Published in UAB Insight, Summer 2007

Complementary treatment modalities optimize outcomes

Coronary artery disease (CAD) has been the number one killer of Americans for more than 80 years. Although CAD remains the leading cause of mortality in the United States, death rates declined 33% from 1994 to 2004 and have fallen more than 60% since 1950. Widely viewed as one of the most important medical achievements of the last century, this dramatic decrease is fueled by growing understanding of cardiovascular biology. New knowledge has led to widespread implementation of evidence-based risk factor modifications, development of effective pharmaceuticals and devices, and use of increasingly sophisticated surgical techniques.

The pace of therapeutic development for cardiovascular disease is rapid — a moving target according to many experts — and clinicians face the challenge of selecting the best option for each patient from a wide range of alternatives, some of which have little long-term data to guide decision making.

Drug-eluting stents (DES), for example, have been approved by the Food and Drug Administration (FDA) for only a few years, but have largely replaced older technologies such as balloon angioplasty and bare-metal stents and now are used in more than 80% of percutaneous coronary interventions (PCI). The FDA has approved two DES; the sirolimus-eluting Cypher stent in 2003 and the paclitaxel-releasing Taxus stent in 2004.

The enthusiastic adoption of stent technology has driven declines in coronary artery bypass surgery (CABG), which has fallen by about a third in the last decade to 365,000 procedures in 2006. In comparison, interventional cardiologists placed more than 1 million stents last year.

Recent investigations comparing mortality among patients receiving stents and those undergoing CABG, as well as new data revealing an unexpected and life-threatening complication of DES (a significant rate of late stent thrombosis) are sparking debate over selection of the most appropriate procedure for individual patients, off-label use of stents, and the optimal duration of dual antiplatelet therapy.

“There is incredible variability in the spectrum of ischemic heart disease,” says James K. Kirklin, MD, director of UAB’s Division of Cardiovascular and Thoracic Surgery. “Many effective drugs and interventions are available. Complementary, evidence-based use of all modalities provides patients with optimal care and offers them the best chance for long-term palliation of their disease.”

UAB interventional cardiologist Silvio E. Papapietro, MD, agrees, noting, “Some patients with chronic stable coronary artery disease can achieve symptom control with medications alone. If symptoms continue, and a coronary arteriogram and additional evaluation indicate the need for revascularization, we consult with our surgical colleagues to evaluate all clinical parameters, including medical history, the location and number of blockages, cardiac function, comorbidities, and patient preferences. Stent implantation and bypass surgery are not mutually exclusive procedures, and in many cases, optimal therapy requires combining treatment modalities.”

UAB clinical experience, which includes the successful treatment of many patients with complex heart disease that often is complicated by advanced age and severe comorbidities, encompasses the full spectrum of treatments for CAD. “There is incredible collegiality at UAB that allows experts to work together to find solutions to the varied problems of ischemic heart disease,” Kirklin says.

Durable Revascularization
CABG has grown in sophistication and safety in the 40 years since its introduction, and operative mortality in large medical centers such as UAB is typically ≤1%. In the last 2 decades the patient population undergoing bypass surgery has become older and more debilitated, Kirklin says. “Beginning in the late 1980s, surgeons began performing bypass surgery on an increasingly complex patient population, and for a time, operative mortality in these individuals rose as high as 4%. Surgeons have since introduced a number of techniques aimed at increasing the safety of bypass surgery,” he says. “The use of partial or full arterial grafting, enhanced protection of heart tissue, improved management of bleeding and inflammation, and advances in perioperative care have produced better outcomes and lower mortality for all patients.”

Randomized controlled trials comparing outcomes among patients undergoing CABG versus PCI with stenting have produced mixed results, with some showing equivalent survival, and others indicating a longevity benefit with CABG, particularly in patients with severe CAD with impaired left ventricular function and those with diabetes mellitus. Many trials randomized small numbers (≤5%) of potential participants, creating selection bias toward low-risk individuals with relatively uncomplicated CAD.

