Vascular surgery is a constantly evolving specialty, and evidence-based care is a rapidly moving target. Treatment of vascular disease has changed dramatically over the 24 years since the North American Symptomatic Carotid Endarterectomy Trial (NASCET),1 the earliest clinical trial referenced in this chapter, was published. Although new medications, procedures, and strategies have greatly expanded the number of treatment options available to vascular surgeons and their patients, they also create challenges in generalizing prospective trial results and applying them to individual patients.
Several studies covered in this chapter compare medical versus procedure-based management strategies for vascular disease. When interpreting study results, it is important to remember that within clinical practice these treatments are typically utilized in an additive fashion; that is, procedure-based treatments are often performed in addition to (rather than instead of) aggressive medical therapy. It can be challenging, however, to determine how advances in medical therapy should impact procedural intervention criteria when trial-based head-to-head comparisons include outdated approaches. The NASCET1 and Asymptomatic Carotid Artery Stenosis (ACAS)2 trials exemplify this phenomenon. Although both of these studies were well designed and contributed important evidence to guide management of symptomatic and asymptomatic carotid stenosis, respectively, advances in medical therapy since their publication (including more standardized approaches to cardiovascular risk reduction, routine use of statin therapy, and availability of more aggressive antiplatelet regimens) have likely narrowed the gap in outcomes between medical and procedure-based treatment. Although many practitioners using contemporary medical therapy for carotid stenosis have transitioned to more conservative utilization of procedural intervention (particularly for asymptomatic disease) based on improved medical treatment outcomes, updated evidence is not available to precisely define objective management criteria. New randomized trials comparing contemporary medical therapy alone with and without procedural intervention for carotid stenosis are currently underway, and it is foreseeable that additional trials may be warranted in the future as medical and procedural treatments continue to advance. Similar challenges exist for healthcare providers trying to use results from randomized trials comparing medical versus procedural management to guide treatment of venous thromboembolism3,4 and symptomatic renal artery stenosis,5 particularly when medical options are unacceptable or have failed.
Prospective trials comparing different approaches to procedural intervention (often open surgical vs. endovascular) are another valuable source of clinical evidence. Randomized comparisons between open and endovascular treatment of carotid stenosis, abdominal aortic aneurysm (AAA), and peripheral arterial disease (PAD) are abundant in the vascular surgery literature, and we include examples of each in this chapter.6,7,8 None of the included studies was the first randomized comparison published between the treatments under consideration, but rather the most recent contribution to a larger group of randomized studies, many of which may have different inclusion criteria, endpoints, and conclusions. Those seeking to gain a more comprehensive understanding of the issues, controversies, and limitations related to these trials should refer to the previous randomized trials referenced in the discussion of each included study. Because device innovation and redesign proceed at a pace that exceeds high-quality evidence from randomized clinical trials, providers often have access to next-generation devices without direct evidence to guide how (or if) the new technology should affect treatment selection. The trials in this chapter exemplify the importance of using randomized studies to critically evaluate outcomes associated with new treatments, many of which demonstrate similar long-term outcomes between treatments that differ significantly in cost, invasiveness, and perioperative adverse events.
The articles and references included in this chapter should be considered as a means of accessing key evidence, controversies, and unanswered questions for readers in vascular surgery. Readers seeking a broader overview of evidence-based care should also refer to published consensus guidelines, which rely heavily on comparative effectiveness, observational, and case-control study designs in addition to randomized trials.9,10,11,12,13
Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
North American Symptomatic Carotid Endarterectomy Trial Collaborators
NEJM. 1991;325(7):445–453.Takeaway Point: Carotid endarterectomy (CEA), in conjunction with medical therapy, reduces the risk of significant ipsilateral fatal and nonfatal stroke in patients with symptomatic high-grade stenosis of 70–99%.
Commentary: Carotid endarterectomy has been used in the treatment of carotid artery stenosis since the 1950s. Prior to NASCET and its European counterpart, the European Carotid Surgery Trial (ECST),14 evaluation of CEA in comparison with best medical management had not been undertaken in patients with symptomatic carotid artery stenosis. NASCET demonstrated the clear benefit of CEA compared to medical management for patients with symptomatic carotid artery stenosis of 70–99%. The absolute 2-year reduction in ipsilateral fatal and nonfatal stroke was 17%. The exclusion criteria in NASCET were relatively robust and excluded all patients over the age of 80 as well as those with any cardiac rhythm disorder. It is also important to recall that the best medical management of the NASCET era included aspirin at doses of 1300 mg. Studies are presently underway to evaluate the effectiveness of CEA against more modern medical management.
