and statistically, and the hazard ratio represents the average risk during the 5 years after the index procedure. All analyses were performed with SAS, version 9.2 (SAS Institute Inc., Cary, North Carolina), and Stata, version 7.0 (StataCorp LP, College Station, Texas).
Results
Patients enrolled in the 3 cohorts were of a similar age (mean 63 to 64 years), and by design, approximately 1/3 women, and at least 20% nonwhite ( Table 1 ). Cohorts 4 and 5 presented with a greater prevalence of co-morbid conditions than their cohort 2 counterpart with greater body mass indexes, worsening renal insufficiency, higher rates of type 2 diabetes mellitus, hypertension, hypercholesterolemia, and a high prevalence of current and former smoking ( Table 1 ). The number of patients presenting for PCI with multiple co-morbidities increased over time, whereas the percentage presenting with zero or a single co-morbidity decreased ( Figure 1 ). Patients in cohort 5 were more than twice as likely as those in cohort 2 to rely on public assistance for their insurance coverage ( Table 1 ).
| Characteristics Years of Follow-Up Number at Follow-Up/Enrolled | Cohort 2 1999–2004 (n = 1,666/2,105), % | Cohort 4 2004–2009 (n = 1,965/2,112), % | Cohort 5 2006–2011 (n = 2,077/2,176), % | p Value (Test for Trend) |
|---|---|---|---|---|
| Mean age (yrs) | 63.2 | 63.7 | 64.0 | 0.05 |
| Age >65 yrs | 45.8 | 46.4 | 46.8 | 0.58 |
| Women | 36.9 | 32.8 | 32.8 | 0.01 |
| Nonwhite | 20.6 | 22.9 | 24.7 | 0.003 |
| Mean body mass index (kg/m 2 ) | 28.8 | 29.2 | 29.6 | <0.001 |
| Previous percutaneous procedure | 25.3 | 29.7 | 34.3 | <0.001 |
| Reason for revascularization | ||||
| Unstable angina pectoris | 44.9 | 34.7 | 32.6 | <0.001 |
| Acute MI | 27.6 | 28.4 | 29.4 | 0.22 |
| Previous CABG | 16.2 | 19.3 | 17.6 | 0.16 |
| Previous MI | 30.6 | 25.0 | 22.4 | <0.001 |
| Renal disease | 4.6 | 8.6 | 9.0 | <0.001 |
| Hypertension | 63.6 | 77.2 | 77.6 | <0.001 |
| Hypercholesterolemia | 62.5 | 75.0 | 78.6 | <0.001 |
| Diabetes mellitus | 27.0 | 33.5 | 34.0 | <0.001 |
| Current treatment for diabetes | ||||
| Diet | 15.0 | 13.3 | 12.6 | |
| Oral medication | 50.0 | 54.6 | 54.9 | 0.95 |
| Insulin | 35.0 | 32.2 | 32.5 | |
| Congestive heart failure | 9.1 | 8.9 | 10.2 | 0.25 |
| Ejection fraction, mean, median | 53.1, 55 | 51.7, 55 | 52.6, 55 | 0.38 |
| Smoker | ||||
| Never | 32.3 | 37.4 | 35.8 | |
| Current | 27.4 | 22.6 | 25.5 | 0.10 |
| Former | 40.3 | 40.0 | 38.7 | |
| Discharge medication | ||||
| Aspirin | 93.9 | 96.6 | 98.2 | <0.001 |
| β Blocker | 69.9 | 80.8 | 82.3 | <0.001 |
| Cholesterol-modifying agent | 61.2 | 86.9 | 88.2 | <0.001 |
| Angiotensin-converting enzyme inhibitor | 36.5 | 55.2 | 50.9 | <0.001 |
| Thienopyridine | 92.1 | 97.9 | 98.3 | <0.001 |
| Method of payment | ||||
| Medicare | 44.2 | 34.4 | 38.2 | |
| Public | 7.8 | 15.5 | 17.9 | 0.62 |
| Private | 42.7 | 45.9 | 41.0 | |
| Self | 5.4 | 4.2 | 2 | |
| CAD location | ||||
| Left anterior descending, left circumflex, and left main | 2.2 | 4.2 | 4.8 | <0.001 |
| Triple-vessel disease | 24.1 | 30.6 | 28.6 | 0.05 |
| Left main with a stenosis ≥50% | 3.6 | 6.0 | 6.9 | <0.001 |
| Any total occlusion | 34.2 | 38.4 | 37.5 | 0.05 |
| Mean number significant lesions | 2.8 | 3.1 | 3.1 | <0.001 |
| Drug-eluting stent implanted | 0 | 74.3 | 90.0 | <0.001 |
| Technically amenable to complete revascularization with CABG | 86.5 | 77.0 | 72.7 | <0.001 |
| Technically amenable to complete revascularization with PCI | 82.3 | 87.4 | 90.8 | <0.001 |
| Procedural success | 98.0 | 98.5 | 99.1 | 0.004 |
| Attempted lesions | (n = 2,417) | (n = 2,627) | (n = 2,863) | p Value |
| Calcified | 24.4 | 25.2 | 32.0 | <0.001 |
| ACC/AHA classification | ||||
| A | 12.9 | 10.8 | 11.7 | |
| B1 | 32.2 | 36.3 | 29.8 | <0.001 |
| B2 | 38.3 | 32.8 | 29.5 | |
| C | 16.5 | 20.2 | 28.9 | |
| Drug type | ||||
| Paclitaxel | 0 | 23.9 | 31.9 | <0.001 |
| Limus drugs (everolimus, zotarolimus, and sirolimus) | 0 | 45.4 | 54.6 | <0.001 |
| PCI success | 96.4 | 97.9 | 98.5 | <0.001 |
Over time, there was an increase in lesion complexity, with treated lesions in cohorts 4 and 5 more likely to be calcified, totally occluded, located in the left main artery with at least a 50% stenosis, and classified as type C ( Table 1 ). Approximately 2/3 of each cohort had 1- and 2-vessel diseases. Triple-vessel disease, however, was more common in cohorts 4 and 5 compared with cohort 2. The indication for PCI was acute coronary syndrome in approximately 2/3 of each cohort ( Table 1 ). There was a significant increase in the percentage of patients having ≥1 of the aforementioned angiographic characteristics ( Figure 1 ).
Despite increasing patient and lesion complexity, the 5-year death rate was unchanged from 2004 to 2011, even when adjusted for age, body mass index, race/ethnicity, co-morbid conditions, reason and acuity for initial revascularization including cardiogenic shock, and lesion characteristics ( Table 2 ). The incidence of death, MI, and repeat PCI was similar at 5 years across the 3 recruitment cohorts ( Table 2 and Figure 2 ). For cohort 2, a large proportion of repeat PCIs were performed in the vessel stented at the time of enrollment and likely due to in-stent restenosis ( Figure 2 ). For cohorts 4 and 5, more repeat PCIs were performed for stenoses outside of the index vessel, likely due to disease progression ( Figure 3 ). The incidence of CABG decreased significantly over time ( Table 2 and Figure 2 ), and the overall need for repeat revascularization decreased with time, driven by the decrease in CABG. Both emergency and planned bypass grafting decreased over time as operators reported a higher rate of successful percutaneous revascularization ( Table 1 ).