Registry data better reflect real-world clinical situations in patients with multivessel disease. Researchers at Duke University retrospectively analyzed outcomes of more than 18,000 patients with >75% stenosis in ≥1 coronary artery. Patients were treated with CABG, PCI, or medical therapy alone. Investigators found a statistically significant survival advantage for patients with stenosis in >2 arteries treated with CABG versus those treated with PCI, which included the use of bare-metal, but not drug-eluting, stents (Ann Thor Surg. 2006;86[82]:1420-1429).

An analysis of two New York state cardiac registries of almost 60,000 patients also found a survival advantage for CABG in patients with ≥2 diseased arteries: 3-year mortality was 15.6% for stenting (again, with bare-metal stents) and 10.7% for CABG. Patients who received stents had higher reintervention rates than those who had CABG (35% vs 5%). Investigators note the survival advantage seen with CABG was greatest in patients with three-vessel disease and involvement of the proximal left anterior descending artery or two-vessel disease without anterior descending involvement (N Engl J Med. 2005;352:2174-2183).

“Compared with stents, bypass surgery inherently provides more extensive, durable revascularization that produces superior outcomes in patients with diffuse disease. Surgery often is a better option for patients with poor ventricular function who are less able to tolerate reocclusion,” Kirklin says. “Patients with long lesions, chronic total occlusions, branched vessels, left main coronary disease, and other complex conditions also may benefit from bypass surgery in terms of survival and a lower rate of repeat procedures.”

Off-label Use, Antiplatelet Therapy
Few experts question the benefits of DES for patients with FDA-approved on-label indications, which include short de novo lesions. For these patients, DES produce excellent outcomes and low rates of target lesion revascularization at long-term follow-up (≥3-year), according to the FDA Circulatory Devices Advisory Panel. The panel convened in December 2006 to consider emerging, and often conflicting, DES safety data from meta-analyses of randomized controlled trials, registry reports, and other sources. Of particular concern was off-label use of DES (up to 75% of all DES are used in patients with complex CAD).

“Current data show drug-eluting stents reduce restenosis by two thirds compared with bare-metal stents, but are associated with a small increase in very late [>1 year] stent thrombosis,” Papapietro says. “Risks are higher for those who receive stents off-label compared with those who have stents placed for approved indications [0.5% vs 1.1% at 3 years]. The absolute risk of stent thrombosis is quite low, however, while the number of patients who benefit from drug-eluting stents in terms of reduced restenosis is high.”

The FDA panel concurred, concluding concerns about thrombosis do not outweigh benefits of DES and that when compared to bare-metal stents, DES are not associated with an increased rate of all-cause mortality (Update on the FDA Statement to coronary drug-eluting stents. www.fda.gov/cdrh/news/010407.html. Accessed July 27, 2007).

A number of factors contribute to the increased risk of late stent thrombosis with DES, including delayed re-endothelialization of stent struts, local inflammation, and certain patient and lesion characteristics, which remain undefined. “What is clear is that dual antiplatelet therapy [clopidogrel plus aspirin] attenuates the risk of stent thrombosis,” Papapietro says. The FDA panel recommended patients receiving DES who are at low risk for bleeding complications be maintained on antiplatelet therapy for at least a year, and Papapietro says for these individuals, he advises lifelong aspirin therapy and indefinite continuation of clopidogrel.

“Long-term antiplatelet therapy introduces significant issues, including patient compliance, the low but serious risk of bleeding complications, and high cost, which at $4 a pill for clopidogrel could translate into more than a billion dollars a year nationally,” he says. “Resistance to clopidogrel and aspirin is another concern. Hyporesponders and nonresponders are at increased risk for stent thrombosis, and no clinically available tests can determine responder status.”

Both the FDA panel and Papapietro point out results from a number of ongoing randomized controlled trials comparing DES and CABG and investigating the optimal duration of antiplatelet therapy and other issues will answer many outstanding questions, but “by then there will be new devices and new questions,” he says. “Industry will produce safer devices and more effective pharmaceuticals, and surgeons will continue to refine techniques for complex disease. All these tools are extremely effective. Our challenge as clinicians is to use them in the most complementary, beneficial manner for our individual patients.”

For more information
Dr. James Kirklin
Dr. Silvio Papapietro
1.800.UAB.MIST
mist@uabmc.edu