Introduction: The role of carotid endarterectomy (CEA) in the treatment of patients with symptomatic carotid artery stenosis has long been questioned, due to initial negative trials and high complication rates. Improved medical therapy, in particular antiplatelet drugs, raised further questions regarding the appropriate role of CEA.
Objectives: To determine whether carotid endarterectomy reduces the risk of stroke among patients with a recent adverse cerebrovascular event and ipsilateral stenosis.
Trial Design: Multicenter randomized controlled trial.
Inclusion Criteria: Patients <80 years old with a previous transient ischemic attack, monocular blindness, or nondisabling stroke within the preceding 120 days and an associated stenosis of 70–99% of the ipsilateral internal carotid artery by arteriography. Participating medical centers had to have a rate of <6% for stroke and death occurring within 30 days of operation for at least 50 consecutive CEAs performed in the preceding 24 months.
Exclusion Criteria: No angiographic information; intracranial lesions more severe than extracranial lesion; kidney, liver, or lung failure; cancer likely to cause death in the next 5 years; disabling cerebral infarction on either side; symptoms attributed to nonatherosclerotic disease; cardiac valvular or rhythm disorders that could produce cardiogenic symptoms; prior ipsilateral CEA.
Intervention: Patients were given antiplatelet treatment with 1300 mg aspirin and appropriate medical management of their comorbidities. Patients randomized to the surgery arm received CEA in addition to medical management. Patients were assessed at 30 days, every 3 months for the first year, and every 4 months until death or stroke.
Primary Endpoint: Fatal or nonfatal stroke ipsilateral to the carotid lesion.
Secondary Endpoints: Any stroke, any stroke or death, major or fatal ipsilateral stroke, any major or fatal stroke, any major stroke or death.
Sample Size: 662 patients were enrolled between January 1, 1988 and February 21, 1991 at 50 medical centers in the United States and Canada. 331 were randomized to the medical arm and 328 to the surgical arm.
Statistical Analysis: Mantel–Haenszel χ2 test and Kaplan–Meier survival curves. All p values were reported as two-tailed.
Baseline Data: Three patients in the analysis group were excluded because they did not meet entry criteria. There were no significant differences between the medical and surgical arm.
Outcomes: Twenty-one medical patients (6.3%) underwent CEA and one surgical patient refused CEA. In the 30 days after randomization, there was a 5.8% rate of perioperative total stroke and death in the surgical group and a 2.1% rate of severe stroke and/or death. In the medical group, the overall stroke rate was 0.9% at 32 days from randomization. The 24-month risk of any fatal or nonfatal ipsilateral stroke in the surgical group was 9% versus 26% in the medical group, resulting in an absolute risk reduction of 17% (p < 0.001) and a relative risk reduction of 65%. The overall number needed to treat to prevent an ipsilateral stroke was six. Among patients who did not die or have a major stroke in the first 30 days, the risk of any major or fatal stroke within 24 months was 12.2% in the medical group and 1.2% in the surgical group for an absolute risk reduction of 10.6% (p < 0.001).
Conclusion: CEA in addition to medical therapy reduces the risk of ipsilateral fatal and nonfatal stroke in patients with symptomatic high-grade stenosis of 70–99%.
Limitations: Excluded significant number of patients based on comorbidities. This study allowed enrollment only from centers with both high volume and low stroke rates, potentially decreasing reproducibility of these results at centers with less volume or expertise.
Endarterectomy for asymptomatic carotid artery stenosis.
Executive Committee for the Asymptomatic Carotid Atherosclerosis Study
JAMA. 1995;273(18):1421–1428.Takeaway Point: Carotid endarterectomy (CEA) reduces the 5-year risk of stroke compared to medical management alone in patients with asymptomatic carotid artery stenosis of >60%.
Commentary: The ACAS trial addresses the need for surgical intervention in asymptomatic carotid artery disease. The study was designed to evaluate the 5-year stroke risk reduction of surgical intervention compared to medical management alone. Medical management in this study was the addition of aspirin as well as best treatment guidelines for all medical conditions. Advances in best medical management have occurred in the decade since ACAS was published. Presently, research is being undertaken to better understand how current medical therapy regimens compare to CEA in asymptomatic patients. The study was halted after a median of 2.7 years of follow-up as the surgical arm reached a relative risk reduction of 53% (p 0.004) as compared to the medical arm. The authors noted that women had a higher perioperative complication rate of stroke and death as compared to men and their 5-year relative risk reduction was only 17%. At present, initial screening is recommended by the Society of Vascular Surgery in patients who are older than 55 and who have cardiovascular risk factors. The consensus is that asymptomatic patients should have a yearly ultrasound to follow the progression of disease.
Introduction: Progression from asymptomatic to symptomatic carotid artery disease is variable, with the concern that patients may present with a devastating neurologic event. Prior studies have not addressed surgical treatment of asymptomatic disease.
Objectives: To determine whether the addition of carotid endarterectomy to aggressive medical management can reduce the incidence of cerebral infarction in patients with asymptomatic carotid artery stenosis.
Trial Design: Prospective randomized multicenter trial.
Inclusion Criteria: Age 40–79 years with hemodynamically significant carotid stenosis documented by one of three criteria: (1) arteriography within the previous 60 days indicating stenosis with at least 60% reduction in diameter, (2) ultrasound evaluation with a frequency or velocity greater than the instrument specific cutoff point with 95% positive predictive value (PPV), or (3) ultrasound examination showing a frequency or velocity greater than the instrument specific 90% PPV cutpoff point confirmed by ocular pneumoplethysmography.
Exclusion Criteria: Previous cerebrovascular events in the distribution of the relevant carotid artery, contraindications to aspirin therapy, “a disorder that could seriously complicate surgery,” a condition that could lead to disability or death within 5 years.
Intervention: The patients in the medical therapy study arm were given 325 mg aspirin daily. The surgical arm included aspirin, a preoperative arteriogram, and a carotid endarterectomy (CEA).
Primary Endpoints: Stroke or transient ischemic attack (TIA) occurring in the distribution of the study artery at any time point. All strokes or deaths occurring within 30 days after randomization in the surgical group and 42 days after randomization in the medical group.
Secondary Endpoints: Ipsilateral TIA, or perioperative TIA, stroke, or death.
Sample Size: 1662 patients at 39 centers between 1987 and 1993. Three patients were lost to follow up and excluded from analysis. 825 patients were in the surgical and 834 in the medical therapy arms. 101 patients in the surgical arm received medical therapy alone and 45 in the medical arm underwent CEA. In the surgical arm 414 patients underwent arteriography prior to CEA.
Statistical Analysis: Intention-to-treat analysis. Two-sided test of the null hypothesis, χ2 test, Kaplan–Meier estimates.
Baseline Data: Baseline characteristics were similar between medical and surgical treatment groups, although a history of prior stroke or TIA was more prevalent in the medical treatment group.
Outcomes: During the perioperative period 19 patients (2.3%) in the surgical group and 3 patients (0.4%) in the medical group had a stroke or died. Only 414 patients in the surgical arm underwent arteriography prior to CEA. In this group there was a complication rate of 1.2%. The authors estimated that if all CEA patients in the study had undergone arteriography, there would be a combined perioperative stroke or death rate of 2.7%. The estimated 5-year risk of ipsilateral stroke and any perioperative stroke was 11% in the medical group and 5.1% in the surgical group (p 0.004). The relative risk reduction was 53%.
Conclusion: Carotid endarterectomy (CEA) confers a 53% 5-year relative stroke risk reduction as compared to full-strength aspirin therapy alone in treatment of asymptomatic carotid artery stenosis greater than 60%.
Limitations: Although arteriography was mandated by study protocol for all CEA patients, only 414 patients underwent this. In patients who received arteriography, 33 were excluded as the degree of stenosis was found to be <60%. Women were underrepresented in this study. They also had a higher perioperative stroke or death rate. The relative 5-year risk reduction for women was only 17%. There was also a high crossover rate of 9% with the majority in the CEA group.
A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep vein thrombosis.
Decousus H, Leizorovicz A, Parent F, Page Y, Tardy B, Girard P, Laporte S, Faivre R, Charbonnier B, Barral FG, Huet Y, Simonneau G
NEJM. 1998;338(7):409–415.Takeaway Point: Placement of inferior vena cava filters reduces short-term rates of symptomatic and asymptomatic pulmonary embolism but has no effect on long-term prevention of pulmonary embolism, and is associated with an increased risk of recurrent deep-vein thrombosis.
Commentary: Patients who develop proximal deep-vein thrombosis (DVT) are at risk of subsequent pulmonary embolism (PE) due to proximal clot migration. With the development of easily used percutaneous caval filters, over 30,000 filters were being placed annually in the United States in the early 1990s.15 Prior to this study there was little evidence to support or refute this practice. This study examined the effectiveness of inferior vena cava (IVC) filters in patients who were receiving therapeutic anticoagulation. At the time of the PREPIC study, the third edition of the American College of Chest Physicians consensus statement regarding the treatment of venous thromboembolic disease recommended caval filters for patients who had DVTs or PEs who had contraindications to therapeutic anticoagulation or failure of anticoagulation therapy.16 The 2 × 2 factorial design in this study allowed the authors to examine both the benefit and risk of prophylactic IVC filter placement, as well as the effect of low-molecular-weight heparin versus unfractionated heparin on the study’s primary and secondary outcomes.
Introduction: Patients who develop proximal deep-vein thrombosis are at risk for subsequent pulmonary embolism. The use of caval filters as a risk reduction strategy in this population had previously not been well examined.
Objectives: To evaluate the benefits and risks of prophylactic filter placement in addition to anticoagulant therapy in patients with proximal deep-vein thrombosis (DVT) who were considered at high risk for pulmonary embolism (PE).
Trial Design: A 2 × 2 factorial designed multicenter randomized trial.
Inclusion Criteria: Patients >18 years of age with acute proximal DVT confirmed by venography, with or without synchronous symptomatic PE, or at high risk for a PE (high risk was defined by the treating provider).
Exclusion Criteria: Previous filter placement, contraindication/failure of anticoagulation, therapeutic anticoagulant for >48 hours, indications for thrombolysis, short life expectancy, iodine allergy, hereditary thrombophilia, severe renal or hepatic disease, or pregnancy.
Intervention: Patients were randomized to either IVC filter or no filter, and to low- molecular-weight heparin or unfractionated heparin. All patients underwent ventilation–perfusion scanning within 48 hours of enrollment to determine presence of existing PE. If ventilation–perfusion scanning was abnormal, they underwent pulmonary arteriography to confirm PE. All patients underwent either pulmonary angiography or ventilation–perfusion scan between 8 and 12 days after randomization to detect asymptomatic PE.
Primary Endpoint: Occurrence of PE within the first 12 days after randomization.
Secondary Endpoints: Recurrent DVT, death, major filter complications, and major bleeding.
Sample Size: 400 patients were recruited between September 1991 and February 1995 at 44 French medical centers. 200 patients were randomly assigned filters and 200 were in the no-filter group. 195 patients were assigned to receive low-molecular-weight heparin and 205 to receive unfractionated heparin.
Statistical Analysis: Intention-to-treat analysis. χ2 test, Fisher’s exact test, and Student’s t-test. Kaplan–Meier analysis was performed to examine the cumulative rate of events. Statistical significance was assessed with the Mantel–Haenszel method.
Baseline Data: Baseline characteristics across treatment groups were equivalent. 28 patients did not have screening tests performed for asymptomatic PE.
Outcomes: Within the first 12 days from randomization there were more PEs in the no-filter group compared to the filter group (4.8% vs. 1.1%, p 0.03) but there was no difference in symptomatic PEs at the end of 2 years. Patients assigned to filter had more recurrent DVTs than those in the no-filter group (20.8% vs. 11.6% OR 1.87; 95% CI 1.1–3.2; p 0.02). There was no difference in thromboembolism, mortality, or major bleeding between the low-molecular-weight heparin compared with unfractionated heparin.
Conclusion: In addition to heparin therapy, the use of a permanent caval filter reduces the short-term occurrence of symptomatic or asymptomatic PEs without an observed effect on immediate or long-term mortality. Filters were also associated with an increase in recurrent DVTs.
Limitations: The anticoagulation protocol did not extend beyond 3 months, potentially introducing bias related to long-term DVT rates. Ventilation–perfusion scanning was used to diagnose PE; the sensitivity and specificity of this test are affected by a variety of factors that may have resulted in incorrect classification (including missed events for patients with small PE). CTA is presently considered the gold standard for PE diagnosis in clinical practice.
Immediate repair compared with surveillance of small abdominal aortic aneurysms.
Lederle FA, Wilson SE, Johnson GR, Reinke DB, Littooy FN, Acher CW, Ballard DJ, Messina LM, Gordon IL, Chute EP, Krupski WC, Busuttil SJ, Barone GW, Sparks S, Graham LM, Rapp JH, Makaroun MS, Moneta GL, Cambria RA, Makhoul RG, Eton D, Ansel HJ, Freischlag JA, Bandyk D, Aneurysm Detection and Management Veterans Affairs Cooperative Study Group
NEJM. 2002;346(19):1437–1444.Takeaway Point: Early intervention in abdominal aortic aneurysms (AAAs) of 4.0–5.4 cm conveys no survival advantage compared to surveillance alone.
Commentary: Prior to this trial the elective surgical repair of abdominal aortic aneurysms remained controversial. Elective repair had been recommended for patients who had aneurysms of ≥4.0 cm in diameter who did not have medical contraindications.17 The authors randomized patients at all national Veterans Affairs Medical Centers who were between 50 and 79 years of age who had AAA of 4.0–5.4cm in size to either immediate repair or surveillance. They found no survival advantage to immediate repair of AAAs. The patient population was predominately male (>98%), and this study has been criticized about the extrapolation of its results to women.
Introduction: The size for surgical intervention in the treatment of abdominal aortic aneurysms (AAAs) has been controversial. Prior studies had not evaluated the survival effect of early intervention.
Objectives: To determine whether early surgical intervention or observation results in higher rates of survival for patients with small abdominal aortic aneurysms (AAAs).
Trial Design: Prospective randomized multicenter clinical trial.
Inclusion Criteria: Age 50–79 years with an abdominal aortic aneurysm measuring 4.0–5.4 cm in diameter by CT within 12 weeks of randomization.
Exclusion Criteria: Prior aortic surgery; evidence of rupture of the aneurysm; expansion of the aneurysm of ≥1.0 cm in the last year or ≥0.7 cm in the last 6 months; suprarenal or juxtarenal aortic aneurysm; thoracic aortic aneurysm; severe heart, lung, or liver disease; a serum creatinine ≥2.5; a history of major surgical procedure or angioplasty in the past 3 months; expected survival of <5 years; severe debilitation.
Intervention: In the immediate repair group patients underwent standard open surgical repair with interposition of a synthetic graft within 6 weeks of randomization. In the surveillance group patients were followed without repair until the aneurysm reached at least 5.5 cm in diameter or enlarged by ≥1.0 cm in a year or ≥0.7 cm in 6 months. They underwent ultrasound evaluation or CT every 6 months.
Primary Endpoint: Rate of death from any cause.
Secondary Endpoints: Rate of death related to abdominal aortic aneurysm defined as death caused directly or indirectly by rupture or repair.
Sample Size: Between 1992 and 2000, 5038 patients with aneurysm were considered for randomization. Of these 1136 met criteria and were included in this study. 569 patients were assigned to the immediate repair group and 567 to surveillance.
Statistical Analysis: Intention to treat analysis. Cumulative survival curves were generated by the product limit method with log-rank test. Cox proportional-hazards model, χ2 tests, Student’s t-tests.
Baseline Data: The two groups did not differ significantly at baseline with the exception of a slightly higher creatinine in the immediate repair group (1.2 ± 0.3 vs. 1.0 ± 0.3, p 0.02). Greater than 98% of the population was male.
Outcomes: Mean duration of follow-up was 4.9 years. In the immediate repair group 92.6% underwent aneurysm repair, and 72.1% of these repairs were performed within the proscribed 6 weeks after randomization. In the surveillance group 61.6% underwent surgical repair by the end of the study; 9% of patients in the surveillance group who underwent repair did not meet study criteria for repair. There was no significant difference between the two groups in the primary outcome of the rate of death from any cause (relative risk 1.21 for repair vs. surveillance; 95% CI 0.95–1.54). The rate of death due to AAA was not reduced by immediate repair. Operative mortality associated with repair was 2% at 30 days.
Conclusion: Immediate repair of AAA of 4.0–5.4 cm in male patients provides no survival advantage over surveillance.
Limitations: This study did not have equal gender distribution and is limited as to what can be concluded for female patients. Over half of the patients in the surveillance group underwent operative intervention prior to the conclusion of the study with 9% not meeting criteria for open intervention as defined by the study.
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